SAMD11 – Retinitis Pigmentosa

SAMD11 has been implicated as a novel autosomal recessive cause of Retinitis pigmentosa, the most common inherited retinal dystrophy characterized by progressive degeneration of rod and cone photoreceptors. Using homozygosity mapping and whole-exome sequencing, a homozygous nonsense SAMD11 mutation was identified in five adult-onset RP individuals from two unrelated consanguineous Spanish families (PMID:27734943). This finding established an AR inheritance pattern, with affected individuals homozygous for loss-of-function alleles segregating with disease in both pedigrees.

Genetic evidence includes five probands across two families with confirmed biallelic SAMD11 variants. Variant spectrum comprises two truncating alleles and at least one missense change. The recurrent LoF variant c.1039C>T (p.Arg347Ter) was observed in multiple affected individuals (PMID:27734943). No additional unrelated carriers have been reported, consistent with the rarity of these alleles.

Functional studies demonstrate that SAMD11 interacts with the photoreceptor transcription factor CRX, suggesting a role in transcriptional regulation of retinal genes. Immunoblotting confirmed strong expression of SAMD11 in human retina, while immunolocalization detected the protein in all three nuclear layers, with differential expression in cones versus rods. These data support a loss-of-function mechanism whereby absence of SAMD11 disrupts photoreceptor maintenance and survival.

A subsequent analysis of human SAMD11 splice variants revealed up to 45 alternative transcripts and widespread tissue expression, but did not find CRX-dependent transcriptional regulation or marked effects on cell proliferation (PMID:23978614). While these findings underscore complexity in SAMD11 biology, they do not contradict its role in retinal degeneration under biallelic LoF conditions.

In summary, genetic and experimental evidence converge to support a moderate clinical validity for SAMD11 in autosomal recessive RP. The combination of homozygous truncating variants in multiple affected individuals and concordant retinal expression and protein interaction data provides a clear rationale for inclusion of SAMD11 in gene panels and diagnostic testing. Key take-home: SAMD11 loss-of-function is a clinically actionable cause of AR retinitis pigmentosa.

References

• Scientific Reports | 2016 | Identification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa. PMID:27734943
• Gene | 2013 | Identification and characterization of novel alternative splice variants of human SAMD11. PMID:23978614

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