Alternative titles; symbols
HGNC Approved Gene Symbol: KIT
SNOMEDCT: 397012002, 6479008, 703827008, 718122005; ICD10CM: D47.01, E70.39;
Cytogenetic location: 4q12 Genomic coordinates (GRCh38): 4:54,657,957-54,740,715 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q12 | Gastrointestinal stromal tumor, familial | 606764 | Autosomal dominant; Isolated cases | 3 |
| Germ cell tumors, somatic | 273300 | 3 | ||
| Leukemia, acute myeloid, somatic | 601626 | 3 | ||
| Mastocytosis, cutaneous | 154800 | Autosomal dominant | 3 | |
| Mastocytosis, systemic, somatic | 154800 | 3 | ||
| Piebaldism | 172800 | Autosomal dominant | 3 |
The tyrosine kinase receptor KIT and its ligand, KITLG (184745), function in hematopoiesis, melanogenesis, and gametogenesis (Rothschild et al., 2003).
Kasamatsu et al. (2008) stated that KIT is expressed as a 145-kD glycosylated transmembrane protein with an extracellular domain, a transmembrane region, and a tyrosine kinase domain. The extracellular domain consists of 5 Ig-like domains. A soluble form of KIT (sKIT) is released from membrane-bound KIT (mKIT) upon stimulation. sKIT is a glycoprotein of about 100 kD.
Vandenbark et al. (1992) demonstrated that the KIT gene spans more than 70 kb of DNA and includes 21 exons. The longest transcript is 5,230 bp and is alternatively spliced. The overall gene structure of KIT closely resembles that of the CSF1R gene.
The provirus of the Hardy-Zuckerman 4 feline sarcoma virus was molecularly cloned. A segment from the middle of the provirus, showing homology to mammalian genomic DNA, was termed v-Kit. Its human homolog was assigned to chromosome 4 by Barker et al. (1985) using human-mouse somatic cell hybrids. By in situ hybridization, Mattei et al. (1987) mapped the KIT gene to chromosome 4q11-q12, with the largest number of grains being in the q12 band; see d'Auriol et al. (1988). By the same method, Yarden et al. (1987) assigned the KIT gene to chromosome 4cen-q21. Brannan et al. (1991) detected a HaeIII polymorphism in the KIT gene that was linked to other 4q markers. Using pulsed field gel electrophoresis, Vandenbark et al. (1992) demonstrated that the KIT gene and the PDGFRA gene (173490), which maps to chromosome 4q12, reside on the same 700 kb BssHI fragment.
Yarden et al. (1987) demonstrated that the Kit gene is on chromosome 5 in the mouse.
Packer et al. (1995) found that depletion of Kit in mouse testis via neutralizing antibody resulted in greatly increased apoptosis in differentiating type A spermatogonia, as well as in spermatocytes around the time of meiotic division.
Alternative splicing of mouse Kit ligand (Kl) produces 2 variants, Kl1 and Kl2, both of which encode membrane-bound proteins that can be processed to generate soluble proteins. Using Western blot and immunohistochemical analyses, Vincent et al. (1998) found that membrane-bound Kl2 was expressed on Sertoli cells from the peripheral to the adluminal compartment of the tubule at stages VII to VIII, when spermatocytes enter meiosis. Kit was expressed on the surface of germ cells up to the pachytene stage. Blocking interaction of Kl2 with Kit via blocking antibody or treatment with soluble Kl protein inhibited the appearance of haploid cells and completion of meiosis.
Using a knockin strategy, Kissel et al. (2000) mutated the binding site for the p85 subunit (PIK3R1; 171833) of phosphoinositide 3-kinase (PI3K) in mouse Kit. Mice homozygous for the Kit mutation, tyr719 to phe (Y719F), had no pigment deficiency or impairment of steady-state hematopoiesis, but gametogenesis was affected, and tissue mast cell numbers were differentially affected. Homozygous mutant males were sterile due to a block at the premeiotic stages in spermatogenesis, and adult males developed Leydig cell hyperplasia. In mutant females, follicle development was impaired at the cuboidal stages, resulting in reduced fertility. Adult mutant females also developed ovarian cysts and ovarian tubular hyperplasia. Kissel et al. (2000) concluded that KIT-mediated PI3K signaling is critical in gametogenesis.
Signaling from the KIT receptor tyrosine kinase is essential for primordial germ cell growth both in vivo and in vitro. Many downstream effectors of the KIT signaling pathway have been identified in other cell types, but how these molecules control primordial germ cell survival and proliferation are unknown. Determination of the KIT effectors acting in primordial germ cells has been hampered by the lack of effective methods to manipulate easily gene expression in these cells. De Miguel et al. (2002) overcame this problem by testing the efficacy of retroviral-mediated gene transfer for manipulating gene expression in mammalian germ cells. They found that primordial germ cells can successfully be infected with a variety of types of retroviruses. They used this method to demonstrate an important role of the AKT1 (164730) in regulating primordial germ cell growth.
Rothschild et al. (2003) found that steroidogenesis in mouse Leydig cells was dependent on Kitl signaling and involved PI3K. Leydig cells of mice homozygous for the Kit Y719F mutation were unable to respond effectively to Kitl stimulation; however, mutant animals had normal serum testosterone levels. The findings suggested a model in which the mutant Leydig cells initially produce lower levels of testosterone, reducing testosterone negative feedback on the hypothalamic-pituitary axis, which leads to elevated luteinizing hormone (LH; see 152780) secretion and restoration of normal serum testosterone levels. Rothschild et al. (2003) concluded that KITL, acting via PI3K, is a paracrine regulator of Leydig cell steroidogenesis.
Kondo et al. (2007) showed that both ligand-activated wildtype KIT and KIT carrying the asp816-to-val (D816V; 164920.0009) mutation activated the stress-related survival factor HSP32 (HMOX1; 141250). Activated KIT and KIT with the D816V mutation induced HSP32 promoter activity and expression of HSP32 mRNA and protein. Moreover, pharmacologic inhibitors of HSP32 inhibited proliferation and induced apoptosis in neoplastic mast cells. Kondo et al. (2007) concluded that HSP32 supports neoplastic mast cell survival.
