Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: PDGFRB
SNOMEDCT: 1172898008, 776417008;
Cytogenetic location: 5q32 Genomic coordinates (GRCh38): 5:150,113,839-150,155,845 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q32 | Basal ganglia calcification, idiopathic, 4 | 615007 | Autosomal dominant | 3 |
| Kosaki overgrowth syndrome | 616592 | Autosomal dominant | 3 | |
| Myeloproliferative disorder with eosinophilia | 131440 | Autosomal dominant | 4 | |
| Myofibromatosis, infantile, 1 | 228550 | Autosomal dominant | 3 | |
| Premature aging syndrome, Penttinen type | 601812 | Autosomal dominant | 3 |
The PDGFRB gene encodes platelet-derived growth factor receptor-beta, a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family (see, e.g., PDFGB, 190040). Activation of the receptor leads to activation of downstream signaling pathways, inducing cellular proliferation, differentiation, survival, and migration (summary by Nicolas et al., 2013).
See also PDGFRA (173490).
Stimulation of cell proliferation of the receptor for PDGF (190040) has been implicated in atherogenesis and in cell transformation by the SIS oncogene. Escobedo et al. (1986) sequenced the receptor and cloned its gene.
Gronwald et al. (1988) cloned a cDNA coding for human PDGFR and studied its expression. The cDNA contained an open reading frame that coded for a protein of 1,106 amino acids. In transfectants, Gronwald et al. (1988) found that the PDGFR clone expressed a high affinity receptor specific for the BB isoform of PDGF, i.e., PDGF dimers composed of 2 B chains. There may be a separate class of PDGF receptor that binds both the homodimers and the heterodimer.
Claesson-Welsh et al. (1988) determined the structure of the human PDGF receptor as deduced from a full-length cDNA clone. The receptor expressed in Chinese hamster ovary cells was found to bind specifically to B-chain-containing PDGF molecules (190040). With the description of a second PDGF receptor (173490), it is necessary to use the symbol PDGFR1. Matsui et al. (1989) designated the second type of PDGFR as type alpha because PDGF binding was blocked by AA as well as BB isoforms of the ligand; the product of the earlier cloned PDGF receptor was termed type beta.
The PDFGRB gene is expressed in pericytes in the developing vascular walls of mouse brain (Lindahl et al., 1997). It is expressed particularly in the basal ganglia and dentate nucleus of the cerebellum (summary by Nicolas et al., 2013).
Di Pasquale et al. (2003) characterized 43 cell lines as permissive or nonpermissive for adeno-associated virus type 5 (AAV-5) transduction and compared the gene expression profiles derived from cDNA microarray analyses of those cell lines. A statistically significant correlation was observed between expression of PDGFR-alpha (173490) and AAV-5 transduction. Subsequent experiments confirmed the role of PDGFR-alpha and PDGFR-beta as receptors for AAV-5.
Gilbertson and Clifford (2003) presented data confirming that PDGFRB is preferentially expressed in metastatic medulloblastoma (155255) and suggested that it may prove useful as a prognostic marker and as a therapeutic target for the disease.
Svegliati Baroni et al. (2006) presented evidence showing that stimulatory autoantibodies to PDGFR are a specific hallmark of scleroderma (181750). These antibodies appeared to trigger an intracellular loop that involves Ras (190020), ERK1 (601795)/ERK2 (176948), and reactive oxygen species (ROS) and that leads to increased type I collagen (120150) expression. The authors suggested that the biologic activity of PDGFR antibodies on fibroblasts has a causal role in the pathogenesis of the disease. Tan (2006) suggested that the profibrotic phenotype of fibroblasts in patients with scleroderma is maintained by at least 3 mechanisms involving TGFB1 (190180), PDGFR, and the Ras-ERK1/ERK2-ROS cascade.
