FKRP was first reported in relation to autosomal recessive myopathy caused by variation in FKRP (muscular dystrophy-dystroglycanopathy included), in 2001 (Brockington et al., PMID: 11592034). At least 100 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, etc.) have been reported in humans according to ClinVar and HGMD with various historical diagnoses such as Muscle-Eye-Brain Disease, Walker-Warburg Syndrome, and LGMDR9 (LGMD2I). Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Variants in this gene have been reported in at least 14 probands in 3 publications (PMIDs: 11592034, 11741828, 15121789). Many more probands are reported in the literature, but the maximum score for genetic evidence (12 pts) has been reached. Variants are associated with a variety of phenotypes including both congenital muscle-eye-brain or WWS or later-onset LGMD based on the residual α-Dystroglycan glycosylation activity, with higher activity correlating to a less severe presentation. The mechanism for disease is biallelic loss of function, with variants causing reduced glycosylation activity and a resulting lack of functional α-Dystroglycan. As this is an essential component in the complex responsible for stabilizing skeletal or cardiac muscle, as well as brain/eye functionality, the resulting disruption causes the presenting phenotypes such as muscle weakness, cardiac and respiratory involvement, and brain/eye abnormalities.
This gene-disease association is supported by many years of experimental evidence. This includes its well-known function in the O-mannosylation of α-Dystroglycan, as well as the formation of a complex with other proteins implicated in muscular dystrophy dystroglycanopathy such as FKTN and TMEM5 and the oligomerization/activity of FKRP mutants being significantly less than the WT protein. There are several well-supported mouse models as well, with knock-in models of both L276I and P448L showing dystrophic features (PMIDs: 20675713, 26574668).
In summary,FKRP is definitively associated with myopathy caused by variation in FKRP. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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