Kasamatsu et al. (2008) stated that the first 3 Ig-like domains of mKIT are involved in binding SCF (KITLG), and that the fourth Ig-like domain of KIT is involved in receptor dimerization. Binding and dimerization of KIT subsequently cause autophosphorylation at tyrosine residues, followed by the activation of downstream signaling cascades. Kasamatsu et al. (2008) found that recombinant sKIT inhibited binding of radiolabeled SCF to mKIT in a dose-dependent manner, and that sKIT inhibited SCF-induced phosphorylation of mKIT. TACE (ADAM17; 603639) and some matrix metalloproteases (see MMP1; 120353) activated sKIT release from human melanocytes and inhibited SCF-induced melanogenesis. Expression of mKIT was slightly increased, and expression of sKIT was decreased, after exposure of human melanocytes to ultraviolet B (UVB) radiation, suggesting a role of mKIT signaling during UBV-induced melanogenesis. Kasamatsu et al. (2008) concluded that SCF/mKIT signaling is involved in human skin pigmentation and that this signaling pathway is regulated by sKIT.
In addition to its role in hematopoietic maintenance, growth, and differentiation, KIT regulates cell shape, motility, and adhesion via cytoskeletal changes. Mani et al. (2009) found that Kit ligand-induced stimulation resulted in tyrosine phosphorylation of Wasp (WASF1; 605035), Wip (WIPF1; 602357), and Arp2/3 (ACTR2; 604221). Kit ligand-induced filopodia were significantly reduced in size and number, and Kit ligand-induced calcium influx was impaired in Wasp -/- bone marrow-derived mast cells (BMMCs). Kit ligand induced outgrowth of Wasp-positive cells from a mixture of Wasp -/-, Wasp +/-, and wildtype cells, suggesting a selective advantage for Wasp-expressing cells. Comparison of the genetic profile of Wasp -/- and wildtype BMMCs revealed that, of the approximately 1,500 genes that were up- or downregulated in response to Kit stimulation, about one-third were Wasp dependent. Mani et al. (2009) concluded that WASP is required for KIT-mediated signaling, cytoskeletal changes, and gene expression.
Chi et al. (2010) demonstrated that ETV1 (600541) is highly expressed in the subtypes of interstitial cells of Cajal (ICCs) sensitive to oncogenic KIT-mediated transformation, and is required for their development. In addition, ETV1 is universally highly expressed in gastrointestinal stromal tumors (GISTs; see 606764) and is required for growth of imatinib-sensitive and -resistant GIST cell lines. Transcriptome profiling and global analyses of ETV1-binding sites suggested that ETV1 is a master regulator of an ICC-GIST-specific transcription network mainly through enhancer binding. The ETV1 transcriptional program is further regulated by activated KIT, which prolongs ETV1 protein stability and cooperates with ETV1 to promote tumorigenesis. Chi et al. (2010) proposed that GIST arises from ICCs with high levels of endogenous ETV1 expression that, when coupled with an activating KIT mutation, drives an oncogenic ETS transcriptional program. This model differs from other ETS-dependent tumors such as prostate cancer, melanoma, and Ewing sarcoma where genomic translocation or amplification drives aberrant ETS expression. Chi et al. (2010) also stated that this model of GIST pathogenesis represents a novel mechanism of oncogenic transcription factor activation.
Mastocytosis is a hematologic malignancy characterized by clonal accumulation of mast cells in 1 or more organs. The somatic D816V mutation in KIT is present in about 85% of patients with mastocytosis. Using RT-PCR, immunofluorescence, and Western blot analyses, Polivka et al. (2021) showed that the hedgehog (Hh) pathway was activated in neoplastic MCs from patients with mastocytosis and Greig cephalopolysyndactyly syndrome (GCPS; 175700), which results from haploinsufficiency for the Hh repressor GLI3 (165240), and that the Hh signaling pathway cooperated with constitutively activate KIT in the onset of mastocytosis. Analysis with a GCPS mouse model revealed that mutated Gli3 synergized with the Kit D816V mutant to promote tumorigenicity, as Gli3 haploinsufficiency and high Gli3a activator (Gli3a)/Gli3 repressor (Gli3r) ratio inhibited apoptosis and enhanced proliferation, especially when Kit was mutated. Analysis with HMC1.2 cells confirmed that Gli3 was a tumor suppressor, as expression of GLI3R drastically inhibited proliferation of HMC1.2 cells. Analysis with Hh antagonists confirmed that the Hh pathway was essential for MC transformation, and inhibition of the Hh pathway suppressed neoplastic MC proliferation in vitro and extended the survival time of mice with aggressive systemic mastocytosis.
In humans, KIT loss-of-function mutations result in piebaldism (172800), an autosomal dominant disorder of pigmentation characterized by patches of white skin and hair. In contrast, KIT gain-of-function mutations are associated with gastrointestinal stromal cell tumors (GISTs; 606764) and other cancers. In addition, somatic activating mutations in the KIT gene have been identified in most sporadic patients with mastocytosis (154800), both children and adults (Kambe et al., 2010); and in rare families with cutaneous mastocytosis, germline activating mutations have been reported.
Piebaldism
In a patient with classic autosomal dominant piebaldism (172800), Giebel and Spritz (1991) identified heterozygosity for a missense mutation in the KIT gene (G664R; 164920.0001).
Fleischman et al. (1991) analyzed the KIT gene in 7 unrelated patients with piebaldism and identified heterozygous deletion of KIT in 1 patient (164920.0002).
In affected individuals from 3 unrelated families with piebaldism, Spritz et al. (1992) identified heterozygosity for a missense mutation (F584L; 164920.0003) and 2 frameshift mutations (164920.0004; 164920.0005), respectively, in the KIT gene.
In 1 of 10 unrelated individuals with piebaldism, Fleischman (1992) identified a missense mutation in the KIT gene (E583K; 164920.0006).
In affected individuals from 2 large families segregating autosomal dominant piebaldism, Spritz et al. (1992) identified heterozygosity for a frameshift mutation (164920.0007) and a splice site mutation (164920.0008), respectively.
n a South African girl of Xhosa ancestry, who had severe piebaldism and profound congenital sensorineural deafness, Spritz and Beighton (1998) identified a heterozygous missense mutation in the KIT gene (R796G; 164920.0016). Her mother and brother were reported to be similarly affected, but were not available for study.
In a Japanese mother and daughter with piebaldism, Nomura et al. (1998) identified heterozygosity for a missense mutation in KIT (T847P; 164920.0019).
In affected individuals from 2 families and a sporadic patient with piebaldism, Syrris et al. (2000) identified 3 different heterozygous missense mutations in the KIT gene (see, e.g., 164920.0022).
In a mother and daughter with progressive piebaldism, including total hair depigmentation in the mother, Richards et al. (2001) identified heterozygosity for a missense mutation in KIT (V620A; 164920.0025).