Greenberg et al. (2008) defined a role for VEGF (192240) as an inhibitor of neovascularization on the basis of its capacity to disrupt vascular smooth muscle cell function. Specifically, under conditions of PDGF-mediated angiogenesis, VEGF ablates pericyte coverage of nascent vascular sprouts, leading to vessel destabilization. At the molecular level, VEGF-mediated activation of VEGFR2 (191306) suppresses PDGFRB signaling in vascular smooth muscle cells through the assembly of a receptor complex consisting of PDGFRB and VEGFR2. Inhibition of VEGFR2 not only prevents assembly of this receptor complex but also restores angiogenesis in tissues exposed to both VEGF and PDGF. Finally, genetic deletion of tumor cell VEGF disrupts PDGFRB/VEGFR2 complex formation and increases tumor vessel maturation. Greenberg et al. (2008) concluded that their findings underscored the importance of vascular smooth muscle cells/pericytes in neovascularization and revealed a dichotomous role for VEGF and VEGFR2 signaling as both a promoter of endothelial cell function and a negative regulator of vascular smooth muscle cells and vessel maturation.
Nazarian et al. (2010) showed that acquired resistance of BRAF(V600E) (164757.0001)-positive melanomas to PLX4032, a novel class I RAF-selective inhibitor, develops by mutually exclusive PDGFRB upregulation or NRAS (164790) mutations but not through secondary mutations in BRAF(V600E). Nazarian et al. (2010) used PLX4032-resistant sublines artificially derived from BRAF(V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumors and tumor-matched, short-term cultures from clinical trial patients. Induction of PDGFRB RNA, protein, and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sublines, patient-derived biopsies, and short-term cultures. PDGFRB-upregulated tumor cells had low activated RAS levels and, when treated with PLX4032, did not reactivate the MAPK (see 176872) pathway significantly. In another subset, high levels of activated NRAS resulting from mutations led to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRB or NRAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRB or mutated NRAS conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, Nazarian et al. (2010) showed that MAPK reactivation predicts MEK inhibitor sensitivity. Thus, Nazarian et al. (2010) concluded that melanomas escape BRAF(V600E) targeting not through secondary BRAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.
Lui et al. (2014) analyzed differential gene coexpression relationships between mouse and human and demonstrated that the growth factor PDGFD (609673) is specifically expressed by radial glia in human, but not mouse, corticogenesis. Lui et al. (2014) also showed that the expression domain of PDGFRB is evolutionarily divergent, with high expression in the germinal region of dorsal human neocortex but not in the mouse. Pharmacologic inhibition of PDGFD-PDGFRB signaling in slice culture prevents normal cell cycle progression of neocortical radial glia in human, but not mouse. Conversely, injection of recombinant PDGFD or ectopic expression of constitutively active PDGFRB in developing mouse neocortex increases the proportion of radial glia and their subventricular dispersion. The authors concluded that their findings highlighted the requirement of PDGFD-PDGFRB signaling for human neocortical development and suggested that local production of growth factors by radial glia supports the expanded germinal region and progenitor heterogeneity of species with large brains.
Lee et al. (2019) modeled the LMNA-related dilated cardiomyopathy (CMD1A; 115200) in vitro using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). These cardiomyocytes were developed from a large family cohort, members of which carried a frameshift mutation in LMNA that led to early termination of translation. Electrophysiologic studies showed that the mutant iPSC-CMs displayed aberrant calcium homeostasis that led to arrhythmias at the single-cell level. Mechanistically, Lee et al. (2019) showed that the platelet-derived growth factor (PDGF) signaling pathway, in particular PDGFRB, is activated in mutant iPSC-CMs compared to isogenic control iPSC-CMs. Conversely, pharmacologic and molecular inhibition of the PDGF signaling pathway ameliorated the arrhythmic phenotypes of mutant iPSC-CMs in vitro. The findings of Lee et al. (2019) suggested that the activation of the PDGF pathway contributes to the pathogenesis of LMNA-related DCM, and that PDGFRB is a potential therapeutic target.
By Southern blotting of DNA from somatic cell hybrids and by in situ hybridization, Francke et al. (1986) mapped the gene for PDGFR to 5q31-q32. The gene is flanked proximally by GMCSF (138960) and distally by FMS (164770). All 3 loci may be implicated in the 5q- syndrome (153550). See also Yarden et al. (1986). Buchberg et al. (1989) cited unpublished observations indicating that Pdgfr is located on mouse chromosome 18.
The Treacher Collins Syndrome Collaborative Group (1996) determined that the PDGFRB gene is located within approximately 900 kb proximal of the TCOF1 gene (606847).
