Alternative titles; symbols
HGNC Approved Gene Symbol: DCHS1
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38): 11:6,621,330-6,655,809 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.4 | Mitral valve prolapse 2 | 607829 | Autosomal dominant | 3 |
| Van Maldergem syndrome 1 | 601390 | Autosomal recessive | 3 |
The DCHS1 gene encodes a transmembrane cell adhesion molecule that belongs to the protocadherin superfamily. DCHS1 is a ligand for FAT4 (612411), which is another protocadherin; DCHS1 and FAT4 form an apically located adhesive complex in the developing brain (summary by Cappello et al., 2013).
To elucidate the molecular basis of fibroblast cell-cell adhesion, Matsuyoshi and Imamura (1997) investigated cadherin expression in human fibroblasts by RT-PCR using degenerate primers based on well-conserved amino acid sequences of cadherins. They isolated partial cDNAs encoding PCDH2 (603627), FAT (600976), and 3 novel cadherins, which they named FIB1, FIB2 (603058), and FIB3 (603059). RT-PCR analysis revealed that FIB1 is expressed in fibroblasts but not in melanocytes or keratinocytes.
By RNA in situ hybridization and immunohistochemistry in mouse embryos and fetuses, Durst et al. (2015) demonstrated expression of Dchs1 in endocardial and mesenchymal cells of atrioventricular valve leaflets at all time points examined.
Van Maldergem Syndrome 1
In 4 patients from 3 unrelated consanguineous families with Van Maldergem syndrome-1 (VMLDS1; 601390), Cappello et al. (2013) identified 3 different homozygous mutations in the DCHS1 gene (603057.0001-603057.0003). The mutations were found by autozygosity mapping combined with targeted genomic capture of the region. Two of the mutations resulted in premature termination. Clinical features included periventricular nodular heterotopia, intellectual disability, deafness, renal hypoplasia, tracheal anomalies, and skeletal dysplasia.
Mitral Valve Prolapse 2
In 3 unrelated families with mitral valve prolapse (MVP2; 607829), Durst et al. (2015) identified heterozygosity for 2 missense mutations in the DCHS1 gene, R2513H (603057.0004) and R2330C (603057.0005), that segregated fully with disease in the respective families.
Green et al. (2010) published a draft sequence of the Neandertal genome. Comparisons of the Neandertal genome to the genomes of 5 present-day humans from different parts of the world identified a number of genomic regions that may have been affected by positive selection in ancestral modern humans, including genes involved in metabolism and in cognitive and skeletal development. Green et al. (2010) found 78 nucleotide substitutions that change the protein coding capacity of genes where modern humans are fixed for a derived state and where Neandertals carry the ancestral (chimpanzee-like) state. Thus, relatively few amino acid changes have become fixed in the last few hundred thousand years of human evolution, an observation consistent with a complementary study (Burbano et al., 2010). There are only 5 genes with more than 1 fixed substitution changing the primary structure of the encoding proteins. One of these is PCD16, which encodes fibroblast cadherin-1, a calcium-dependent cell-cell adhesion molecule that may be involved in wound healing. Green et al. (2010) also showed that Neandertals shared more genetic variants with present-day humans in Eurasia than with present-day humans in sub-Saharan Africa, suggesting that gene flow from Neandertals into the ancestors of non-Africans occurred before the divergence of Eurasian groups from each other.
Cappello et al. (2013) found that Fat4-null and Dchs1-null embryonic mice had no evidence of a malformation of cortical development at days E16 and E18, respectively. Postnatal examination was precluded by the lethality of both genotypes. These findings indicated a discordance between the human and mice knockout models. However, intraventricular electroporation of shRNAs against Fat4 and Dchs1 in mouse embryos showed that the electroporated cells accumulated in the proliferative zones of the developing cortex, with significantly fewer cells reaching the cortical plate in the knockdown embryos compared to controls. This was observed also at later stages (P7), when many electroporated cells failed to migrate to the upper layers or accumulated below the gray matter, forming distinct regions of neuronal heterotopia that were reminiscent of the periventricular neuronal heterotopia phenotype in human patients with mutations in these genes. Immunostaining studies indicated increased proliferation of the cells in the ventricular and subventricular zones as well as a decrease in neuronal cell differentiation. These effects were countered by concurrent knockdown of Yap (606608), a transcriptional effector of the Hippo signaling pathway. These findings implicated Dchs1 and Fat4 upstream of Yap as key regulators of mammalian neurogenesis.