Gastrointestinal Stromal Tumors
Gastrointestinal stromal tumors (GISTs; 606764) are the most common mesenchymal neoplasms in the human digestive tract. Hirota et al. (1998) investigated the mutational status of KIT in 58 mesenchymal tumors that developed in the gastrointestinal wall (4 in the esophagus, 36 in the stomach, 14 in the small intestine, and 4 in the large intestine). KIT expression was examined by immunohistochemistry. Eight authentic glial leiomyomas and an authentic schwannoma did not express KIT. The remaining 49 mesenchymal tumors were diagnosed as GISTs, and 94% (46 of 49) of these expressed KIT. Examination of these tumors for expression of CD34 (142230), which is a reliable marker for GISTs, revealed that 82% (40 of 49) were CD34-positive, and 78% (38 of 49) were positive for both KIT and CD34. Three of 5 KIT-negative GISTs were also CD34-negative. Hirota et al. (1998) compared the immunohistochemical characteristic of GISTs with those of interstitial cells of Cajal (ICCs), which regulate autonomous contraction of the GI tract. They found that ICCs are double-positive for KIT and CD34. In 5 GISTs, they found mutations in the region between the transmembrane and tyrosine kinase domains (164920.0011-164920.0015). All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF; 184745). Stable transfection of the mutant KIT cDNAs induced malignant transformation of murine lymphoid cells, suggesting that the mutations contribute to tumor development. Hirota et al. (1998) suggested that GISTs may originate from the interstitial cells of Cajal (ICCs) because the development of ICCs is dependent on the SCF-KIT interaction and because, like GISTs, these cells express both KIT and CD34. It is noteworthy that the 5 mutations identified in GISTs lay between codons 550 and codon 559.
Most GISTs are solitary and the gain-of-function mutations found by Hirota et al. (1998) were somatic. Nishida et al. (1998) described a family with multiple GISTs. Affected members all had a germline KIT mutation (164920.0017) occurring between the transmembrane and tyrosine kinase domains, which is also the region where mutations had been demonstrated in solitary GISTs. The KIT mutation in this family was detected not only in tumors but also in leukocytes, indicating that GISTs constitute a familial cancer syndrome. Seven individuals in 5 sibships of 4 generations of the family were affected by either benign and/or malignant GISTs. Two members of the family reported by Nishida et al. (1998) were reported to have hyperpigmentation of the perineum.
Lasota et al. (1999) found that mutations in exon 11 of KIT occur preferentially in malignant versus benign GISTs, and do not occur in leiomyomas or leiomyosarcomas. Furthermore, the conservation of the KIT mutation pattern, observed in consecutive lesions from the same patients, suggested that these mutations may be useful tumor markers in monitoring recurrence or minimal residual disease.
In a French mother and son with multiple GISTS, Isozaki et al. (2000) identified heterozygosity for a missense mutation in the KIT gene (K642E; 164920.0024).
Beghini et al. (2001) studied an Italian family in which 4 members over 3 generations, including a father and son, had multiple hyperpigmented spots on the skin of the face, trunk, extremities and mucous membranes. At 18 years of age, the father developed multiple GISTs. The proband's 14-year-old son underwent evaluation of his skin lesions, and histology revealed groups of tightly packed round-to-ovoid mast cells around vessels of the upper and middle dermis; he was diagnosed with urticaria pigmentosa. Both father and son carried a germline missense mutation in the KIT gene (V559A; 164920.0023).
KIT has tyrosine kinase activity. Mutations in KIT result in ligand-independent tyrosine kinase activity, autophosphorylation of KIT, uncontrolled cell proliferation, and stimulation of downstream signaling pathways. Joensuu et al. (2001) demonstrated that STI571, an inhibitor of tyrosine kinase activity in BCR/ABL-positive leukemia (see 151410), was effective in treating GISTs. STI571, known as imatinib and by the trade name Gleevec, was approved by the Food and Drug Administration in February, 2002, for the treatment of GISTs (Savage and Antman, 2002).
Mastocytosis, Cutaneous - Germline Mutations
n 5 affected individuals over 3 generations of a family with diffuse cutaneous mastocytosis (154800), Tang et al. (2004) identified heterozygosity for a missense mutation (A533D; 164920.0026) in the KIT gene. The mutation was not found in 3 unaffected family members or in 56 controls. The germline nature of the mutation was confirmed by the presence of A533D in DNA extracted from buccal washing of the proband and his affected father.
In a Polish father and 2 children who exhibited urticaria pigmentosa as the only manifestation of mastocytosis, Wasag et al. (2011) identified heterozygosity for a germline missense mutation in the KIT gene (N822I; 164920.0027). Functional analysis demonstrated that N822I is an activating mutation that results in predominantly immature KIT isoforms and is resistant to the tyrosine kinase-inhibitor imatinib.
Mastocytosis, Systemic and Cutaneous - Somatic Mutations
In the human mast cell leukemia (see 154800) line HMC-1, Furitsu et al. (1993) identified a missense mutation in the KIT gene (D816V; 164920.0009) that they determined plays a major role in constitutive activation of c-Kit product in HMC-1 cells.
In peripheral blood mononuclear cells (PBMCs) from 4 patients with mastocytosis associated with a hematologic disorder with predominantly myelodysplastic features (see 154800), Nagata et al. (1995) identified the somatic D816V mutation in the KIT gene.
In mast cells from a patient with aggressive systemic mastocytosis with massive splenic involvement, Longley et al. (1996) identified heterozygosity for the D816V substitution in KIT. The somatic mutation was not found in ectodermally-derived epithelial cells of the buccal mucosa or in non-mast cell leukocytes.
In a 44-year-old man with aggressive mast cell disease, who did not carry the D816V mutation, Pignon et al. (1997) identified a different somatic mutation in the KIT gene (D820G; 164920.0010).
In PBMCs from 16 (25%) of 65 patients with systemic mastocytosis, Worobec et al. (1998) identified the D816V KIT mutation. Patients carrying D816V manifested a more severe disease pattern and commonly had osteosclerotic bone involvement as well as immunoglobulin dysregulation and peripheral blood abnormalities. Pedigree analysis of 3 families provided evidence that the mutation was somatic.
Longley et al. (1999) examined KIT cDNA in skin lesions of 22 patients with sporadic mastocytosis and 3 patients with familial mastocytosis. All patients with adult sporadic mastocytosis had somatic KIT mutations in codon 816 causing substitution of valine for aspartate and spontaneous activation of mast cell growth factor receptor. A subset of 4 childhood-onset cases with clinically unusual disease also had codon 816 activating mutations substituting valine, tyrosine, or phenylalanine for aspartate. Typical pediatric patients, however, lacked codon 816 mutations, but limited sequencing showed that 3 of 6 had a novel dominant inactivating mutation substituting lysine for glutamic acid at position 839, the site of a potential salt bridge that is highly conserved in receptor tyrosine kinases. No KIT mutations were found in the entire coding region of 3 patients with familial mastocytosis. Thus, Longley et al. (1999) concluded that KIT somatic mutations substituting valine in position 816 of KIT are characteristic of sporadic adult mastocytosis and may cause this disease. Similar mutations causing activation of the mast cell growth factor receptor were found in children apparently at risk for extensive or persistent disease. In contrast, typical pediatric mastocytosis patients lacked these mutations and may express inactivating KIT mutations. Familial mastocytosis, however, may occur in the absence of KIT coding mutations.
