MERTK – MERTK-related Autosomal Recessive Retinitis Pigmentosa

MERTK encodes the MER proto-oncogene tyrosine kinase, a key receptor in the retinal pigment epithelium (RPE) phagocytosis pathway. Loss-of-function variants in MERTK disrupt clearance of photoreceptor outer segments, leading to rod-cone dystrophy and autosomal recessive retinitis pigmentosa (PMID:15111602; PMID:11062461). The disease manifests in childhood or early adolescence with night blindness, peripheral field loss, and progressive visual decline.

Genetic evidence supports an autosomal recessive inheritance mode. Compound heterozygous and homozygous MERTK variants have been reported in multiple consanguineous and outbred families, with segregation confirmed in affected siblings and cousins (PMID:15111602; PMID:22180149). A Moroccan pedigree exhibited three affected siblings homozygous for c.2323C>T (p.Arg775Ter), co-segregating with disease and absent in unaffected relatives (PMID:22180149). Founder analysis in the Faroe Islands identified a homozygous 91 kb deletion in seven patients, accounting for ~30% of local cases (PMID:21677792).

The variant spectrum includes nonsense (e.g., c.2164C>T (p.Arg722Ter)), missense (e.g., c.2530C>T (p.Arg844Cys)), frameshift, splice-site mutations (e.g., IVS16+1G>T), and large genomic deletions (25 kb and 91 kb) identified by CNV analysis (PMID:15111602; PMID:28324114; PMID:21677792). c.2530C>T (p.Arg844Cys) affects a conserved residue in the kinase domain and is never observed in controls. These alleles collectively account for ~2% of inherited retinal dystrophy cases globally.

Functional studies demonstrate loss of kinase activity and protein instability. In HEK293T cells, the p.Arg844Cys mutant shows reduced expression, fails to autophosphorylate, and has accelerated turnover compared to wild-type and p.Arg865Trp (PMID:15111602). Patient-derived iPSC-RPE carrying truncating MERTK alleles exhibit defective phagocytosis of photoreceptor outer segments, recapitulating the RPE dysfunction seen in vivo (PMID:26263531).

No significant conflicting or disputed reports have emerged; all identified MERTK variants in retinitis pigmentosa cohorts demonstrate concordant genotype-phenotype correlations. The consistency across multiple populations and methodologies reinforces pathogenicity.

Integration of genetic and functional data yields a definitive gene–disease relationship. MERTK loss-of-function variants produce a uniform rod-cone dystrophy phenotype, with molecular assays and animal models confirming the RPE phagocytosis defect. Genetic testing for MERTK variants is therefore clinically useful for diagnosis, carrier screening, and patient selection for emerging gene replacement therapies.

Key Take-home: Pathogenic MERTK variants reliably cause autosomal recessive retinitis pigmentosa, and MERTK genetic testing should be integrated into diagnostic panels to inform clinical management and therapeutic trials.

References

• Investigative ophthalmology & visual science • 2004 • MERTK arginine-844-cysteine in a patient with severe rod-cone dystrophy: loss of mutant protein function in transfected cells. PMID:15111602
• European journal of ophthalmology • 2012 • Homozygous mutation in MERTK causes severe autosomal recessive retinitis pigmentosa. PMID:22180149
• Molecular vision • 2011 • A novel MERTK deletion is a common founder mutation in the Faroe Islands and is responsible for a high proportion of retinitis pigmentosa cases. PMID:21677792
• Scientific reports • 2015 • Human iPSC derived disease model of MERTK-associated retinitis pigmentosa. PMID:26263531
• Nature Genetics • 2000 • Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. PMID:11062461

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