The PDGFRB gene and the CSF1R gene (164770) encode proteins that belong to the same subfamily of receptor tyrosine kinases (Yarden and Ullrich, 1988). Both genes are located on 5q and are linked physically in a head-to-tail array with less than 500 bp between the polyadenylation signal of the PDGFRB gene and the transcription start point of the CSF1R gene (Roberts et al., 1988). (This finding is inconsistent with the conclusion that the PDGFRB gene is located at 5q31-q32 and the presumed assignment of CSF1R to 5q33.2-q33.3. One of the assignments must be in error.) Close linkage of the 2 genes has been demonstrated also in the mouse and How et al. (1996) demonstrated that in the pufferfish (Fugu rubripes) the 2 genes are linked tandemly in a head-to-tail array with 2.2 kb of intragenic sequence.
Gross (2013) mapped the PDGFRB gene to chromosome 5q32 based on an alignment of the PDGFRB sequence (GenBank BC032224) with the genomic sequence (GRCh37).
PDGFRB Fusion Genes
Abe et al. (1997) reported that in a patient with acute myelogenous leukemia (AML; 601626), the TRIP11 gene (604505), which they called CEV14, was fused to the PDGFRB gene as a result of a t(5;14)(q33;q32) translocation. On initial diagnosis, this patient had exhibited a sole t(7;11) translocation, but the t(5;14)(q33;q32) translocation appeared during the relapse phase. The CEV14-PDGFRB chimeric gene consisted of the 5-prime region of CEV14 fused to the 3-prime region of PDGFRB.
Apperley et al. (2002) noted that a small proportion of patients with chronic myeloproliferative disorders have constitutive activation of the PDGFRB gene, resulting in many cases from a chromosome translocation such as t(5;12), which creates a fusion gene with ETV6 (600618). Fusions between PDGFRB and H4/D10S170 (601985), rabaptin-5 (RABPT5; 603616), and huntingtin-interacting protein-1 (HIP1; 601767) have also been reported in cases of chronic myeloproliferative disorders. The protein tyrosine kinase activity of PDGFRB, like that of ABL1 (189980) and KIT (164920), is inhibited by imatinib mesylate. The compound has been shown to be effective in the treatment of chronic myeloid leukemia (151410) and gastrointestinal stromal tumors (606764), which are caused by abnormalities in the ABL1 and KIT genes, respectively. Apperley et al. (2002) demonstrated that imatinib mesylate was also effective in the treatment of chronic myeloproliferative disorders with rearrangements of the PDGFRB gene. Three of 4 patients presented with leukocytosis and eosinophilia (see 131440), and their leukemia cells carried the ETV6-PDGFRB fusion gene.
Steer and Cross (2002) reviewed the acquired reciprocal chromosomal translocations that involve 5q31-q33 and are associated with a significant minority of patients with BCR-ABL-negative chronic myeloid leukemias. The most common of these fuses the ETV6 gene to the PDGFRB gene, but at the time of the review 4 additional partner genes were known: H4 (D10S170), HIP1, CEV14 (TRIP11), and rabaptin-5. Clinically, most patients present with a myeloproliferative disorder with eosinophilia, eosinophilic leukemia, or chronic myelomonocytic leukemia and thus fall into the broad category of myeloproliferative disorders/myelodysplastic syndromes (MPD/MDS). With the advent of targeted signal transduction therapy, patients with rearrangement of PDGFRB might be better classified as a distinct subgroup of MPD/MDS.
In 9 patients with BCR-ABL-negative chronic myeloproliferative disorders or MPD/MDS, Baxter et al. (2003) described translocations involving chromosome bands 5q31 or 5q33, resulting in fusion of the PDGFRB gene with other genes. They commented that several PDGFRB partner genes remained to be characterized.
Pierce et al. (2008) showed that expression of TEL/PDGFRB in murine myeloid FDCP-Mix cells prevented cell differentiation, increased cell survival, increased the level of phosphatidylinositol 3,4,5-trisphosphate (PtdInsP3), and increased the expression and phosphorylation of Thoc5 (612733). Elevated Thoc5 expression also led to increased cell survival and PtdInsP3 levels, suggesting that the effects associated with TEL/PDGFRB expression were due, at least in part, to Thoc5 upregulation.