Fritsche-Polanz et al. (2001) screened KIT cDNA in bone marrow mononuclear cells of 28 patients with myelodysplastic syndromes and 12 patients with systemic mastocytosis. All 11 patients with systemic indolent mastocytosis tested positive for the KIT 2468A-T mutation (D816V; see 164920.0009). In contrast, no mutation was identified in the 1 case of aggressive mastocytosis. Among patients with myelodysplastic syndromes, no patient showed a somatic mutation in KIT.
In 6 of 12 patients with systemic mastocytosis who had mutations in the TET2 gene (612839), Tefferi et al. (2009) also detected the D816V mutation in KIT. The authors concluded that TET2 mutations are frequent in systemic mastocytosis and segregate with the D816V mutation in KIT.
Bodemer et al. (2010) analyzed the entire c-KIT sequence from cutaneous biopsies of 50 children with mastocytosis and identified heterozygosity for somatic activating mutations in 43 (86%). In 21 (42%) of the children, the mutation involved codon 816, including 18 with D816V, 2 with D816Y, and 1 with D816I. Unexpectedly, half of the mutations were located in the fifth Ig loop of the KIT extracellular domain, encoded by exons 8 and 9, including 9 changes involving codon 419. Bodemer et al. (2010) observed no clear genotype/phenotype correlation and no significant change in the relative expression of the short (GNNK) or long (GNNK+) isoforms of KIT, which had been shown (Caruana et al., 1999) to signal through different pathways and to have distinct transforming activities. Bodemer et al. (2010) concluded that most cases of childhood-onset mastocytosis are clonal in nature and are associated with activating mutations in c-KIT; they also noted that the question of how the pediatric form can spontaneously resolve if it is a clonal disease remained to be resolved.
Acute Myeloid Leukemia
In a patient with acute myeloid leukemia of the M2 subtype (see 601626), characterized by the massive presence of mast cells in bone marrow and rapid progression of disease, Beghini et al. (1998) identified a somatic missense mutation in the KIT gene (D816Y; 164920.0018).
Germ Cell Tumors
In 2 different germ cell tumors (GCTs; see 273300), a seminoma and a mixed ovarian dysgerminoma/yolk sac tumor, Tian et al. (1999) identified a somatic missense mutation in the KIT gene (D816H; 164920.0021). The mixed ovarian GCT had the mutation in each tumor component.
Spritz et al. (1992) found deletion of both the KIT gene and the PDGFRA gene in a patient with piebaldism, mental retardation, and multiple congenital anomalies associated with a 46,XY,del(4)(q12q21.1) karyotype. The patient was hemizygous for the 2 deleted genes.
Mutations at the W locus in the mouse produce changes that include white coat color, sterility, and anemia that are attributable to failure of stem cell populations to migrate and/or proliferate effectively during development. The Kit protooncogene, which encodes a putative transmembrane tyrosine kinase receptor, maps in the same region as the W locus. Geissler et al. (1988) showed that the mouse Kit gene was disrupted in 2 spontaneous mutant W alleles. A strong structural homology of KIT to the CSF1 receptor (164770) and the platelet-derived growth factor receptor (173490) suggests a model for the action of the KIT gene product during differentiation. The phenotypes of W mutants suggest that 3 cell populations in which KIT function is critical are the pluripotent hematopoietic stem cell, the migrating melanoblast during early embryonic development, and the primordial germ cell during this same period of development. Identification of the ligand for KIT will help in the understanding of its function. A genetic clue to its nature may be found through characterization of the Sl ('steel') locus of the mouse. The phenotypes of mutants at this locus closely resemble mutants at the W locus; however, unlike W, the defect in Sl is not intrinsic to the progenitor stem cells of the affected tissues, but rather lies in the environment in which melanoblast, germ cell, and hematopoietic progenitors differentiate and proliferate. Chabot et al. (1988) also related Kit to a W mutation in the mouse. These findings will prompt search for comparable changes in disorders such as Fanconi anemia (227650). In the dominant W(42) spotting phenotype in the mouse, Tan et al. (1990) demonstrated an asp790-to-asparagine mutation in the KIT protein product. Asp790 is a conserved residue in all protein kinases. Nocka et al. (1990) identified mutations in other alleles at the W locus: W(37), E-to-K at position 582; W(v), T-to-M at position 660; and W(41), V-to-M at position 831. The W mutation is the result of a 78-amino acid deletion that includes the transmembrane of the KIT protein. Nocka et al. (1990) detected a 125-kD KIT protein in homozygous W/W mast cells that lacked kinase activity and did not express KIT on the cell surface. Thus, in mice, the c-Kit receptor tyrosine kinase is the gene product of the W locus, whereas Sl encodes the ligand for this growth factor receptor. Microphthalmia (mi/mi) in mice also shows deficiency in melanocytes and mast cells. In addition, whereas W and Sl mutants can be anemic and sterile, 'mi' mice are osteopetrotic due to a monocyte/macrophage defect. Dubreuil et al. (1991) found that the fms gene (164770) complements the mitogenic defect in mast cells of mutant W mice but not of mi/mi mice.
The KIT-encoded transmembrane tyrosine kinase receptor for stem cell factor (SCFR) is required for normal hematopoiesis, melanogenesis, and gametogenesis. The role of individual KIT/SCFR-induced signaling pathways in the control of developmental processes in the intact animal were completely unknown. To examine the function of SCF-induced phosphatidylinositol (PI) 3-prime-kinase activation in vivo, Blume-Jensen et al. (2000) employed the Cre-loxP system to mutate the tyr719 codon, the PI 3-prime-kinase binding site in Kit/Scfr, to phe in the genome of mice by homologous recombination. Homozygous (Y719F/Y719F) mutant mice were viable. The mutation completely disrupted PI 3-prime-kinase binding to Kit/Scfr and reduced Scf-induced PI 3-prime-kinase-dependent activation of Akt (164730) by 90%. The mutation induced a gender- and tissue-specific defect. Although there were no hematopoietic or pigment defects in homozygous mutant mice, males were sterile due to a block in spermatogenesis, with initially decreased proliferation and subsequent extensive apoptosis occurring at the spermatogonial stem cell level. In contrast, female homozygotes were fully fertile. This was said to be the first demonstration of the role of an individual signaling pathway downstream of Kit/Scfr in the intact animal.
