Alternative titles; symbols
HGNC Approved Gene Symbol: DCC
Cytogenetic location: 18q21.2 Genomic coordinates (GRCh38): 18:52,340,197-53,535,899 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q21.2 | Colorectal cancer, somatic | 114500 | 3 | |
| Esophageal carcinoma, somatic | 133239 | 3 | ||
| Gaze palsy, familial horizontal, with progressive scoliosis, 2 | 617542 | Autosomal recessive | 3 | |
| Mirror movements 1 and/or agenesis of the corpus callosum | 157600 | Autosomal dominant | 3 |
The DCC gene encodes a functional receptor for netrin (NTN1; 601614) and mediates axon outgrowth and the steering response (summary by Li et al., 2004).
Vogelstein et al. (1988) found that chromosome 18 sequences were lost frequently in colorectal carcinomas (73%) and in advanced adenomas (47%), but only occasionally in earlier-stage adenomas (11 to 13%). Taken in connection with other findings of changes in chromosome 17, as well as chromosome 5, these findings suggested a model wherein the steps required for malignancy often involve the activation of a dominantly acting oncogene coupled with the loss of several genes that normally suppress tumorigenesis. The critical area in chromosome 18 appeared to reside between 18q21.3 and the telomere.
Fearon et al. (1990) cloned a contiguous stretch of DNA, comprising 370 kb, from the region of 18q suspected to contain the tumor suppressor gene. Potential exons in the 370-kb region were defined by human-rodent sequence identities, and the expression of potential exons was assessed by an 'exon-connection' strategy based on the polymerase chain reaction. Expressed exons were used as probes for screening of cDNA to obtain clones that encoded a gene the authors termed DCC ('deleted in colorectal carcinomas'). This cDNA was encoded by at least 8 exons. The predicted amino acid sequence specified a protein with sequence similarity to neural cell adhesion molecules (116930) and related cell surface glycoproteins. While the DCC gene was expressed in most normal tissues, including colonic mucosa, its expression was greatly reduced or absent in most colorectal carcinomas tested. Somatic mutations within the DCC gene observed in colorectal cancers included a homozygous deletion of the 5-prime end, a point mutation within one of the introns, and 10 examples of DNA insertions within a 0.17-kb fragment immediately downstream of 1 of the exons.
In the embryonic mouse brain, Jamuar et al. (2017) found expression of the Dcc gene in the telencephalic cortical plate as well as in the developing brainstem nuclei.
Cho et al. (1994) commented that the DCC gene encodes a protein with sequence similarity to cell adhesion molecules such as N-CAM (116930). Studying a YAC contig containing the entire DCC coding region, they showed that the DCC gene spans approximately 1.4 Mb. They used lambda phage clones to demonstrate the existence of 29 DCC exons, and the sequences of the exon-intron boundaries were determined.
Crystal Structure
Xu et al. (2014) determined the structures of a functional NTN1 (601614) region, alone and in complexes with NEO1 (601907) and DCC. NTN1 has a rigid elongated structure containing 2 receptor-binding sites at opposite ends through which it brings together receptor molecules. The ligand/receptor complexes reveal 2 distinct architectures: a 2:2 heterotetramer and a continuous ligand/receptor assembly. The differences result from different lengths of the linker connecting receptor domains fibronectin type III domain 4 (FN4) and FN5, which differs among DCC and NEO1 splice variants, providing a basis for diverse signaling outcomes.
Using molecular markers in an interspecific backcross between C57BL/6J and Mus spretus, Justice et al. (1992) mapped the corresponding gene to mouse chromosome 18.
Vogelstein (1995) stated that the precise location of the DCC gene was thought to be 18q21.3.
Thiagalingam et al. (1996) evaluated sporadic colon cancer tumors for allelic deletions. They defined a minimally lost region (MLR) on chromosome 18q21 which extended between markers D18S535 and D18S858. It encompassed 16 cM between D18S535 and 20CO3 and included 2 candidate tumor suppressor genes: DPC4 (600993) and DCC. DPC4 was deleted in up to one-third of cases and DCC or a neighboring gene was deleted in the remaining tumors.
