FSCN2 – Autosomal dominant Retinitis Pigmentosa

The FSCN2 gene encodes an actin‐bundling protein critical for photoreceptor outer segment structure. Heterozygous variants in FSCN2 have been proposed to cause autosomal dominant retinitis pigmentosa (Retinitis Pigmentosa), a progressive photoreceptor degeneration disorder.

In genetic studies, a frameshift variant, c.72del (p.Thr25fs), was identified in four unrelated individuals with retinitis pigmentosa with no reported segregation in affected relatives ([PMID:18450588]). No additional missense or LoF variants in FSCN2 have been definitively linked to disease in large ADRP cohorts.

Conflicting evidence arises from an allelic copy number analysis showing that c.72del (p.Thr25fs) occurs in both patients and healthy controls without allelic imbalance, suggesting it may be a non‐pathogenic polymorphism ([PMID:18450588]). No cosegregation data or recurrent founder variants have been reported.

Functional assays demonstrate that Fscn2 haploinsufficiency in mice (Fscn2(+/p) and Fscn2(+/g) models) leads to progressive photoreceptor degeneration and diminished rod/cone ERGs, recapitulating key features of human RP ([PMID:16043865]). Further, splicing of FSCN2 transcripts is disrupted by mutant PRPF31 and modulated by DHX38 activity in cellular assays, linking general splicing factor mutations to FSCN2 misprocessing ([PMID:17350276]; [PMID:35385551]).

Integration of these data indicates that while functional studies support a haploinsufficiency mechanism, the genetic evidence for FSCN2 in ADRP remains limited and conflicting. Additional well‐characterized familial segregation and case‐control studies are needed to clarify variant pathogenicity.

Key Take‐home: FSCN2 LoF variants have supportive functional evidence for retinal degeneration but limited genetic validation; variant interpretation requires caution in diagnostic settings.

References

• Investigative ophthalmology & visual science • 2005 • Targeted disruption of FSCN2 gene induces retinopathy in mice. PMID:16043865
• Investigative ophthalmology & visual science • 2008 • Allelic copy number variation in FSCN2 detected using allele-specific genotyping and multiplex real-time PCRs. PMID:18450588
• Neurobiology of disease • 2007 • Identification of photoreceptor genes affected by PRPF31 mutations associated with autosomal dominant retinitis pigmentosa. PMID:17350276
• PloS one • 2022 • Retinitis pigmentosa-linked mutation in DHX38 modulates its splicing activity. PMID:35385551

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