Walz et al. (2009) reported a 51-year-old male with imatinib-responsive eosinophilia associated with atypical myeloproliferative neoplasm who presented with a t(5;17)(q33-34;q11.2). The translocation resulted in the fusion of MYO18A (610067) intron 40 to PDGFRB intron 9, and RT-PCR confirmed in-frame fusion between MYO18A exon 40 and PDGFRB exon 10. The predicted 2,661-amino acid chimeric protein contains almost all of the MYO18A sequence fused to the PDGFRB transmembrane, WW-like, and kinase domains. RT-PCR also detected the reciprocal PDGFRB-MYO18A transcript, with PDGFRB exon 9 fused to MYO18A exon 41.
Idiopathic Basal Ganglia Calcification 4
In affected members of a large 3-generation family with idiopathic basal ganglia calcification-4 (IBGC4; 615007), Nicolas et al. (2013) identified a heterozygous mutation in the PDGFRB gene (L658P; 173410.0001). The mutation, which was identified by exome sequencing of 2 affected individuals and confirmed by Sanger sequencing, segregated with the disorder in this family and was not found in several large exome databases. Many mutation carriers were asymptomatic, but 1 had late-onset parkinsonism and dementia, and several had depression or migraine. Nicolas et al. (2013) noted that animal models have shown a key role for Pdgfrb in the development of pericytes in vessels within the brain, and that pericytes have a key role in maintaining the integrity of the blood-brain barrier, which is hypothesized to be impaired in IBGC. In addition, the PDGFB-PDGFRB pathway appears to be involved in phosphate-induced calcifications in vascular smooth muscle cells by modulating expression of the phosphate transporter SLC20A1 (137570) (Villa-Bellosta et al., 2009); IBGC1 (213600) is caused by mutation in a related phosphate transporter SLC20A2 (158378). These findings suggest that cerebral phosphate homeostasis may play a role in vascular calcifications.
Infantile Myofibromatosis 1
In affected members of 4 unrelated families with infantile myofibromatosis-1 (IMF1; 228550), Cheung et al. (2013) identified the same heterozygous missense mutation in the PDGFRB gene (R561C; 173410.0003). The families were of Chinese, European, French Canadian, and French origin, respectively. The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing in the first 2 families, segregated with the phenotype in all families and was not found in several large control databases. In addition, tumor tissue from 1 of the patients who carried a germline R561C mutation harbored an additional somatic PDGFRB mutation (N666K) that was predicted to be damaging. Structural modeling indicated that the R561C mutation occurs in the cytoplasmic juxtamembrane (JM) region between the helical transmembrane segment and the kinase domain, and was predicted to compromise the autoinhibitory role of the JM domain, leading to increased kinase firing and promoting the formation of myofibromas in tissues with high PDGFRB signaling activity. Modeling also predicted that the N666K mutation would favor an active kinase formation. In vitro functional studies were not performed. Sequencing the PDGFRB gene in 5 individuals with nonfamilial IMF did not identify any causative mutations.
Martignetti et al. (2013) identified a heterozygous R561C mutation in the PDGFRB gene in affected members from 7 unrelated families with autosomal dominant infantile myofibromatosis. The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder and was not found in several large control databases. Another family with the disorder carried a different heterozygous mutation in the PDGFRB gene (P660T; 173410.0004).
Kosaki Overgrowth Syndrome
In 2 unrelated Japanese girls with overgrowth, facial dysmorphism, hyperelastic fragile skin, scoliosis, and neurologic deterioration (KOGS; 616592), Takenouchi et al. (2015) identified heterozygosity for a missense mutation in the PDGFRB gene (P584R; 173410.0005) that was de novo in each proband.
In 2 unrelated females with KOGS, Minatogawa et al. (2017) identified the same heterozygous missense mutation in the PDGFRB gene (W566R; 173410.0007). The mutation was identified by exome sequencing and confirmed by Sanger sequencing.
In a 10-year-old boy with KOGS, Gawlinski et al. (2018) identified de novo heterozygosity for the previously reported P584R mutation (173410.0005) in the PDGFRB gene. The mutation was identified by trio whole-exome sequencing. The patient had several characteristic features of KOGS, including typical facies, overgrowth, and tall stature, but also some progressive features not previously reported in this syndrome, suggesting expansion of the phenotype.
Premature Aging Syndrome, Penttinen Type
In 4 unrelated patients with the Penttinen type of premature aging syndrome (PENTT; 601812), Johnston et al. (2015) identified heterozygosity for a missense mutation in the PDGFRB gene (V665A; 173410.0006). The mutation arose de novo in the 2 probands for whom parental DNA was available.
