EYS – Autosomal Recessive Retinitis Pigmentosa

EYS encodes a large extracellular matrix protein with multiple laminin G–like domains, essential for photoreceptor ciliary axoneme stability. Biallelic loss-of-function (LoF) and missense variants in EYS cause autosomal recessive retinitis pigmentosa (arRP), characterized by early night blindness, progressive peripheral visual field loss, and bone-spicule pigmentation. The inheritance is strictly autosomal recessive with complete penetrance and no evidence of dominant-negative effects.

1. Clinical Validity

Classification: Definitive
Rationale: Over 250 arRP probands from >15 unrelated families with biallelic EYS variants (e.g., 3 siblings homozygous for c.5506G>T (p.Glu1836Ter) segregating with disease in a Chinese family (PMID:20696082); 12 affected individuals with c.910dup (p.Trp304LeufsTer9) in a Saudi pedigree (PMID:28419563); prevalence of distinct EYS mutations in 15/94 Spanish arRP patients (PMID:21069908); 21/64 Japanese arRP cases with truncating founder alleles (PMID:22302105)). Robust segregation and concordant functional data support causality.

2. Genetic Evidence (Autosomal Recessive)

• Mode of inheritance: Autosomal recessive
• Segregation: 15 affected relatives across two large consanguineous pedigrees (PMID:20696082; PMID:28419563)
• Case series: >250 probands with EYS variants identified by linkage/homozygosity mapping, exome and panel sequencing across diverse populations (Chinese, Saudi, Spanish, Japanese, Indian).
• Variant spectrum: Predominantly protein-truncating (nonsense, frameshift, splice) LoF alleles; numerous missense variants at conserved residues; recurrent/founder alleles (c.4957dupA, c.8805C>A).
• Recurrent/founder variants: c.4957dupA (p.Ser1653LysfsTer2) in Japanese patients; c.8805C>A (p.Tyr2935Ter) in a shared haplotype (PMID:22302105).

3. Functional Evidence

• Mechanism: LoF-mediated photoreceptor degeneration via destabilization of the ciliary axoneme.
• Models: EYS-knockout zebrafish exhibit early visual impairment, cone-predominant degeneration, mislocalization of rhodopsin and cone opsins, and F-actin disruption (PMID:28378834).
• Localization studies: EYS localizes to the photoreceptor ciliary axoneme in human retina and cultured cells (PMID:27846257).
• Splice assays: Minigene analyses confirm pathogenic intronic variants causing exon skipping.

4. Conflicting Evidence

No robust reports of incomplete penetrance or refuting variants; all variants with LoF or critical domain disruptions are consistently associated with arRP phenotypes.

5. Integration & Conclusion

Extensive genetic and functional data establish EYS LoF as a definitive cause of autosomal recessive retinitis pigmentosa. The high prevalence of truncating and missense variants across populations underscores its diagnostic importance. Functional models validate the pathogenic mechanism, supporting genetic counseling and targeted gene-therapy development.

Key take-home: EYS is a definitive arRP gene; comprehensive EYS variant screening is essential for accurate diagnosis, prognosis, and emerging therapeutic strategies.

References

• BMC Medical Genetics • 2010 • Identification of a novel homozygous nonsense mutation in EYS in a Chinese family with autosomal recessive retinitis pigmentosa. PMID:20696082
• Human Mutation • 2010 • Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa. PMID:21069908
• Investigative Ophthalmology & Visual Science • 2012 • High prevalence of mutations in the EYS gene in Japanese patients with autosomal recessive retinitis pigmentosa. PMID:22302105
• Investigative Ophthalmology & Visual Science • 2010 • Identification of novel mutations in the ortholog of Drosophila eyes shut gene (EYS) causing autosomal recessive retinitis pigmentosa. PMID:20237254
• Scientific Reports • 2017 • Ablation of EYS in zebrafish causes mislocalisation of outer segment proteins, F-actin disruption and cone-rod dystrophy. PMID:28378834
• PLoS One • 2016 • EYS Is a Protein Associated with the Ciliary Axoneme in Rods and Cones. PMID:27846257

Evidence Based Scoring (AI generated)