The pacemaker activity in the mammalian gut is responsible for generating anally propagating phasic contractions. Although the cellular basis for this intrinsic activity is unknown, the smooth muscle cells of the external muscle layers and the innervated cellular network of interstitial cells of Cajal (ICC), which is closely associated with the external muscle layers, have both been proposed to stimulate pacemaker activity. The interstitial cells of Cajal were identified in the 19th century but their developmental origin and function remained unclear until the studies of Huizinga et al. (1995). Injection of antibodies directed against the extracellular domain of Kit into newborn mice leads to changes in the in vitro contraction patterns in the small intestine and absence of Kit mRNA in the myenteric plexus area. Huizinga et al. (1995) found that mice with W mutations at the Kit locus lacked the network of ICC in the myenteric plexus region. Using a polyclonal antibody directed against the intracellular domain of the Kit receptor tyrosine kinase, they demonstrated that wildtype and heterozygous mice showed high levels of Kit expression between the longitudinal and circular muscle layers at the level of the Auerbach plexus. By contrast, no Kit immunoreactivity was found in or between the muscle layers of homozygous W/W mice. Huizinga et al. (1995) suggested that functional gut abnormalities and megacolon observed in patients with piebaldism (Bolognia and Pawelek, 1988) reflects an identical function of the KIT signaling pathway in the development of the interstitial cells of Cajal in humans; see 172800 for a discussion of megacolon in association with piebald trait. Mutations in RET (164761), another member of the receptor tyrosine kinase family that is expressed in neural crest-derived ganglion cells, are also associated with megacolon.
As outlined earlier, networks of interstitial cells of Cajal embedded in the musculature of the gastrointestinal tract are involved in the generation of electrical pacemaker activity for gastrointestinal motility. This pacemaker activity manifests itself as rhythmic slow waves in membrane potential, and controls the frequency and propagation characteristics of gut contractile activity. Mice that lack a functional Kit receptor failed to develop the network of interstitial cells of Cajal. Thomsen et al. (1998) provided direct evidence that a single Cajal cell generates spontaneous contractions and a rhythmic inward current that is insensitive to L-type calcium channel blockers.
Comparative mapping data suggested that the 'dominant white' coat color in pigs may be due to a mutation in KIT. Johansson Moller et al. (1996) reported that dominant white pigs lack melanocytes in the skin, as would be anticipated for a KIT mutation. They found, furthermore, a complete association between the dominant white mutation and a duplication of the KIT gene, or part of it, in samples of unrelated pigs representing 6 different breeds. Duplication was revealed by SSCP analysis and subsequent sequence analysis showing that white pigs transmitted 2 nonallelic KIT sequences. The presence of a gene duplication in white pigs was confirmed with quantitative Southern blot, quantitative PCR, and fluorescence in situ hybridization (FISH) analyses. FISH analysis showed that KIT and the very closely linked gene encoding platelet-derived growth factor receptor are located on pig 8p12. The results of Johansson Moller et al. (1996) demonstrated an extremely low rate of recombination in the centromeric region of this chromosome since the closely linked (0.5 cM) serum albumin (103600) locus had previously been mapped by FISH to 8q12. The authors noted that pig chromosome 8 shares extensive conserved synteny with human chromosome 4, but the gene order is rearranged.
Marklund et al. (1998) reported that the dominant white phenotype in domestic pigs is caused by 2 mutations in the KIT gene, 1 gene duplication associated with a partially dominant phenotype and a splice mutation in 1 of the copies leading to the fully dominant allele. The splice mutation is a G-to-A substitution in the first nucleotide of intron 17, leading to a skipping of exon 17. The duplication is most likely a regulatory mutation affecting KIT expression, whereas the splice mutation is expected to cause a receptor with impaired or absent tyrosine kinase activity. Immunocytochemistry showed that this variant form is expressed in 17- to 19-day-old pig embryos. Hundreds of millions of white pigs around the world are assumed to be heterozygous or homozygous for the 2 mutations.
Giuffra et al. (2002) studied the basis of the dominant white locus (I/KIT), one of the major coat color loci in the pig. Previous studies had shown that the 'dominant white' and 'patch' alleles are both associated with a duplication including the entire KIT coding sequence. Giuffra et al. (2002) constructed a BAC contig spanning the 3 closely linked tyrosine kinase receptor genes PDGFRA, KIT, and KDR (191306) located on chromosome 4q12. The size of the duplication was estimated at 450 kb and included KIT, but not PDGFRA or KDR. Sequence analysis revealed that the duplication arose by unequal homologous recombination between 2 LINE elements flanking KIT. Comparative sequence analysis indicated that the distinct phenotypic effect of the duplication occurs because the duplicated copy (which is shared by several alleles across breeds, implying that they are descendants of a single duplication event) lacks some regulatory elements located more than 150 kb upstream of KIT exon 1 and necessary for normal KIT expression.
Reinsch et al. (1999) presented evidence suggesting that KIT is a candidate gene for the degree of spotting in cattle. They did a quantitative trait loci (QTL) scan over all chromosomes covered by 229 microsatellite marker loci in 665 animals of German Simmental and Holstein bovine families. On bovine chromosome 6, a QTL for the proportion of white coat with large effects was found, and a less important one on bovine chromosome 3 was also identified. Chromosome 6 in cattle was known to harbor the KIT locus. Several groups had mapped QTL for milk production to chromosome 6 in Holsteins and other breeds. Some had identified dairy cattle with a higher white percentage as better producers. Reinsch et al. (1999) raised the possibility that this result could be caused by linkage disequilibrium between a white percentage QTL and a QTL for milk production.
By generating mice with mutations at both the W locus and the Nf1 gene (613113), Ingram et al. (2000) found that mice homozygous for W41 and heterozygous for Nf1 had 60 to 70% restoration of coat color. However, Nf1 haploinsufficiency increased peritoneal and cutaneous mast cell numbers in wildtype and W41 mice, and it increased wildtype and W41/W41 bone marrow mast cells in in vitro cultures containing Steel factor, a mast cell mitogen (184745).
