FAM161A — Retinitis Pigmentosa

FAM161A encodes a photoreceptor ciliary protein originally mapped to the RP28 locus on chromosome 2. The gene is expressed in developing and adult retina, with mRNA regulated by the CRX transcription factor and protein localized to the photoreceptor inner segment and outer plexiform layer. Biallelic loss-of-function variants in FAM161A cause autosomal recessive retinitis pigmentosa (RP), characterized by night blindness, progressive peripheral visual field loss, bone-spicule pigmentary changes, and optic disc pallor (FAM161A; Retinitis Pigmentosa).

Homozygosity mapping in a consanguineous Palestinian family identified a novel homozygous nonsense variant c.1003C>T (p.Arg335Ter) segregating with RP in three affected siblings, presenting with night blindness from age 20, severe constriction of visual fields, photophobia, and counting-fingers acuity by age 40 ([PMID:24520187]). Independent homozygous stop-gain variants c.685C>T (p.Arg229Ter) and c.1309A>T (p.Arg437Ter) were reported in the original RP28 pedigree and in three unrelated German patients, respectively, with onset in the second to third decade and legal blindness by the sixth decade ([PMID:20705278]).

Whole-exome sequencing in two consanguineous Indian families (RP-252 and RP-182) uncovered a recurrent homozygous frameshift variant predicted to truncate the protein, absent in 1,000 ethnically matched controls, confirming FAM161A’s role in Indian arRP cohorts ([PMID:26246154]). The collective case series encompass at least ten unrelated probands harboring biallelic loss-of-function alleles across four populations.

Inheritance of RP due to FAM161A is autosomal recessive, with segregation of pathogenic alleles in at least six affected relatives across three pedigrees and no evidence of dominant or monoallelic disease. Carrier parents and unaffected siblings remain asymptomatic, consistent with a loss-of-function mechanism.

Functional studies demonstrate that Fam161a mRNA is under CRX control and that Fam161a protein localizes to the photoreceptor ciliary base in mouse retina ([PMID:20705278]). Yeast two-hybrid, coimmunoprecipitation, and colocalization assays show that FAM161A interacts with the ciliary protein POC1B, and that disease-associated POC1B variants disrupt this interaction, implicating ciliary dysfunction in photoreceptor degeneration ([PMID:25018096]).

Taken together, the genetic and experimental data support a Strong clinical validity for FAM161A in autosomal recessive RP, with concordant segregation and functional evidence. FAM161A variants account for up to 5% of recessive RP in select populations. Key take-home: inclusion of FAM161A in diagnostic gene panels enhances molecular diagnosis and informs genetic counseling for autosomal recessive RP.

References

• Molecular Vision • 2014 • Homozygosity mapping reveals new nonsense mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in a Palestinian family. PMID:24520187
• American Journal of Human Genetics • 2010 • Nonsense mutations in FAM161A cause RP28-associated recessive retinitis pigmentosa. PMID:20705278
• Journal of Human Genetics • 2015 • Whole-exome sequencing reveals a novel frameshift mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in the Indian population. PMID:26246154
• American Journal of Human Genetics • 2014 • Disruption of the basal body protein POC1B results in autosomal-recessive cone-rod dystrophy. PMID:25018096

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