SCAPER – Autosomal Recessive Retinitis Pigmentosa

SCAPER was first implicated in human disease through a homozygous splice variant causing intellectual disability in an Iranian family (autosomal recessive inheritance), laying the groundwork for a syndromic retinitis pigmentosa (RP) phenotype ([PMID:38927727]). Subsequent whole-exome sequencing in three unrelated families from Israel and Spain confirmed biallelic SCAPER mutations in autosomal recessive RP with intellectual disability ([PMID:28794130]). Further reports expanded the phenotype to include attention-deficit/hyperactivity disorder, dysmorphic features, and ocular manifestations such as nystagmus and glaucoma ([PMID:38927727]; [PMID:40159802]).

To date, 37 probands have been described with biallelic SCAPER variants in eight unrelated families ([PMID:38927727]; [PMID:28794130]; [PMID:31069901]). Segregation is consistent with autosomal recessive transmission, with homozygous or compound heterozygous genotypes co-segregating with disease in affected sibships. The variant spectrum includes splice (c.2023-2A>G), nonsense (c.2605A>T [PMID:40159802]), frameshift (c.2973_2976del), missense (c.3656G>A), and in-frame deletion (c.1850AAG[3] (p.Glu620del)) alleles across diverse populations ([PMID:28794130]; [PMID:31069901]). One recurrent Arab founder splice variant (c.2023-2A>G) accounts for multiple consanguineous cases ([PMID:38927727]).

Functional studies demonstrate ubiquitous SCAPER expression in human and mouse retina and brain, with upregulation during embryonic cortical development and localization to photoreceptor layers ([PMID:28794130]; [PMID:31069901]). Drosophila ssp3 knockout models recapitulate key features of meiosis failure and ciliary dysfunction, and both human SCAPER and fly Ssp3 bind microtubules in vitro, supporting a role in cell cycle regulation and ciliary function ([PMID:32527956]). No conflicting evidence disputing the SCAPER–RP association has been reported.

Collectively, genetic and experimental data support a loss-of-function mechanism in SCAPER leading to autosomal recessive RP with intellectual disability and variable ocular features. Additional large-scale cohort studies may further refine variant-specific phenotypic correlations. Key take-home: SCAPER should be included in genetic testing panels for syndromic RP to enable early diagnosis and management.

References

• Journal of medical genetics • 2017 • Mutations in SCAPER cause autosomal recessive retinitis pigmentosa with intellectual disability. PMID:28794130
• American journal of medical genetics. Part A • 2019 • Homozygous variants in the gene SCAPER cause syndromic intellectual disability. PMID:31069901
• Genes • 2024 • SCAPER-Related Autosomal Recessive Retinitis Pigmentosa with Intellectual Disability: Confirming and Extending the Phenotypic Spectrum and Bioinformatics Analyses. PMID:38927727
• Journal of medical genetics • 2021 • Absence of SCAPER causes male infertility in humans and Drosophila by modulating microtubule dynamics during meiosis. PMID:32527956
• Ophthalmic genetics • 2025 • Intellectual disability and retinitis pigmentosa due to a homozygous null SCAPER variant: a clinical and genetic insight with review of the literature. PMID:40159802

Evidence Based Scoring (AI generated)