To create a mouse model for the study of constitutive activation of Kit in oncogenesis, Sommer et al. (2003) used a knockin strategy to introduce into the mouse genome a Kit exon 11-activating mutation, val558del, which corresponds to a val559del mutation (164920.0017) found in human familial GISTs. Heterozygous male and female mice were fertile, but fertility was impaired with increasing age. Heterozygous mice developed symptoms of disease and eventually died from pathology in the GI tract. Patchy hyperplasia of Kit-positive cells was evident within the myenteric plexus of the entire GI tract. Neoplastic lesions indistinguishable from human GISTs were observed in the cecum of the mutant mice with high penetrance. In addition, mast cell numbers in the dorsal skin were increased. Sommer et al. (2003) concluded that mice heterozygous for a val558 deletion in the Kit gene reproduce human familial GISTs and may be used as a model for studying the role and mechanisms of Kit in neoplasia. Importantly, these results demonstrated that constitutive Kit signaling is critical and sufficient for induction of GIST and hyperplasia of interstitial cells of Cajal.
Rubin et al. (2005) generated a mouse model of GIST using an activating Kit mutation (K641E) associated with human familial GIST (K642E (164920.0024) in humans; see Isozaki et al., 2000). Homozygous and heterozygous Kit K641E mice developed gastrointestinal pathology with complete penetrance, and all homozygotes died by age 30 weeks due to gastrointestinal obstruction by hyperplastic interstitial cells of Cajal (ICC) or GISTs. Heterozygous mice had less extensive ICC hyperplasia and smaller GISTs, suggesting a dose-response relationship between oncogenically activated Kit and ICC proliferation. Homozygous Kit K641E mice also exhibited loss-of-function Kit phenotypes, including white coat color, decreased numbers of dermal mast cells, and sterility, indicating that despite oncogenic activity the mutant form cannot accomplish many activities of the wildtype gene.
Paramutation is a heritable epigenetic modification induced in plants by crosstalk between allelic loci. Rassoulzadegan et al. (2006) reported a similar modification of the mouse Kit gene in the progeny of heterozygotes with the null mutant Kit(tm1Alf) (a lacZ insertion). In spite of a homozygous wildtype genotype, their offspring maintained, to a variable extent, the white spots characteristic of Kit mutant animals. Efficiently inherited from either male or female parents, the modified phenotype results from a decrease in Kit mRNA levels with the accumulation of nonpolyadenylated RNA molecules of abnormal sizes. Sustained transcriptional activity at the postmeiotic stages, at which time the gene is normally silent, leads to the accumulation of RNA in spermatozoa. Microinjection into fertilized eggs either of total RNA from Kit(tm1Alf/+) heterozygotes or of Kit-specific microRNAs induced a heritable white tail phenotype. Rassoulzadegan et al. (2006) concluded that their results identified an unexpected mode of epigenetic inheritance associated with the zygotic transfer of RNA molecules.
Reasoning that human piebaldism (172800), like mouse dominant white spotting (W), might be a result of mutation in the KIT gene, Spritz and Giebel (1991) and Giebel and Spritz (1991) designed primers for PCR amplification of the 21 coding exons. Studies of DNA from a patient with classic autosomal dominant piebaldism showed that he was heterozygous for a single base change, resulting in a glycine-to-arginine substitution at codon 664, within the ATP-binding site of the tyrosine kinase domain. This substitution was not found in 40 normal individuals. A genetic linkage analysis of the mutation in the proband's family, which could trace its inheritance for 15 generations, yielded a lod score of 6.02 at theta = 0.0. This substitution was not observed in 3 other unrelated probands with piebaldism.
Fleischman et al. (1991) examined the KIT gene by Southern blot analysis in 7 unrelated individuals with piebaldism (172800). One subject, although cytogenetically normal, had a heterozygous deletion of KIT which involved also the closely linked PDGFRA gene. Fluorescence in situ hybridization independently confirmed the deletion.
In the female proband from a 4-generation family with severe piebaldism (172800), including white forelock and extensive nonpigmented patches on the chest, arms, and legs, Spritz et al. (1992) demonstrated substitution of leucine for phenylalanine at codon 584 (F584L) within the tyrosine kinase domain of the KIT gene. They suggested that this mutation was consistent with 'dominant-negative' effect of the missense KIT polypeptides on the function of the dimeric receptor.
In 4 affected individuals over 3 generations of a Caucasian family with piebaldism (154800), Spritz et al. (1992) identified deletion of 2 bases from the AAA triplet of codon 642 within exon 13 in the tyrosine kinase domain. This resulted in a frameshift distal to codon 641, terminating only 6 residues downstream at a novel in-frame TAA. The proband and other members of the family had no dysmorphia or heterochromia iridis, and hearing was normal. However, the proband reported chronic severe constipation.
In the male proband from a large 4-generation family with piebaldism (154800), previously reported by Selmanowitz et al. (1977), Spritz et al. (1992) demonstrated heterozygosity for a 1-bp duplication in codon 561 (GAG to GGAG) within exon 11 in the tyrosine kinase domain. This resulted in a frameshift distal to codon 560, terminating 18 residues downstream at a novel in-frame TGA. The proband was a Caucasian male with mild piebaldism, exhibiting only nonpigmented patches on both legs. Spritz et al. (1992) commented that the phenotype appeared to be milder in loss-of-function mutations such as this than in dominant-negative mutations such as that represented by 164920.0003.
In a patient with piebaldism (172800) who was previously studied by Fleischman et al. (1991), Fleischman (1992) found a variant single-strand conformation polymorphism pattern for the first exon encoding the kinase domain of KIT. DNA sequencing demonstrated a heterozygous 1747G-A transition resulting in a glu583-to-lys (E583K) substitution at a conserved residue near the ATP-binding pocket. This mutation is identical to the mouse W37 mutation, which abolishes autophosphorylation of the protein product and causes more extensive depigmentation than do null mutations. This was interpreted as a 'dominant-negative' effect, and indeed the mutation in the human kindred was associated with unusually extensive depigmentation. Fleischman (1992) observed that the mouse mutation was associated with more diffuse and apparently random pattern of dorsal pigmentation in contrast to the nearly complete sparing of the central back in the human kindred, an almost invariant feature of human piebald trait.
In affected members of a large 4-generation family with piebaldism (172800), Spritz et al. (1992) used combined SSCP/heteroduplex analysis of the 21 KIT exons to demonstrate an aberrant pattern for exon 2. A subsequent study revealed heterozygosity for a 1-bp deletion in codon 85 (GAA to AA) near the beginning of the extracellular ligand-binding domain. This resulted in a frameshift distal to codon 85, with an 18-amino acid nonsense peptide terminating at a novel in-frame TAA at codons 103-104.
In a large 4-generation family with piebaldism (172800), Spritz et al. (1992) demonstrated an aberrant SSCP/heteroduplex band pattern for exons 12 and 18. Further study demonstrated that the atypical exon 18 pattern resulted from a silent DNA sequence polymorphism. The pathologic KIT mutation was a G-to-A transition at the first base of IVS12, abolishing the 5-prime splice site of IVS12. Spritz et al. (1992) demonstrated that the IVS12 mutation cosegregated with the piebald phenotype in the family, whereas the exon 18 polymorphism did not.
