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SEMA4A and Cone-Rod Dystrophy

Semaphorin 4A (SEMA4A) has been implicated in autosomal recessive cone-rod dystrophy following mutation screening of 190 unrelated patients with retinitis pigmentosa (n = 135), cone-rod dystrophy (n = 25) and Leber congenital amaurosis (n = 30). Two heterozygous missense variants, c.1033G>C (p.Asp345His) and c.1049T>G (p.Phe350Cys), affecting conserved residues in the semaphorin domain were observed exclusively in affected individuals and absent in 100 ethnically matched controls and unaffected family members (PMID:16199541).

Functional studies in knock-in mouse models demonstrate that p.Phe350Cys disrupts Sema4A localization, impairs endosomal sorting critical for photoreceptor survival and recapitulates retinal degeneration; furthermore, gene transfer rescues degeneration in both Sema4A(F350C/F350C) and Sema4A(−/−) mice, indicating a loss-of-function mechanism (PMID:23360997).

While genetic evidence is currently limited to two probands without segregation data, concordant in vivo and rescue experiments provide strong mechanistic support. Sequencing of SEMA4A should be considered in undiagnosed cone-rod dystrophy patients to guide diagnosis and potential gene therapy approaches.

References

  • Journal of medical genetics • 2006 • Identification of novel mutations in the SEMA4A gene associated with retinal degenerative diseases. PMID:16199541
  • Nature communications • 2013 • A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration. PMID:23360997

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Two probands with heterozygous missense variants in conserved domains; no segregation data ([PMID:16199541])

Genetic Evidence

Limited

2 probands with conserved semaphorin domain missense variants, absent in controls and unaffected relatives ([PMID:16199541])

Functional Evidence

Moderate

Knock-in and knockout mouse models recapitulate cone-rod degeneration and gene transfer rescue demonstrates loss-of-function mechanism ([PMID:23360997])