In 2 unrelated patients with lipodystrophy, acroosteolysis, and severe vision impairment, reminiscent of a severe form of Penttinen syndrome, Bredrup et al. (2019) identified the same de novo missense mutation in the PDGFRB gene (N666S; 173410.0008). Functional studies using patient fibroblasts and transduced HeLa cells showed that the variant caused autophosphorylation of PDGFR-beta and induced phosphorylation of several downstream signaling proteins. Extensive apoptosis was seen in short-term patient-derived skin fibroblast cultures. Imatinib was a strong in vitro inhibitor of the mutant PDGFR-beta protein, suggesting an option for treatment of these patients.
Klinghoffer et al. (2001) created 2 complementary lines of knockin mice in which the intracellular signaling domains of one PDGFR had been removed and replaced by those of the other PDGFR. While both lines demonstrated substantial rescue of normal development, substitution of the Pdgfrb signaling domains with those of Pdgfra resulted in varying degrees of vascular disease.
Armulik et al. (2010) demonstrated a direct role of pericytes at the blood-brain barrier in vivo. Using a set of adult viable pericyte-deficient mouse mutants, they showed that pericyte deficiency increases the permeability of the blood-brain barrier to water and a range of low molecular mass and high molecular mass tracers. The increased permeability occurs by endothelial transcytosis, a process that is rapidly arrested by the drug imatinib. Furthermore, Armulik et al. (2010) showed that pericytes function at the blood-brain barrier in at least 2 ways: by regulating blood-brain barrier-specific gene expression patterns in endothelial cells, and by inducing polarization of astrocyte end-feet surrounding central nervous system (CNS) blood vessels. Armulik et al. (2010) concluded that their results indicated a novel and critical role for pericytes in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the blood-brain barrier.
Daneman et al. (2010) independently showed that the blood-brain barrier is formed during embryogenesis as endothelial cells invade the CNS and pericytes are recruited to the nascent vessels, over a week before astrocyte generation. Analyzing mice with null and hypomorphic alleles of Pdgfrb, which have defects in pericyte generation, they demonstrated that pericytes are necessary for the formation of the blood-brain barrier, and that absolute pericyte coverage determines relative vascular permeability. Daneman et al. (2010) demonstrated that pericytes regulate functional aspects of the blood-brain barrier, including the formation of tight junctions and vesicle trafficking in CNS endothelial cells. Pericytes do not induce blood-brain barrier-specific gene expression in CNS endothelial cells, but inhibit the expression of molecules that increase vascular permeability and CNS immune cell infiltration. Daneman et al. (2010) concluded that pericyte-endothelial cell interactions are critical to regulate the blood-brain barrier during development, and that disruption of these interactions may lead to blood-brain barrier dysfunction and neuroinflammation during CNS injury and disease.
In affected members of a large 3-generation family with idiopathic basal ganglia calcification-4 (IBGC4; 615007), Nicolas et al. (2013) identified a heterozygous 1973T-C transition in the PDGFRB gene, resulting in a leu658-to-pro (L658P) substitution at a highly conserved residue within the tyrosine kinase domain. The mutation, which was identified by exome sequencing of 2 affected individuals and confirmed by Sanger sequencing, segregated with the disorder in this family and was not found in several large exome databases. No functional studies were performed. Many mutation carriers were asymptomatic, but 1 had late-onset parkinsonism and dementia, and several had depression or migraine.
In a 66-year-old woman with sporadic occurrence of IBGC4 (615007), Nicolas et al. (2013) identified a heterozygous 2959C-T transition in the PDGFRB gene, resulting in an arg987-to-trp (R987W) substitution at a highly conserved residue. The mutation was not found in multiple exome databases. No functional studies were performed. The patient presented with a mild cognitive dysexecutive syndrome and bradykinesia and pyramidal signs.