Keino-Masu et al. (1996) noted that the establishment of neuronal connections involves the accurate guidance of developing axons to their targets through the combined actions of attractive and repulsive guidance cues in the extracellular environment. Diffusible chemoattractants secreted by target cells are involved, as well as diffusible chemorepellents secreted by nontarget cells which generate exclusion zones that axons avoid (Keynes and Cook, 1995). Two families of guidance molecules, the netrins (see netrin-1, 601614) and semaphorins (see 601281 and 601124), are proteins that can function as diffusible attractants or repellents for developing neurons, but the receptors and signal transduction mechanisms through which they produce their effects are poorly understood. Netrins are chemoattractants for commissural axons in the vertebral spinal cord. Keino-Masu et al. (1996) showed that DCC, a transmembrane protein of the immunoglobulin superfamily, is expressed on spinal commissural axons and possesses netrin-1-binding activity. Moreover, an antibody to DCC selectively blocked the netrin-1-dependent outgrowth of commissural axons in vitro. These results indicated that DCC is a receptor or a component of a receptor that mediates the effects of netrin-1 on commissural axons, and they complement genetic evidence for interactions between DCC and netrin homologs in C. elegans (UNC40; see Chan et al., 1996) and Drosophila (frazzled; see Kolodziej et al., 1996).
Using RT-PCR, Gotley et al. (1996) detected DCC mRNA in all colonic tissue specimens through all stages of tumor development. Using monoclonal antibodies against DCC, they found DCC protein is abundant in normal human bladder and is detectable in colon, pancreas and kidney, but not in liver. DCC protein could be detected in varying abundance in all specimens of normal colonic mucosa analyzed as well as in all specimens of adenomatous polyps, colorectal carcinoma and colorectal liver metastases. In some patients, tumor tissue contained less DCC protein than the adjacent normal mucosa. Gotley et al. (1996) found no cases of complete loss of DCC mRNA or protein in colon cancers or metastases.
Mehlen et al. (1998) showed that DCC induces apoptosis in the absence of ligand binding, but blocks apoptosis when engaged by netrin-1. Furthermore, DCC is a caspase substrate, and mutation of the site at which caspase-3 (CASP3; 600636) cleaves DCC suppresses the proapoptotic effect of DCC completely. These results indicated the DCC may function as a tumor-suppressor protein by inducing apoptosis in settings in which ligand is unavailable (for example, during metastasis or tumor growth beyond local blood supply) through functional caspase cascades by a mechanism that requires cleavage of DCC at asp1290.
The axonal chemoattractant netrin-1 guides spinal commissural axons by activating its receptor DCC. Galko and Tessier-Lavigne (2000) found that chemical inhibitors of metalloproteases potentiate netrin-mediated axon outgrowth in vitro. Galko and Tessier-Lavigne (2000) also found that DCC is a substrate for metalloprotease-dependent ectodomain shedding, and that the inhibitors block proteolytic processing of DCC and cause an increase in DCC protein levels on axons within spinal cord explants. Thus, Galko and Tessier-Lavigne (2000) suggested that potentiation of netrin activity by inhibitors may result from stabilization of DCC on the axons, and proteolytic activity may regulate axon migration by controlling the number of functional extracellular axon guidance receptors.
Stein et al. (2001) demonstrated that netrin-1 binds DCC and that the DCC cytoplasmic domain fused to a heterologous receptor ectodomain can mediate guidance through a mechanism involving derepression of cytoplasmic domain multimerization. Activation of the adenosine A2B receptor (600446), proposed to contribute to netrin effects on axons, is not required for rat commissural axon outgrowth or Xenopus spinal axon attraction to netrin-1. Thus, Stein et al. (2001) concluded that DCC plays a central role in netrin signaling of axon growth and guidance independent of A2B receptor activation. Note that an expression of concern has been published for the article by Stein et al. (2001).
Axonal growth cones that cross the nervous system midline change their responsiveness to midline guidance cues: they become repelled by the repellent Slit (603746) and simultaneously lose responsiveness to the attractant netrin. These mutually reinforcing changes help to expel growth cones from the midline by making a once-attractive environment appear repulsive. Stein and Tessier-Lavigne (2001) provided evidence that these 2 changes are causally linked: in the growth cones of embryonic Xenopus spinal axons, activation of the Slit receptor Roundabout (Robo; 602430) silences the attractive effect of netrin-1, but not its growth-stimulatory effect, through direct binding of the cytoplasmic domain of Robo to that of the netrin receptor DCC. Biologically, this hierarchical silencing mechanism helps to prevent a tug-of-war between attractive and repulsive signals in the growth cone that might cause confusion. Molecularly, silencing is enabled by a modular and interlocking design of the cytoplasmic domains of these potentially antagonistic receptors that predetermines the outcome of their simultaneous activation. Note that an expression of concern was published for the article by Stein and Tessier-Lavigne (2001).
