ORPHA: 1872; DO: 0111017;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q22 | Cone-rod dystrophy 10 | 610283 | Autosomal recessive | 3 | SEMA4A | 607292 |
A number sign (#) is used with this entry because of evidence that cone-rod dystrophy-10 (CORD10) can be caused by compound heterozygous mutation in the SEMA4A gene (607292) on chromosome 1q22.
Cone-rod dystrophy-10 (CORD10) is characterized by progressive loss of visual acuity and color vision, followed by night blindness and loss of peripheral vision. Patients may experience photophobia and epiphora in bright light (Abid et al., 2006).
Mutation in SEMA4A can also cause a form of retinitis pigmentosa (RP35; 610282).
For a general phenotypic description and a discussion of genetic heterogeneity of cone-rod dystrophy, see 120970.
From a cohort of 190 unrelated patients with retinal degeneration, Abid et al. (2006) reported 2 with cone-rod dystrophy (CORD) and mutation in the SEMA4A gene. Patients in the cohort were diagnosed with CORD if they had progressive loss of visual acuity and color vision, followed by night blindness and loss of peripheral vision. Most of the CORD patients experienced severe photophobia and epiphora in bright light. Funduscopy revealed a high degree of fundus granularity with marked macular degeneration and a significant level of peripheral retinal pigmentation. Limited clinical information was provided.
The transmission pattern of CORD10 in family RODS006, reported by Abid et al. (2006), was consistent with autosomal recessive inheritance.
Abid et al. (2006) screened 135 Pakistani patients with retinitis pigmentosa (RP35; 610282), 25 with cone-rod dystrophy and 30 with congenital blindness, for mutations in the SEMA4A gene. They identified compound heterozygosity for 2 substitutions, D345H (607292.0001) and F350C (607292.0002), in 2 RP and 2 CORD patients. None of the mutations were found in 100 ethnically matched controls.
Using a retroviral gene-trapping strategy, Rice et al. (2004) generated Sema4a -/- mice and observed severe retinal degeneration and depigmentation at 3 months of age on fundus photography, as well as narrowed vessels on angiography. Electroretinography at 3 weeks of age revealed absence of rod responses up to the maximum intensity tested; cone-dominated responses were also attenuated. Histologic sections through the central sagittal plane of 3-week-old eyes showed a markedly reduced number of photoreceptors in Sema4a-null mice compared to wildtype or heterozygous mice, and there was a decrease in thickness of the outer nuclear layer, primarily in the central retina. At 3 months of age, the outer nuclear layer was reduced to a single row of photoreceptor cells, and the outer plexiform layer was thin and disorganized. Histologic analysis of eyes from Sema4a-null mice over 1 years of age showed progressive retinal degeneration, with no detectable photoreceptors and thinning of the inner nuclear layer and inner plexiform layer. Developmental analysis of Sema4a-null mice revealed abnormal morphology of photoreceptor outer segments in the second postnatal week, during the time at which they establish contacts with apical microvilli of the retinal pigment epithelium; the authors suggested that photoreceptor degeneration might occur primarily due to a defect in the developing outer retina.
Nojima et al. (2013) generated a series of mouse lines with mutations in Sema4a corresponding to the D345H (607292.0001) and F350C (607292.0002) variants that previously had been associated with retinal disease in humans. Only the mice homozygous for F350C showed a retinal phenotype, exhibiting light-induced retinal degeneration starting at birth, similar to that observed in Sema4a -/- mice. However, the authors stated that they could not completely exclude the possibility that the D345H mutation contribute to the pathogenesis of human retinal degenerative disease.
Abid, A., Ismail, M., Mehdi, S. Q., Khaliq, S. Identification of novel mutations in the SEMA4A gene associated with retinal degenerative diseases. (Letter) J. Med. Genet. 43: 378-381, 2006. [PubMed: 16199541] [Full Text: https://doi.org/10.1136/jmg.2005.035055]
Nojima, S., Toyofuku, T., Kamao, H., Ishigami, C., Kaneko, J., Okuno, T., Takamatsu, H., Ito, D., Kang, S., Kimura, T., Yoshida, Y., Morimoto, K., Maeda, Y., Ogata, A., Ikawa, M., Morii, E., Aozasa, K., Takagi, J., Takahashi, M., Kumanogoh, A. A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration. Nature Commun. 4: 1406, 2013. [PubMed: 23360997] [Full Text: https://doi.org/10.1038/ncomms2420]
Rice, D. S., Huang, W., Jones, H. A., Hansen, G., Ye, G.-L., Xu, N., Wilson, E. A., Troughton, K., Vaddi, K., Newton, R. C., Zambrowicz, B. P., Sands, A. T. Severe retinal degeneration associated with disruption of semaphorin 4A. Invest. Ophthal. Vis. Sci. 45: 2767-2777, 2004. [PubMed: 15277503] [Full Text: https://doi.org/10.1167/iovs.04-0020]