In a human mast cell leukemia (see 154800) cell line (HMC-1), Furitsu et al. (1993) found 2 point mutations in KIT that resulted in val560-to-gly and asp816-to-val (D816V) substitutions in the cytoplasmic domain. Amino acid sequences in the regions of the 2 mutations are completely conserved in all of mouse, rat, and human KIT. To determine the causal role of these mutations in constitutive activation, murine Kit mutants encoding gly559 and/or val814, corresponding to human gly560 and/or val816, were constructed by site-directed mutagenesis and expressed in a human embryonic kidney cell line. In the transfected cells, both KitR (gly559, val814) and KitR (val814) were abundantly phosphorylated on tyrosine and activated in immune complex kinase reaction in the absence of SCF, whereas tyrosine phosphorylation and activation of KitR (gly559) or wildtype KitR was modest or little, respectively. Furitsu et al. (1993) suggested that the D816V mutation plays a major role in the constitutive activation of c-Kit product in HMC-1 cells, while the V560G mutation plays a minor role.
In 4 patients with mastocytosis associated with a hematologic disorder (see 154800) with predominantly myelodysplastic features, Nagata et al. (1995) identified a 2468A-T transversion in KIT mRNA, resulting in the D816V substitution. The presence of the mutation in genomic DNA from PBMCs was established in the 1 patient studied. Identical or similar amino acid substitutions in mast cell lines result in ligand-independent autophosphorylation of KIT (mast/stem cell growth factor receptor). The mutation was not identified in 5 patients with other forms of mastocytosis, including 3 with indolent mastocytosis, 1 with aggressive mastocytosis, and 1 with a solitary mastocytoma, or in 1 patient with chronic myelomonocytic leukemia (CMML; see 607785), or in 67 controls.
Longley et al. (1996) found heterozygosity for the D816V substitution in mast cells from a patient with urticaria pigmentosa with aggressive systemic mastocytosis with massive splenic involvement. They were able to demonstrate expression of KIT in mast cells of both skin and spleen. This was said to be the first in situ demonstration of an activating KIT mutation in neoplastic cells. That a somatic mutation was involved was indicated by the fact that ectodermally-derived epithelial cells of the buccal mucosa and non-mast cell leukocytes did not show the mutation.
To determine whether the D816V mutation is associated with identifiable clinical patterns and prognosis of mastocytosis, Worobec et al. (1998) screened 65 patients with systemic mastocytosis for the presence of the mutation in peripheral blood mononuclear cells. They found this mutation in 16 cases (25%): 15 adults and 1 infant, but not in any children with mastocytosis. Patients with the mutation manifested a more severe disease pattern and commonly had osteosclerotic bone involvement as well as immunoglobulin dysregulation and peripheral blood abnormalities. Pedigree analysis of 3 families provided evidence that the mutation was somatic.
Longley et al. (1999) found the D816V mutation in 11 cases of adult sporadic mastocytosis. In 3 of the patients the disorder presented in adulthood with progressive urticaria pigmentosa with systemic involvement. The 8 other cases presented as sporadic, slowly progressive, or persistent adult urticaria pigmentosa without systemic involvement. Thus, all patients with adult sporadic mastocytosis had somatic KIT mutations in codon 816 causing spontaneous activation of mast cell growth factor receptor. The D816V substitution was also detected in 1 pediatric patient with progressive cutaneous disease without systemic involvement.
Fritsche-Polanz et al. (2001) studied 12 patients with systemic mastocytosis. All 11 patients with systemic indolent mastocytosis tested positive for the 2468A-T nucleotide substitution in KIT, resulting in the D816V substitution. In contrast, no mutation was identified in the 1 case of aggressive mastocytosis.
Taylor et al. (2001) demonstrated that the D816V mutation enhances chemotaxis of CD117(+) cells, offering one explanation for increased mast cells derived from CD34(+)CD117(+) mast cell precursors observed in tissues of patients with mastocytosis.
In 6 of 12 patients with systemic mastocytosis who had mutations in the TET2 gene (612830), Tefferi et al. (2009) also detected the D816V mutation in KIT. The authors concluded that TET2 mutations are frequent in systemic mastocytosis and segregate with the D816V mutation in KIT.
In cutaneous biopsies from 18 (36%) of 50 children with mastocytosis, Bodemer et al. (2010) identified heterozygosity for the D816V mutation in KIT. Two of the patients represented familial cases.
In a 44-year-old man with aggressive mast cell disease (MASTCYS; 154800), who was negative for the D816V mutation (164920.0009), Pignon et al. (1997) identified a somatic asp820-to-gly (D820G) substitution in the KIT gene. The patient, who had 40% abnormal mast cells in bone marrow aspirates, died from massive multivisceral involvement of the mastocytosis.
In a somatic gastrointestinal stromal tumor (GIST; 606764), Hirota et al. (1998) found an in-frame deletion of 6 bp in the KIT gene, removing codons 559 and 560 (val-val) from the protein.
In a somatic gastrointestinal stromal tumor (GIST; 606764), Hirota et al. (1998) demonstrated an in-frame deletion of 15 bp in the KIT gene, removing amino acid residues 551 to 555 from the protein.
In a somatic gastrointestinal stromal tumor (GIST; 606764), Hirota et al. (1998) found an in-frame deletion of 15 bp in the KIT gene 164920.0012 as well as a point mutation at codon 550 (AAA to ATA), resulting in a lys550-to-ile (K550I) substitution.
In a somatic gastrointestinal stromal tumor (GIST; 606764), Hirota et al. (1998) found a T-A transversion in the KIT gene, resulting in a val559-to-asp (V599D) substitution.
In a somatic gastrointestinal stromal tumor (606764), Hirota et al. (1998) identified an in-frame deletion of 27 bp from the KIT gene, resulting in deletion of 9 amino acids, 550 to 558, from the KIT protein.
In 2 GISTs with the 550del27 mutation, which encompasses the noncoding region in intron 10 and the coding region in exon 11 of the KIT gene, Chen et al. (2005) elucidated an unusual mechanism of aberrant pre-mRNA splicing resulting in constitutive activation of the oncoprotein. The deletion of noncoding and coding regions encompassing the 3-prime authentic splice site creates a novel intraexonic pre-mRNA 3-prime splice acceptor site, leading to in-frame loss of 27 nucleotides. Three-dimensional structural analysis revealed that loss of the 9 amino acids in this critical location unleashes the protein from autoinhibition, causing KIT to become constitutively activated and resulting in the GIST phenotype.
