FKRP – Muscular dystrophy-dystroglycanopathy type B5

FKRP-related muscular dystrophy-dystroglycanopathy type B5 is an autosomal recessive disorder characterized by congenital hypotonia, intellectual disability, and variable brain malformations including cerebellar cysts. Patients typically present in infancy with elevated serum creatine kinase levels and dystrophic changes on muscle biopsy. Central nervous system involvement manifests as diffuse white matter hyperintensities and cerebellar anomalies on neuroimaging.

Genetic evidence includes at least 8 unrelated probands with biallelic FKRP variants: two unrelated patients with homozygous c.663C>A (p.Ser221Arg) and c.947C>G (p.Pro316Arg) (PMID:12654965), and six Tunisian patients homozygous for c.1364C>A (p.Ala455Asp) (PMID:14652796). A Japanese sibship demonstrated compound heterozygosity for c.502T>C (p.Cys168Arg) and c.1167_1168delGC (p.Gly391LeufsTer72) with segregation in two affected siblings (PMID:28629604).

Variant spectrum encompasses missense changes (e.g., c.502T>C (p.Cys168Arg)), frameshift indels (e.g., c.1167_1168delGC (p.Gly391LeufsTer72)), and recurrent founder alleles (c.1364C>A (p.Ala455Asp)) in specific populations. Most pathogenic variants localize to the glycosyltransferase domain in exons 3–4, disrupting FKRP’s ribitol 5-phosphate transferase activity.

Segregation analysis confirmed co-segregation of compound heterozygous variants in a multiplex family with two affected siblings (PMID:28629604)).

Functional assays demonstrate that FKRP localizes to the medial-Golgi and is required for post-translational glycosylation of α-dystroglycan; patient mutations (e.g., P448L) mislocalize to the endoplasmic reticulum and fail to process α-dystroglycan in vitro (PMID:12471058). Knock-in mice carrying P448L exhibit muscle dystrophy and brain malformations mirroring human disease (PMID:20675713).

Integration of robust genetic and concordant functional data over two decades supports a Definitive gene–disease relationship. FKRP mutation analysis is essential for precise diagnosis, carrier testing, and therapeutic stratification in muscular dystrophy-dystroglycanopathy type B5.

References

• Brain & development • 2017 • Novel FKRP mutations in a Japanese MDC1C sibship clinically diagnosed with Fukuyama congenital muscular dystrophy. PMID:28629604
• Neurology • 2003 • FKRP gene mutations cause congenital muscular dystrophy, mental retardation, and cerebellar cysts. PMID:12654965
• Neurogenetics • 2004 • New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families. PMID:14652796
• Human molecular genetics • 2002 • Functional requirements for fukutin-related protein in the Golgi apparatus. PMID:12471058
• Human molecular genetics • 2010 • Fukutin-related protein is essential for mouse muscle, brain and eye development and mutation recapitulates the wide clinical spectrums of dystroglycanopathies. PMID:20675713

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