Forcet et al. (2002) showed that in embryonic kidney cells expressing full-length, but not cytoplasmic domain-truncated, DCC, NTN1 causes increased transient phosphorylation and activity of ERK1 (601795) and ERK2 (176948), but not of JNK1 (601158), JNK2 (602896), or p38 (MAPK14; 600289). This phosphorylation was mediated by MEK1 (MAP2K1; 176872) and/or MEK2 (MAP2K2; 601263). NTN1 also activated the transcription factor ELK1 (311040) and serum response element-regulated gene expression. Immunoprecipitation analysis showed interaction of full-length DCC with MEK1/2 in the presence or absence of NTN1. Forcet et al. (2002) showed that activation of Dcc by Ntn1 in rat embryonic day-13 dorsal spinal cord stimulates and is required for the outgrowth of commissural axons and Erk1/2 activation. Immunohistochemical analysis demonstrated expression of activated Erk1/2 in embryonic commissural axons, and this expression was diminished in Dcc or Ntn1 knockout animals. Forcet et al. (2002) concluded that the MAPK pathway is involved in responses to NTN1 and proposed that ERK activation affects axonal growth by phosphorylation of microtubule-associated proteins and neurofilaments.
Nishiyama et al. (2003) reported that the ratio of cyclic AMP to cyclic GMP activities sets the polarity of netrin-1-induced axon guidance: high ratios favor attraction, whereas low ratios favor repulsion. Whole-cell recordings of calcium currents in Xenopus spinal neuron growth cones indicated that cyclic nucleotide signaling directly modulates the activity of L-type calcium channels in axonal growth cones. Furthermore, cyclic GMP signaling activated by an arachidonate 12-lipoxygenase metabolite suppressed L-type calcium channel activity triggered by netrin-1 and was required for growth cone repulsion mediated by the DCC-UNC5 (see 603610) receptor complex. By linking cyclic AMP and cyclic GMP signaling and modulation of calcium channel activity in growth cones, these findings delineated an early membrane-associated event responsible for signal transduction during bidirectional axon guidance.
Mehlen et al. (1998) showed that DCC induces apoptosis conditionally: by functioning as a dependence receptor, DCC induces apoptosis unless it is engaged by its ligand netrin-1. Mazelin et al. (2004) demonstrated that inhibition of cell death by enforced expression of netrin-1 in mouse gastrointestinal tract led to the spontaneous formation of hyperplastic and neoplastic lesions. Moreover, in the adenomatous polyposis coli mutant background associated with adenoma formation, enforced expression of netrin-1 engendered aggressive adenocarcinomatous malignancies. Mazelin et al. (2004) concluded that netrin-1 can promote intestinal tumor development, probably by regulating cell survival. Thus, a netrin-1 receptor or receptors function as conditional tumor suppressors.
Netrin proteins play a role in the developing nervous system by promoting both axonal outgrowth and axonal guidance in pathfinding. Liu et al. (2004), Li et al. (2004), and Ren et al. (2004) simultaneously reported a complex network of intracellular signaling downstream from netrin-1 (601614) involving DCC, focal adhesion kinase (FAK; 600758), and FYN (137025), a member of the SRC family kinases (see 190090). In neurons cultured from rat cerebral cortex, Liu et al. (2004) found that netrin-1 induced tyrosine phosphorylation of FAK and FYN, and coimmunoprecipitation studies showed direct interaction of FAK and FYN with DCC. Inhibition of FYN inhibited FAK phosphorylation, and FYN mutants inhibited the attractive turning responses to netrin. Neurons lacking the FAK gene showed reduced axonal outgrowth and attractive turning responses to netrin. In cultured neurons from chick and mouse, Li et al. (2004) found that netrin increased tyrosine phosphorylation of DCC and FAK. Coimmunoprecipitation studies showed that DCC interacted directly with FAK and SRC to form a complex and that FAK and SRC cooperated to stimulate DCC phosphorylation by SRC. Li et al. (2004) suggested that phosphorylated DCC acts as a kinase-coupled receptor and that FAK and SRC act downstream of DCC in netrin signaling. Ren et al. (2004) found that inhibition of FAK phosphorylation inhibited netrin-1-induced axonal outgrowth and guidance. The authors suggested that FAK may also function as a scaffolding protein and play a role in cytoskeletal reorganization that is necessary for neurite outgrowth and turning.