In a South African girl of Xhosa stock with severe piebaldism and profound congenital sensorineural deafness (see 172800), Spritz and Beighton (1998) identified a heterozygous A-to-G transition in the KIT gene, resulting in an arg796-to-gly (R796G) substitution at a highly conserved residue in the intracellular kinase domain. Although auditory anomalies have been observed in mice with dominant white spotting (W) due to KIT mutations, deafness is not typical in human piebaldism. There was a suggestion that the mother and brother of this patient may have been similarly affected, but for logistical reasons, Spritz and Beighton (1998) could not confirm this report.
In affected members of a 4-generation family with multiple gastrointestinal stromal tumors (GIST; 606764), Nishida et al. (1998) identified a germline deletion of 1 of 2 consecutive valine residues (at codons 559 and 560) due to a 3-bp deletion, GTT, in the KIT gene.
In mice, Sommer et al. (2003) used deletion of the comparable amino acid in the Kit gene, val558, to demonstrate the development of GISTs.
In a patient with acute myeloid leukemia of the M2 subtype (see 601626), characterized by the massive presence of mast cells in bone marrow and rapid progression of the disease, Beghini et al. (1998) identified a G-to-T transversion at nucleotide 2467 of the KIT gene, resulting in an asp816-to-tyr (D816Y) amino acid substitution. This mutation corresponds to the D816Y mutation identified and characterized in the murine P815 mastocytoma cell line by Tsujimura et al. (1994).
In lesions from 2 patients with clinically unusual childhood-onset mastocytosis (MASTSYS; 154800), who exhibited extensive cutaneous disease and systemic involvement of the bone marrow, liver, and spleen, Longley et al. (1999) identified heterozygosity for a somatic D816Y mutation.
In cutaneous biopsies from 2 children with mastocytosis, Bodemer et al. (2010) identified heterozygosity for the D816Y mutation in KIT. One patient was a 16-year-old boy with diffuse cutaneous involvement since birth, who had severe systemic manifestations, including hepatomegaly, splenomegaly, and adenopathy. Histologic analysis of a bone marrow biopsy showed infiltration by pathologic mast cells (greater than 10%).
In a Japanese family in which a mother and daughter had piebaldism (172800), Nomura et al. (1998) found that the affected individuals had a 8447A-C transition in the KIT gene, resulting in substitution of threonine by proline at codon 847 (T847P). The patients were heterozygous for the mutation. The proband was a 5-year-old girl who developed leukoderma on the forehead 1 week after birth. Examination at 5 years of age showed a depigmented fleck in the middle of the forehead and various-sized depigmented patches on the abdomen and anterior legs bilaterally. The proband's 30-year-old mother exhibited similar but somewhat less striking changes, which became evident a few weeks after birth. The proband's maternal grandfather was also affected.
In 3 unrelated children with typical childhood-onset cutaneous mastocytosis (MASTC; 154800), Longley et al. (1999) identified heterozygosity for a somatic dominant inactivating mutation in the KIT gene, a glu839-to-lys (E839K) substitution at the site of a potential salt bridge that is highly conserved in receptor tyrosine kinases.
The KIT gene is required for normal spermatogenesis and is expressed in seminomas and dysgerminomas, a subset of germ cell tumors (GCTs; see 273300). Tian et al. (1999) studied primary tissue samples of 33 testicular and ovarian tumors for mutations in the juxtamembrane and phosphotransferase domains of KIT by PCR amplification and DNA sequencing. Of the 17 seminomas/dysgerminomas studied, 2 GCTs, a seminoma and a mixed ovarian dysgerminoma/yolk sac tumor, showed a G-to-C transversion at nucleotide 2467 in exon 17, causing a change from aspartic acid to histidine at amino acid 816. The mixed ovarian GCT had the mutation in each tumor component. The KIT alleles in nonneoplastic tissue from these patients were wildtype, suggesting that the mutant alleles were acquired and selected for during malignant transformation. In cell transfection experiments, the D816H mutant protein was a constitutively activated kinase and was constitutively phosphorylated on tyrosine residues. This was the first description of an activating KIT mutation in GCTs and provided evidence that the KIT signal transduction pathway is important in the pathogenesis of neoplasms with seminoma differentiation.
One of 3 novel mutations described by Syrris et al. (2000) as the cause of piebaldism (172800) was a T-to-G transversion (TTT to TGT) in exon 11, resulting in a phe584-to-cys mutation. A phe-to-leu mutation had previously been described in the same codon; see 164920.0003.
In an Italian man with multiple gastrointestinal stromal tumors (GISTs; 606764) and hyperpigmented spots, Beghini et al. (2001) identified a germline 1697T-C transition in the KIT gene, resulting in a val559-to-ala (V559A) substitution in the juxtamembrane domain. His 14-year-old son, in whom the hyperpigmented lesions had been shown to represent cutaneous mastocytosis (MASTC; 154800), also carried the V559A mutation.
In a French mother and son with multiple gastrointestinal stromal tumors (GISTs; 606764), Isozaki et al. (2000) identified a heterozygous A-to-G transition in the KIT gene, resulting in a lys642-to-glu (K642E) substitution in the kinase I domain. In vitro functional expression studies showed constitutive activation of the mutant protein.
In a mother and her 8-year-old daughter, both of whom had a phenotype of typical piebaldism (172800) but with progressive depigmentation, including total hair depigmentation in the mother, Richards et al. (2001) identified heterozygosity for a 1859T-C transition in the KIT gene, resulting in a val620-to-ala (V620A) substitution in the intracellular tyrosine kinase domain. The mutation was not found in family members with a localized patch of white hair but without depigmentation or in 52 control individuals. Richards et al. (2001) speculated that this mutation may cause melanocyte instability, leading to progressive loss of pigmentation as well as the progressive appearance of hyperpigmented macules.
In 5 affected individuals over 3 generations of a family with diffuse cutaneous mastocytosis (MASTC; 154800), Tang et al. (2004) identified heterozygosity for a germline c.1619C-A transversion in exon 10 of the KIT gene, resulting in an ala533-to-asp (A533D) substitution at a highly conserved residue in the transmembrane domain. The mutation was not found in 3 unaffected family members or in 56 controls. The germline nature of the mutation was confirmed by the presence of A533D in DNA extracted from buccal washing of the proband and his affected father.
In a Polish father and 2 children with urticaria pigmentosa (MASTC; 154800), Wasag et al. (2011) identified heterozygosity for a germline asn822-to-ile (N822I) substitution in the KIT gene. Functional analysis in transfected HEK293T and Ba/F3 cells demonstrated that N822I constitutively activates KIT tyrosine phosphorylation, results in predominantly immature KIT isoforms, and is resistant to the tyrosine kinase-inhibitor imatinib.
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