Durst et al. (2015) performed morpholino knockdown of the zebrafish homolog dachsous1b and observed development of cardiac atrioventricular canal defects that could be rescued by wildtype but not mutant DCHS1. Homozygous knockout of Dchs1 in mice resulted in neonatal lethality and multiorgan impairment, but Dchs1 +/- mice showed mitral valve prolapse with pronounced involvement of the posterior leaflet, which was elongated and shifted the leaflet coaptation anteriorly. Histologic analysis confirmed leaflet thickening and showed myxomatous degeneration with increased proteoglycan accumulation in both mitral leaflets. Evaluation of mitral valves in Dchs1 +/+, +/-, and -/- mice at embryonic and fetal time points showed statistically significant changes in valve length and width in heterozygous and null mice compared to controls. Heterozygotes displayed an intermediate phenotype, demonstrating a gene dosage effect. In vivo lineage-tracing studies allowed visualization of patterning defects of epicardial-derived cells (EPDCs) during migration into the posterior leaflet. In Dchs1 +/- mice, the normal sheet-like migration was disrupted and an increase in EPDCs infiltrating diffusely throughout the valve tissue was observed.
In a girl (D1), born of consanguineous parents, with Van Maldergem syndrome-1 (VMLDS1; 601390), Cappello et al. (2013) identified a homozygous c.2503G-T transversion in exon 6 of the DCHS1 gene, resulting in a gly835-to-ter (G835X) substitution in the CR8 domain. The truncation was predicted to remove the cytoplasmic and transmembrane domains, as well as all but 7 N-terminal cadherin repeats. The mutation was found by autozygosity mapping combined with targeted genomic capture of the region and segregated with the disorder in the family. The patient had previously been reported as patient 3 by Mansour et al. (2012).
In 2 affected sibs, born of consanguineous parents from Yemen (D2), with Van Maldergem syndrome-1 (VMLDS1; 601390), Cappello et al. (2013) identified a homozygous 1-bp deletion (c.2543delC) in exon 6 of the DCHS1 gene, resulting in a frameshift and premature termination (Thr848AsnfsTer30) in the CR8 domain. The truncation was predicted to remove the cytoplasmic and transmembrane domains, as well as all but 7 N-terminal cadherin repeats. The mutation was found by autozygosity mapping combined with targeted genomic capture of the region and segregated with the disorder in the family. The patients had previously been reported as patients 4 and 5 by Mansour et al. (2012).
In a girl (D3), born of consanguineous parents with Van Maldergem syndrome-1 (VMLDS1; 601390), Cappello et al. (2013) identified a homozygous c.7109A-T transversion in exon 19 of the DCHS1 gene, resulting in an asn2370-to-ile (N2370I) substitution at a highly conserved residue in a DXNDN motif in the CR22 domain. This motif resides in the linker region between cadherin domains and mediates the chelation of calcium, which is critical for the adhesive properties of cadherin domain-containing proteins. The mutation was found by autozygosity mapping combined with targeted genomic capture of the region, and was not present in the dbSNP or 1000 Genomes Project databases. The unaffected parents were heterozygous for the mutation. The patient had previously been reported as patient 2 by Mansour et al. (2012).
In affected members of a 5-generation family with mitral valve prolapse (MVP2; 607829), originally reported by Freed et al. (2003), Durst et al. (2015) identified heterozygosity for a c.7538G-A transition in the DCHS1 gene, resulting in an arg2513-to-his (R2513H) substitution. The mutation segregated with disease in the family and was not found in 4,300 European-American individuals from the NHLBI Exome Sequencing project. Western blot analyses of transfected HEK293 cells demonstrated an approximately 70% reduction in protein expression with the R2315H mutant compared to wildtype. Atrioventricular canal defects in zebrafish with morpholino knockdown of the homolog gene dachsous1b could be rescued by wildtype DCHS1 but not by the R2315H mutant.