Colon-Ramos et al. (2007) showed that connectivity between 2 interneurons in C. elegans, AIY and RIA, is orchestrated by a pair of glial cells that express UNC6 (netrin-1). In the postsynaptic neuron RIA, the netrin receptor UNC40 (DCC) plays a conventional guidance role directing outgrowth of the RIA process ventrally toward the glia. The authors determined that in the presynaptic neuron AIY, UNC40 plays an unexpected and theretofore uncharacterized role: it cell-autonomously promotes assembly of presynaptic terminals in the immediate vicinity of the glial cell endfeet. Colon-Ramos et al. (2007) concluded that netrin can be used both for guidance and local synaptogenesis and suggested that glial cells can function as guideposts during the assembly of neural circuits in vivo.
Tcherkezian et al. (2010) found that Ddc partly colocalized with the translational machinery in embryonic mouse spinal commissural axon growth cones and in rat hippocampal neuron dendrites. Ddc coprecipitated with components of translation machinery in transfected 293 cells, and this coprecipitation required the Ddc intracellular domain. Ddc associated particularly with translation initiation components. Mutation analysis and mass spectrometry revealed that the P1 motif of the Ddc intracellular domain interacted specifically and directly with ribosomal protein L5 (RPL5; 603634). Labeling studies revealed that Ddc overlapped with newly synthesized proteins at the tips of commissural neuron filopodia and in hippocampal neurons. Netrin-1 promoted translation in a Ddc-dependent manner and reduced association of Ddc with translation components.
Congenital Mirror Movements 1 and/or Agenesis of the Corpus Callosum
Srour et al. (2010) identified 2 frameshift mutations in the DCC gene in 2 families with congenital mirror movements (MRMV1; 157600). In a large French Canadian family, they identified a splice site mutation in intron 6 leading to a frameshift and exon skipping (120470.0003), and in an Iranian family they identified a single-nucleotide insertion in exon 3 (120470.0004). Srour et al. (2010) proposed that DCC mutations in individuals with congenital mirror movements cause a reduction in gene dosage and less robust midline guidance, which may lead to a partial failure of axonal fiber crossing and development of abnormal ipsilateral connection.
In individuals from 4 unrelated multigenerational families with congenital mirror movements and/or agenesis of the corpus callosum, Marsh et al. (2017) identified heterozygous mutations in the DCC gene (120470.0006-120470.0009). The mutations were found by a combination of methods, including linkage analysis, whole-exome sequencing, and direct sequencing. Two mutations were truncating mutations, predicted to result in haploinsufficiency, and 2 were missense mutations affecting the netrin-1 binding domain. Heterozygous missense DCC mutations were subsequently found in 5 of 70 probands with isolated ACC. Functional studies of the variants and studies of patient cells were not performed. In a review of individuals with mutations in the DCC gene in their study and in the literature, Marsh et al. (2017) found significant incomplete penetrance: the penetrance of mirror movements was estimated to be 42%, and the penetrance of ACC was estimated to be 26%. There was some evidence for a male bias in phenotypic manifestations, and in vitro studies suggested that androgens could influence DCC expression. Marsh et al. (2017) concluded that there are additional genetic, epigenetic, and environmental factors that influence the expression of the disorder, including developmental differences between the corpus callosum and corticospinal tract. Corticospinal axons and callosal axons use slightly different signaling to approach and cross midline, such that a DCC mutation may differentially affect commissural versus subcerebral axon trajectories, resulting in the variable features of mirror movements, ACC, or both. Mirror movements were consistently associated with decreased crossing of descending corticospinal tract projections at the pyramidal decussation; ACC was associated with absence of the hippocampal commissure and cingulate gyri, as well as and dysmorphic lateral ventricles. The individuals had normal to borderline intellectual disability and a more favorable outcome compared to the developmental outcomes associated with syndromic forms of ACC. Marsh et al. (2017) concluded that prenatal detection of isolated ACC related to a pathogenic DCC mutation is indicative of a lower risk of a poor neurodevelopmental outcome.
In 5 members of an Ethiopian Jewish family with MRMV1, Sagi-Dain et al. (2020) identified heterozygosity for a frameshift mutation in the DCC gene (120470.0012). The mutation, which was found by whole-exome sequencing, was also identified in an asymptomatic female family member. A fetus with agenesis of the corpus callosum from a terminated pregnancy in this family was not tested for the mutation.