In affected members of 4 unrelated families with infantile myofibromatosis-1 (IMF1; 228550), Cheung et al. (2013) identified a heterozygous c.1681C-T transition in the PDGFRB gene, resulting in an arg561-to-cys (R561C) substitution at a highly conserved residue. The families were of Chinese, European, French Canadian, and French origin, respectively. The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing in the first 2 families, segregated with the phenotype in all families and was not found in several large control databases. Structural modeling indicated that the R561C mutation occurs in the cytoplasmic juxtamembrane (JM) region between the helical transmembrane segment and the kinase domain, and was predicted to compromise the autoinhibitory role of the JM domain, leading to increased kinase firing and promoting the formation of myofibromas in tissues with high PDGFRB signaling activity. In vitro functional studies were not performed.
Martignetti et al. (2013) identified a heterozygous R561C mutation in the PDGFRB gene in affected members from 7 unrelated families with autosomal dominant infantile myofibromatosis. The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder and was not found in several large control databases.
In affected members of a family with autosomal dominant infantile myofibromatosis-1 (228550) originally reported by Zand et al. (2004), Martignetti et al. (2013) identified a heterozygous c.1978C-A transversion in exon 14 of the PDGFRB gene, resulting in a pro660-to-thr (P660T) substitution at a highly conserved residue in the tyrosine kinase domain. The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder and was found at very low frequency (0.000077) in control databases (rs144050370). In vitro functional studies were not performed.
In 2 unrelated Japanese girls with overgrowth, facial dysmorphism, hyperelastic fragile skin, scoliosis, and neurologic deterioration (KOGS; 616592), Takenouchi et al. (2015) identified de novo heterozygosity for a c.1751C-G transversion (c.1751C-G, NM_002609) in exon 12 of the PDGFRB gene, resulting in a pro584-to-arg (P584R) substitution at a highly conserved residue within the juxtamembrane domain. One of the girls had a myofibroma removed from her mandible at age 8 years. Brain MRI showed extensive periventricular white matter lesions in both patients, but there was no evidence of intracranial calcification on CT scan.
In a 10-year-old boy with KOGS, Gawlinski et al. (2018) identified de novo heterozygosity for the P584R mutation in the PDGFRB gene. The mutation was identified by trio whole-exome sequencing. The patient had several characteristic features of KOGS, including typical facies, overgrowth, and tall stature, but also some progressive features such as premature aging and lipodystrophy beginning at age 8 years. At age 10 years, he did not have psychiatric manifestations, myofibroma, or neurologic deterioration.
In 4 unrelated patients with the Penttinen type of premature aging syndrome (PENTT; 601812), including the Finnish patient originally described by Penttinen et al. (1997) and a girl of North Vietnamese and Chinese ancestry previously reported by Zufferey et al. (2013), Johnston et al. (2015) identified heterozygosity for a c.1994T-C transition (c.1994T-C, NM_002609.3) in the PDGFRB gene, resulting in a val665-to-ala (V665A) substitution within the kinase domain. The mutation arose de novo in the 2 probands for whom parental DNA was available. Functional analysis in transfected HeLa cells demonstrated ligand-independent constitutive signaling through STAT3 (102582) and PLC-gamma (see 172420), indicating that V665A represents a gain-of-function alteration.
In 2 unrelated females with Kosaki overgrowth syndrome (KOGS; 616592), Minatogawa et al. (2017) identified heterozygosity for a c.1696T-C transition (c.1696T-C, NM_002609.3) in exon 12 of the PDGFRB gene, resulting in a trp566-to-arg (W566R) substitution in the juxtamembrane domain. The mutation was found by exome sequencing and confirmed by Sanger sequencing. The mutation occurred de novo in patient 1, and was not present in the unaffected mother and sister of patient 2. The variant was not present in the ExAC and gnomAD databases.
In 2 unrelated patients with lipodystrophy, acroosteolysis, and severe vision impairment, reminiscent of a severe form of Penttinen syndrome (PENTT; 601812), Bredrup et al. (2019) identified a de novo c.1997A-G transition (c.1997A-G, NM_002609.3) in the PDGFRB gene, resulting in an asn666-to-ser (N666S) substitution. The variant was found by whole-genome and Sanger sequencing. Functional studies using patient fibroblasts and transduced HeLa cells showed that the variant caused autophosphorylation of PDGFR-beta and induced phosphorylation of several downstream signaling proteins. Extensive apoptosis was seen in short-term patient-derived skin fibroblast cultures. Imatinib was a strong in vitro inhibitor of the mutant PDGFR-beta protein, suggesting an option for treatment of these patients.
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