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Fukutin-related protein (FKRP) is a putative glycosyltransferase localized to the medial-Golgi apparatus that catalyzes post-translational modification of α-dystroglycan. Pathogenic recessive FKRP variants cause autosomal recessive limb-girdle muscular dystrophy type 2I (MONDO:0011787) and a spectrum of dystroglycanopathies ranging from severe congenital muscular dystrophy to mild adult-onset myopathy. LGMD2I typically presents with proximal muscle weakness, elevated serum creatine kinase, cardiomyopathy, and respiratory impairment without brain involvement. The clinical overlap with Duchenne and Becker muscular dystrophies frequently leads to misdiagnosis prior to genetic testing. FKRP-related LGMD2I shows global prevalence with founder mutations in European and Asian populations. The constellation of genetic, histopathological, and functional data supports a direct causative role of FKRP mutations in LGMD2I. This summary integrates key genetic and experimental findings to inform diagnostics, commercial applications, and future research.
Genetic evidence for the FKRP–LGMD2I association is definitive. At least 200 probands from over 60 unrelated LGMD2I pedigrees have been documented. A Norwegian cohort of 88 patients from 69 families, all homozygous or compound heterozygous for FKRP variants with 76 individuals homozygous for c.826C>A (p.Leu276Ile), established a minimum population prevalence of 1/54,000 and carrier frequency of 1/116 (PMID:20961759). Danish screening of 118 LGMD patients identified 38 LGMD2I cases (27 homozygous, 11 compound heterozygous for c.826C>A), underscoring the mutation’s high regional frequency (PMID:16634037). Brazilian genealogical analysis found 20 affected individuals harboring FKRP mutations across 13 families, with segregation consistent with autosomal recessive inheritance and asymptomatic carriers identified (PMID:14647208). French patients (n=11) exhibited intrafamilial variability and common Leu276Ile alleles in both homozygous (n=4) and heteroallelic (n=6) configurations, demonstrating genotype–phenotype correlations (PMID:19917824). Recessive segregation is further supported by family-based screening yielding seven additional affected relatives (PMID:16344347).
Case reports illustrate the phenotypic spectrum of LGMD2I. A 32-year-old man initially misdiagnosed with Duchenne muscular dystrophy was found to carry compound heterozygous FKRP variants c.169G>A (p.Glu57Lys) and c.692G>A (p.Trp231Ter), confirming LGMD2I (PMID:32351701). Oral ribose supplementation in a homozygous FKRP-mutant patient over six months was well tolerated, reduced creatine kinase levels by 70%, and increased CDP-ribitol concentrations, suggesting a metabolic therapeutic strategy (PMID:38736632). Two LGMD2I siblings with novel Pro89Leu and Leu169Pro variants showed inflammatory changes and good response to corticosteroids, indicating potential immunomodulatory benefits (PMID:17446099). Magnetic resonance imaging in six LGMD2I patients revealed characteristic patterns of muscle involvement that aid differential diagnosis from other LGMD subtypes (PMID:15726252). These reports underscore both the diagnostic challenges and emerging personalized interventions in FKRP-related LGMD2I.
Functional studies elucidate the pathogenic mechanism of FKRP mutations. FKRP is targeted to the medial-Golgi via its N-terminus and transmembrane domain, and overexpression alters post-translational processing of α- and β-dystroglycan in CHO cells (PMID:12471058). Mutations in the DxD motif or Golgi-targeting sequence impair FKRP trafficking without altering in vitro enzyme activity, whereas the P448L mutation mislocalizes FKRP to the ER, abrogating dystroglycan processing (PMID:12471058). Muscle biopsies correlate α-dystroglycan expression with genotype: severe MDC1C alleles result in profound depletion, DMD-like LGMD2I genotypes display moderate reduction, and Leu276Ile homozygotes exhibit subtle labeling defects (PMID:14742276). ER-retention of severe FKRP mutants (Ser221Arg, Ala455Asp, Pro448Leu) leads to proteasomal degradation and chaperone engagement, while the Leu276Ile allele traffics to the Golgi, explaining the milder phenotype (PMID:15574464). Additional in vitro assays confirm that variants between residues 300–321 yield correctly localized but catalytically dead proteins, defining key functional domains (PMID:31268217). Together, these data define mislocalization and loss of glycosyltransferase activity as primary pathogenic mechanisms in LGMD2I.
Animal models recapitulate human FKRP disease spectrum and demonstrate therapeutic rescue. Homozygous-null FKRP knockout is embryonic lethal, whereas P448L knock-in mice lack functional α-DG glycosylation and develop CNS and muscle defects mimicking severe dystroglycanopathies (PMID:20675713). L276I knock-in mice survive but display progressive myopathy with 78% loss of α-DG glycosylation by 20 months, paralleling human LGMD2I (PMID:26574668). Zebrafish FKRP mutants model Walker-Warburg pathologies, and inducible L276I expression yields milder LGMD2I-like phenotypes amenable to chemical screening (PMID:30232282). AAV9-mediated FKRP gene therapy in P448L and L276I mouse models restores α-DG glycosylation, reduces fibrosis, and improves muscle and cardiac function (PMID:23817215; PMID:25048216). Transplantation of pluripotent stem cell-derived myogenic progenitors into FKRP-mutant mice engrafts donor-derived myofibers with restored α-DG glycosylation and augments muscle strength (PMID:32321586). These rescue experiments support both FKRP’s pathogenic role and the feasibility of gene and cell therapies.
Integrating clinical, genetic, and experimental evidence, FKRP mutations underlie autosomal recessive LGMD2I via impaired α-dystroglycan glycosylation, leading to muscle–ECM destabilization and progressive myofiber degeneration. Founder and recurrent variants such as c.826C>A (p.Leu276Ile) facilitate population-specific screening strategies. The definitive gene–disease relationship, supported by segregation in >60 families and >200 probands, robust in vitro and in vivo functional concordance, and reproducible rescue in models and patient-derived cells, justifies clinical genetic testing, targeted diagnostics, and commercial assay development. Emerging therapeutic strategies—including metabolic supplementation, gene replacement, and cell therapy—are informed by these molecular insights. Future longitudinal studies and standardized functional assays will refine genotype–phenotype correlations. Key Take-home: FKRP genetic testing is essential for accurate LGMD2I diagnosis and underpins evolving personalized treatments.
Gene–Disease AssociationDefinitiveOver 200 probands across >60 families, multiple segregation analyses, concordant functional data, and successful therapeutic rescue studies Genetic EvidenceStrong224 probands with recessive segregation in >60 families, founder variants, and genotype–phenotype correlations Functional EvidenceStrongIn vitro and in vivo models demonstrate FKRP’s role in α-dystroglycan glycosylation, with proof-of-concept rescue by gene therapy and cell transplantation |