Familial Horizontal Gaze Palsy with Progressive Scoliosis 2 with Impaired Intellectual Development
In 3 patients from 2 unrelated families with familial horizontal gaze palsy with progressive scoliosis-2 with impaired intellectual development (HGPPS2; 617542), Jamuar et al. (2017) identified homozygous intragenic deletions in the DCC gene (120470.0010-120470.0011), both resulting in premature termination and functional null alleles. The deletion in the first family was found by a combination of homozygosity mapping and CNV analysis; the deletion in the second family was found by targeted sequencing of the DCC gene. The patients had agenesis of the corpus callosum, absence of the anterior and hippocampal commissures, hypoplasia of the pons and midbrain, and midline cleft throughout the brainstem, contributing to a butterfly-shaped medulla. The findings confirmed that DCC is essential for both forebrain and brainstem midline crossing in the human central nervous system. An unrelated patient with ACC and mild intellectual disability was found to have a homozygous missense variant in the DCC gene (Q691K) at a conserved residue in the third fibronectin repeat, but no clinical information was available and functional studies of the variant were not performed.
Loss of Heterozygosity in Tumors
In a study of 28 cases of surgically resected gastric cancer, excluding the diffuse type, Uchino et al. (1992) concluded that loss of heterozygosity (LOH) on chromosome 18q occurs at an earlier stage than LOH on chromosome 17p and that tumor suppressor genes located on these 2 chromosome arms are critically involved in the development of most gastric cancers. Involvement of DCC may be rather selective for gastrointestinal cancers.
Hohne et al. (1992) presented evidence that loss of DCC gene expression is an important factor in the development or progress of pancreatic adenocarcinoma. In 8 of 11 pancreatic carcinoma cell lines and in 4 of 8 primary ductal adenocarcinomas of the pancreas, a complete extinction of DCC gene expression was observed, whereas the KRAS gene (190070) was mutated at codon 12 in 7 of the 8 primary tumors. Reduced or absent DCC expression tended to be associated with undifferentiated pancreatic tumor cell lines, whereas in the more differentiated ones, DCC expression was conserved.
In a panel of primary colorectal tumors, Cho et al. (1994) found that most had lost the region containing DCC.
The DCC protein has structural features in common with certain types of cell-adhesion molecules and may participate with other proteins in cell-cell and cell-matrix interactions. Zetter (1993) found that expression of the DCC gene was absent in most colorectal cancers that were metastatic to the liver, but was lost only in a minority of nonmetastatic cancers. Furthermore, Jen et al. (1994) found that allelic loss of 18q in the region occupied by the DCC gene carried a worse prognosis than that in cases with no loss of chromosome 18q. They developed procedures to examine the status of 18q with microsatellite markers and PCR-amplified DNA from formalin-fixed, paraffin-embedded tumors. Normal tissue and tumor tissue could be examined on the same microscopic slide. Allelic loss of 18q was assessed in 145 consecutively resected stage II or III colorectal carcinomas. The prognosis in patients with stage II cancer (Dukes stage B; tumor extending through the bowel wall, without lymph-node metastasis) was similar to that in patients with stage III cancer, who were thought to benefit from adjuvant therapy. In contrast, patients with stage II disease who did not have chromosome 18q allelic loss in their tumor had a survival rate similar to that of patients with stage I disease and might not require additional therapy.
Shibata et al. (1996) reported findings that extended the observations of Jen et al. (1994), who had found that allelic loss of 18q predicted a poor outcome in patients with stage II colorectal cancer. They studied the DCC gene as a possible specific prognostic marker. Expression of DCC was evaluated immunohistochemically in 132 paraffin-embedded samples from patients with curatively resected stage II or stage III colorectal carcinomas. They found that expression of DCC was a strong positive predictive factor for survival in both stage II and stage III colorectal carcinomas. In patients with stage II disease whose tumors expressed DCC, the 5-year survival rate was 94.3%, whereas in patients with DCC-negative tumors, the survival rate was 61.6%. In patients with stage III disease, the respective survival rates were 59.3% and 33.2%.
Maesawa et al. (1996) screened tumor specimens from 111 patients with esophageal squamous cell carcinoma for LOH at the DCC locus and observed LOH in 10 of 61 informative cases (16%). No statistically significant correlation was observed between DCC-LOH and lymph node metastasis, histopathologic grade, or tumor stage. Survivorship of DCC-LOH patients was not statistically different from that of patients without LOH. These results suggested to Maesawa et al. (1996) that LOH at the DCC locus is not related to the acquisition of metastatic potential or the state of tumor cell differentiation in esophageal squamous cell carcinoma.