In affected members of 2 unrelated families with mitral valve prolapse (MVP2; 607829), Durst et al. (2015) identified heterozygosity for a c.6988C-T transition in the DCHS1 gene, resulting in an arg2330-to-cys (R2330C) substitution that segregated with disease in both families. In the first family, the mutation was present in an affected brother and sister as well as their more mildly affected mother and maternal grandfather; in the second family, a mother and an affected son and daughter carried the mutation, as well as another son with indeterminate MVP status. Analysis of mutant protein half-life showed a significant reduction compared to wildtype. Consistent with observations in Dchs1 +/- mouse embryos, in vitro studies of mitral valve interstitial cells from the proband of the first family, who underwent mitral valve repair for severe myxomatous regurgitation at age 21 years, showed increased migration of epicardial-derived cells into the posterior leaflet.
Burbano, H. A., Hodges, E., Green, R. E., Briggs, A. W., Krause, J., Meyer, M., Good, J. M., Maricic, T., Johnson, P. L. F., Xuan, Z., Rooks, M., Bhattacharjee, A., Brizuela, L., Albert, F. W., de la Rasilla, M., Fortea, J., Rosas, A., Lachmann, M., Hannon, G. J., Paabo, S. Targeted investigation of the Neandertal genome by array-based sequence capture. Science 328: 723-725, 2010. [PubMed: 20448179] [Full Text: https://doi.org/10.1126/science.1188046]
Cappello, S., Gray, M. J., Badouel, C., Lange, S., Einsiedler, M., Srour, M., Chitayat, D., Hamdan, F. F., Jenkins, Z. A., Morgan, T., Preitner, N., Uster, T., and 20 others. Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt cerebral cortical development. Nature Genet. 45: 1300-1308, 2013. [PubMed: 24056717] [Full Text: https://doi.org/10.1038/ng.2765]
Durst, R., Sauls, K., Peal, D. S., deVlaming, A., Toomer, K., Leyne, M., Salani, M., Talkowski, M. E., Brand, H., Perrocheau, M., Simpson, C., Jett, C., and 38 others. Mutations in DCHS1 cause mitral valve prolapse. Nature 525: 109-113, 2015. [PubMed: 26258302] [Full Text: https://doi.org/10.1038/nature14670]
Freed, L. A., Acierno, J. S., Jr., Dai, D., Leyne, M., Marshall, J. E., Nesta, F., Levine, R. A., Slaugenhaupt, S. A. A locus for autosomal dominant mitral valve prolapse on chromosome 11p15.4. Am. J. Hum. Genet. 72: 1551-1559, 2003. [PubMed: 12707861] [Full Text: https://doi.org/10.1086/375452]
Green, R. E., Krause, J., Briggs, A. W., Maricic, T., Stenzel, U., Kircher, M., Patterson, N., Li, H., Zhai, W., Fritz, M. H.-Y., Hansen, N. F., Durand, E. Y., and 44 others. A draft sequence of the Neandertal genome. Science 328: 710-722, 2010. [PubMed: 20448178] [Full Text: https://doi.org/10.1126/science.1188021]
Mansour, S., Swinkels, M., Terhal, P. A., Wilson, L. C., Rich, P., Van Maldergem, L., Zwijnenburg, P. J. G., Hall, C. M., Robertson, S. P., Newbury-Ecob, R. Van Maldergem syndrome: further characterisation and evidence for neuronal migration abnormalities and autosomal recessive inheritance. Europ. J. Hum. Genet. 20: 1024-1031, 2012. [PubMed: 22473091] [Full Text: https://doi.org/10.1038/ejhg.2012.57]
Matsuyoshi, N., Imamura, S. Multiple cadherins are expressed in human fibroblasts. Biochem. Biophys. Res. Commun. 235: 355-358, 1997. [PubMed: 9199196] [Full Text: https://doi.org/10.1006/bbrc.1997.6707]