Submission Details

MAK was first reported in relation to autosomal recessive retinopathy in 2011 (Ozgul et al., PMID: 21835304; Stone et al., PMID: 22110072; Tucker et al., PMID: 21825139). The initial reports described patients with adult-onset retinitis pigmentosa, with some cases described as sectoral retinitis pigmentosa. Patients typically presented with classic symptoms and signs of retinitis pigmentosa, including nyctalopia, constriction of the visual field, and pigmentary changes in the midperipheral retina. Stone et al. (2011; PMID: 22110072) describe a pattern of early superotemporal visual field loss. MAK-related retinopathy appears to cause non-syndromic retinal disease, and no associated extra-ocular features were identified in a cohort specifically screened for potential syndromic features (van Huet et al., 2015; PMID: 25385675). The MAK gene is associated with the phenotype retinitis pigmentosa (or rod-cone dystrophy) (MIM: 614181; ORPHA:791; HP:0000510). However, there is at least one report of a proband with a homozygous MAK variant and a diagnosis of cone-rod dystrophy and bull's eye maculopathy (PMID: 33921607). For consistency with the Retina GCEP curations, the disease entity MAK-related retinopathy has been selected.

Thirteen distinct variants (missense, nonsense, frameshift, Alu repeat insertion) that have been reported in 31 probands in 7 publications (PMIDs: 21835304, 21825139, 22110072, 25255364, 33542393, 29781741, 33921607) are included in this curation. The most frequently reported variant is an insertion of a 353 base pair Alu repeat in exon 9 of MAK (often referred to as MAK-Alu insertion). This was first described by Tucker et al. (2011: PMID: 21825139) who identified it in multiple affected individuals of Ashkenazi Jewish ancestries in a homozygous state. Notably, the MAK-Alu insertion is enriched in the Ashkenazi Jewish population (estimated carrier frequency of 1/55), and haplotype analysis indicated a founder effect (PMIDs: 25255364, 22110072). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.

The mechanism of pathogenicity is known to be loss-of-function (PMID: 34518651). This gene-disease association is also supported by experimental evidence (e.g. animal models, expression studies, protein interactions, animal models, rescue experiments, etc.) (PMIDs: 21825139, 21148103, 34518651). The MAK (male germ cell-associated kinase) gene is important for long-term photoreceptor survival and serves as a negative regulator of cilia length (PMIDs: 21148103, 34518651). MAK is expressed in the photoreceptor cells, especially in the outer nuclear layer, axons, and inner segments (PMID: 21825139). There are two MAK transcripts expressed in the retina, one of which is a retina-specific transcript that contains a 75 base pair exon (exon 12) that is not present in the canonical transcript (PMID: 21825139). Mak is expressed in the developing mouse retina, and Mak knockout mice have photoreceptor degeneration (PMID: 21148103). The mak knockdown zebrafish also show signs of vision impairment and elongated cilia length, both of which can be rescued or partially rescued by injection of human MAK mRNA (PMID: 34518651). In addition, iPSC studies show rescue of the cilia defect in patient-derived fibroblasts when transduced with viral vectors driving canonical or retinal MAK expression (PMID: 34518651). More experimental evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) has been reached.

In summary, MAK is definitively associated with autosomal recessive MAK-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Retina GCEP on the meeting date March 2, 2023 (SOP Version 9).