Somatic Mutations
Cho et al. (1994) found a somatic missense mutation in a colorectal tumor (120470.0001).
Miyake et al. (1994) identified somatic missense mutations and loss of heterozygosity in esophageal tumors (see 120470.0002).
Using exome sequencing, Wei et al. (2011) identified a recurrent somatic gly55-to-glu (G55E) mutation in the DCC gene in 3 (2%) of 167 melanoma (see 155600) samples.
Associations Pending Confirmation
For discussion of a possible association between variation in the DCC gene and hypogonadotropic hypogonadism, see 147950.
Finger et al. (2002) described a spontaneous mutation in mice, 'kanga,' that resulted in mild to severe inability to maintain an upright position. Mutant mice often moved their hind legs in a concerted manner, resulting in a somewhat hopping gait. Finger et al. (2002) found that the kanga phenotype results from deletion of exon 29 of the Dcc gene. Immunohistochemical analysis revealed that the corticospinal tract of kanga/kanga mice showed abnormalities at the pyramidal decussation. While homozygous mutation of the Dcc gene disrupted the decussation of all corticospinal tract axons, in Unc5h3 (603610)-mutant mice corticospinal tract fibers that crossed the midline were found in the contralateral lateral funiculus but not the ventral funiculus. Finger et al. (2002) also found that Unc5h3 and Dcc act synergistically in guiding corticospinal tract axons.
To help elucidate the functions of the DCC gene and to test the suggestion that it functions as a receptor for the axonal chemoattractant netrin-1, Fazeli et al. (1997) inactivated the DCC homolog in the mouse genome through use of homologous recombination and studied the effects of this inactivation on both the intestine and the developing nervous system. They found defects in axonal projections that were similar to those observed in netrin-1-deficient mice, but there was no effect on growth, differentiation, morphogenesis, or tumorigenesis in mouse intestine. These observations failed to support a tumor-suppressor function for DCC in the mouse, but were consistent with the hypothesis that DCC is a component of the receptor for netrin-1.
Using wildtype and Dcc -/- mouse embryos, Shi et al. (2008) found that Dcc was expressed in neurons of the locus ceruleus and that Dcc was required for normal locus ceruleus development. Locus ceruleus-specific gene expression was normal in Dcc-null embryos, but the initiation of tangential migration of locus ceruleus neurons was delayed. Subsequently, locus ceruleus neurons in Dcc-null mice were misdirected to the pons or ectopically located in the cerebellum. Migration of locus ceruleus neurons and the morphology of the locus ceruleus was not compromised in kanga/kanga mice, demonstrating that the C-terminal domain required for commissural axon guidance is not necessary for the proper development of the locus ceruleus.
To investigate the role of DCC-induced apoptosis in the control of tumor progression, Castets et al. (2011) created a mouse model in which the proapoptotic activity of DCC is genetically silenced. Although the loss of DCC-induced apoptosis in this mouse model was not associated with a major disorganization of the intestines, it led to spontaneous intestinal neoplasia at a relatively low frequency. Loss of DCC-induced apoptosis was also associated with an increase in the number and aggressiveness of intestinal tumors in a predisposing APC (611731) mutant context, resulting in the development of highly invasive adenocarcinomas. Castets et al. (2011) concluded that DCC functions as a tumor suppressor via its ability to trigger tumor cell apoptosis.
Krimpenfort et al. (2012) showed that in a mouse model of mammary carcinoma based on somatic inactivation of p53 (191170), additional loss of DCC promotes metastasis formation without affecting the primary tumor phenotype. Furthermore, they demonstrated that in cell cultures derived from p53-deficient mouse mammary tumors, DCC expression controls netrin-1 (601614)-dependent cell survival, providing a mechanistic basis for the enhanced metastatic capacity of tumor cells lacking DCC. Consistent with this idea, in vivo tumor cell survival is enhanced by DCC loss. Krimpenfort et al. (2012) concluded that their data supported the function of DCC as a context-dependent tumor suppressor that limits survival of disseminated tumor cells.
It is of interest that Lynch et al. (1985) found a lod score of 3.19 for linkage between a familial cancer syndrome (Lynch syndrome II; 120435) and Kidd blood group (JK; 111000); the Kidd blood group has been assigned to 18q11-q12.
Bowman et al. (1988) found tumor-specific allele loss at the D18S6 locus on chromosome 18 in 2 patients with familial adenomatous polyposis and in 2 patients with sporadic colon cancer. D18S6 is closely linked to LCFS2 and JK.
