FKTN – Muscular dystrophy-dystroglycanopathy type A

Fukutin (FKTN) is a Golgi-resident glycosyltransferase whose autosomal recessive loss-of-function mutations cause muscular dystrophy-dystroglycanopathy type A (MONDO:0000171). First described in a sibship of three affected siblings with cerebral malformations, ocular anomalies, and dystrophic muscle changes, FKTN variants segregated with disease in a consanguineous pedigree (PMID:1456390).

Genetic evidence includes homozygous and compound heterozygous FKTN variants identified in over 80 probands from diverse ethnic backgrounds, encompassing missense, frameshift, splice-site, and deep-intronic changes. Notably, a Turkish patient harbored a homozygous c.454dup (p.Ser152fs) insertion (PMID:12601708), and four Ashkenazi Jewish families shared a founder c.1167dup (p.Phe390fs) allele (PMID:19266496). Segregation analysis confirmed affected siblings and carrier parents in multiple pedigrees.

Segregation of FKTN variants has been documented in at least 56 Japanese families with genotype-phenotype correlation showing compound heterozygosity for founder and private mutations in severe cases (PMID:10817652). A broad allelic spectrum includes >50 truncating and >30 missense mutations across exonic and intronic regions, with recurrent alleles in specific populations.

Functional assays demonstrate that wild-type FKTN localizes to the medial Golgi and is essential for ribitol phosphate transfer onto α-dystroglycan, whereas pathogenic missense mutants mislocalize to the endoplasmic reticulum and impair glycan maturation (PMID:12471058). Mass spectrometry of α-dystroglycan glycopeptides confirmed loss of ribitol phosphate extension in FKTN-deficient cells (PMID:27601598).

Recent therapeutic work used antisense oligonucleotides to correct pseudoexon inclusion caused by a deep-intronic variant (c.648-1243G>T), restoring normal FKTN mRNA and functional glycosylation in patient myotubes (PMID:36426838).

Overall, the association of FKTN with muscular dystrophy-dystroglycanopathy type A is definitive. The combination of robust segregation, a diverse mutational spectrum, concordant biochemical and cellular functional studies, and emerging therapeutic strategies underscores its clinical utility for diagnosis, carrier screening, and targeted interventions.

References

• Brain & development • 1992 • Clinical variation within sibships in Fukuyama-type congenital muscular dystrophy. PMID:1456390
• Annals of Neurology • 2003 • A new mutation of the fukutin gene in a non-Japanese patient. PMID:12601708
• American Journal of Medical Genetics • 2000 • Haplotype-phenotype correlation in Fukuyama congenital muscular dystrophy. PMID:10817652
• Human Molecular Genetics • 2002 • Functional requirements for fukutin-related protein in the Golgi apparatus. PMID:12471058
• Molecular & Cellular Proteomics • 2016 • Direct Mapping of Additional Modifications on Phosphorylated O-glycans of α-Dystroglycan by Mass Spectrometry Analysis in Conjunction with Knocking Out of Causative Genes for Dystroglycanopathy PMID:27601598
• Human Molecular Genetics • 2023 • Antisense oligonucleotide induced pseudoexon skipping and restoration of functional protein for Fukuyama muscular dystrophy caused by a deep-intronic variant. PMID:36426838

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