Tanaka et al. (1991) demonstrated that transfer of a normal human chromosome 18 into a colon carcinoma cell line through microcell hybridization severely reduced the cloning efficiency of the hybrid cells in soft agar and completely suppressed tumorigenicity in athymic nude mice. Similar results were obtained when a normal chromosome 5, which carries the locus for adenomatous polyposis coli (611731), was transferred into the cells, but the growth properties of the hybrid cells were unchanged when chromosome 11 was introduced.
Nigro et al. (1991) observed a curious phenomenon of scrambled exons in the DCC gene in a variety of normal and neoplastic cells of rodent and human origin. Abnormally spliced transcripts showed that exons were joined accurately at consensus splice sites, but in an order different from that present in the primary transcript. Thus, a novel type of RNA product resulted.
To look for structural alterations of the DCC gene, Cho et al. (1994) analyzed 60 colorectal cancers matched with normal DNA samples from the same individual, using Southern blot hybridization to DCC cDNA probes. In 1 tumor, an altered pattern of EcoRI fragments was found and shown to have its basis in a somatically acquired point mutation in intron 13. The sequences flanking the mutation had features suggestive of an exon, including a short open reading frame and consensus splice acceptor and donor sites. These findings suggested that the tumor contained a mutation in an alternatively utilized exon. To search for more subtle alterations, Cho et al. (1994) evaluated several exons and their flanking intron sequences for the presence of mutations in 30 colorectal cancers by an RNase protection assay. A C-to-A transversion at position 4124 in exon 28 was identified in 1 tumor. This mutation was predicted to result in a nonconservative amino acid change from proline to histidine. It was absent from the DNA of normal lymphocytes from the same patient.
Since the tumor suppressor gene DCC shows amino acid sequence homology to the neural cell adhesion molecule (116930), Miyake et al. (1994) considered the possibility that DCC might be related to tumor metastasis. They examined 51 cases of primary esophageal carcinoma for point mutations and loss of the gene. By screening using PCR-single strand conformation polymorphism analysis, they found point mutations in 2 cases. One case with lymph node metastasis showed an ATG-(met)-to-ACC-(thr) missense mutation in codon 168. Another case showed a CGA (arg)-to-GGA (gly) mutation in codon 201, which might be a polymorphic change, and 2 other mutations resulting in no amino acid change. Forty-four of the 51 cases (86%) were informative for loss of heterozygosity of the DCC gene; of these, 10 (23%) showed allelic deletion. The further away the lymph node metastasis was from the primary tumor, the higher the frequency of allelic deletions. They also found allelic deletions in moderately and poorly differentiated squamous cell carcinomas but not in well-differentiated ones. They interpreted these findings to indicate that alterations in the DCC gene are related to the degree of lymph node metastasis and the degree of differentiation.
In a large 4-generation French Canadian family segregating autosomal dominant congenital mirror movements (MRMV1; 157600) with incomplete penetrance, Srour et al. (2010) identified a G-to-A transition at nucleotide 1140 of the DCC gene, at the splice donor site of intron 6 (1140+1G-A). This mutation led to skipping of exon 6 and a frameshift after amino acid 329 with the introduction of a stop codon 15 amino acids further down the new reading frame (Val329GlyfsTer15). This mutation segregated with the risk haplotype and was not found in 760 unrelated Caucasian controls, including 512 French Canadians. Copy number variation analysis in 315 French Canadian controls did not reveal any structural variations encompassing DCC exons.
In a 5-generation Iranian family with congenital mirror movements (MRMV1; 157600), initially described by Sharafaddinzadeh et al. (2008), Srour et al. (2010) identified insertion of a guanine at nucleotide 571 in exon 3 of the DCC gene, resulting in frameshift with a termination codon 35 amino acids later (571dupG; Val191GlyfsTer35). This mutation was absent in 538 unrelated control individuals.
In 4 affected members of a 3-generation Italian family with congenital mirror movements (MRMV1; 157600), Depienne et al. (2011) identified a heterozygous 2-bp deletion (3835delCT) in exon 26 of the DCC gene, resulting in a frameshift and premature termination. The patients had onset in infancy or early childhood of involuntary mirror movements affecting the upper limbs and hands. Three had a stable condition; 1 had mild improvement during childhood. The mutation likely resulted in nonsense-mediated mRNA decay and haploinsufficiency. The mutation was not found in 340 control chromosomes.
In 7 members of a 3-generation family (family 3) with congenital mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600), Marsh et al. (2017) identified a heterozygous c.823C-T transition (c.823C-T, NM_005215.3) in the DCC gene, resulting in an arg275-to-ter (R275X) substitution in the N-terminal extracellular domain. The mutation was not found in the dbSNP, 1000 Genomes Project, or ExAC databases. The family was originally reported by Meneret et al. (2014) as having congenital mirror movements, but was not described in detail. According to the pedigree provided by Marsh et al. (2017), there were 7 confirmed mutation carriers in the family, including 2 (a male and female) with mirror movements and partial ACC, 3 (2 males and a female) with isolated mirror movements with normal brain imaging, 1 female with complete ACC and without mirror movements, and 1 unaffected female mutation carrier, indicating incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed.
In affected members of a large multigenerational family (family 1) with congenital mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600), Marsh et al. (2017) identified a heterozygous 1-bp deletion (c.925delA, NM_005215.3) in the DCC gene, resulting in a frameshift and premature termination (Thr309ProfsTer26) in the N-terminal extracellular domain. The mutation, which was found by a combination of linkage analysis and exome sequencing, was confirmed by Sanger sequencing. It was not found in the dbSNP, 1000 Genomes Project, or ExAC databases. The mutation segregated with the disorder in the family, but there was evidence of incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed.
In affected members of a 3-generation family (family 2) with congenital mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600), Marsh et al. (2017) identified a heterozygous c.2378T-G transversion (c.2378T-G, NM_005215.3) in the DCC gene, resulting in a val793-to-gly (V793G) substitution in the netrin-1 binding domain. The mutation, which was found by a combination of linkage analysis and exome sequencing, was confirmed by Sanger sequencing. It was not found in the dbSNP, 1000 Genomes Project, or ExAC databases. The mutation segregated with the disorder in the family, but there was evidence of incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to be disruptive.
In 4 members of a 3-generation family (family 4) with congenital mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600), Marsh et al. (2017) identified a heterozygous c.2414G-A transition (c.2414G-A, NM_005215.3) in the DCC gene, resulting in a gly805-to-glu (G805E) substitution in the netrin-1 binding domain. The mutation was found by direct sequencing and was not present in the dbSNP, 1000 Genomes Project, or ExAC databases. The mutation segregated with the disorder in the family, but there was evidence of incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to be disruptive.
In 2 brothers, born of Mexican parents, with familial horizontal gaze palsy with progressive scoliosis-2 with impaired intellectual development (HGPPS2; 617542), Jamuar et al. (2017) identified a homozygous 7,682-bp deletion (chr18.49,867,185-49,874,867del, GRCh37) affecting exon 1 and intron 1 of the DCC gene. Analysis of patient cells showed that the deletion resulting in the skipping of exon 1, a frameshift, and premature termination (Pro11ThrfsTer15), resulting in a functional null allele. The deletion, which was found by a combination of homozygosity mapping and CNV analysis, was not found in the dbSNP (build 146), 1000 Genomes Project, ExAC, or Exome Variant Server databases, or in an internal exome database. The mother was a heterozygous carrier; DNA from the father was unavailable.
In a girl, born of consanguineous Saudi Arabian parents, with familial horizontal gaze palsy with progressive scoliosis-2 with impaired intellectual development (HGPPS2; 617542), Jamuar et al. (2017) identified a homozygous 7-bp deletion (chr18.50,450,167-50,450,173del, GRCh37) in exon 4 of the DCC gene, resulting in a frameshift and premature termination (Val263AlafsTer36) and a functional null allele. The deletion, which was found by targeted sequencing of the DCC gene, was present in the heterozygous state in each parent, but was not found in the dbSNP (build 146), 1000 Genomes Project, ExAC, or Exome Variant Server databases, or in an internal exome database of over 1,000 samples from Middle Eastern individuals.
In 5 patients from 2 generations of an Ethiopian Jewish family with congenital mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600), Sagi-Dain et al. (2020) identified heterozygosity for a 1-bp duplication (c.2774dupA, NM_005215) in the DCC gene, predicted to result in a frameshift and premature termination (Asn925LysfsTer17). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was also identified in an asymptomatic female family member. A fetus with agenesis of the corpus callosum from a terminated pregnancy in this family was not tested for the mutation. The mutation was not present in the dbSNP or gnomAD databases or in an in-house database.
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