FKTN – Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A4

Fukutin, encoded by FKTN (HGNC:3622), is a ribitol 5-phosphate transferase essential for post-translational glycosylation of α-dystroglycan in the medial-Golgi apparatus. Loss-of-function mutations in FKTN cause Fukuyama congenital muscular dystrophy (FCMD; MONDO:0009678), an autosomal recessive disorder characterized by early hypotonia, progressive muscle weakness, dystrophic histology and cobblestone lissencephaly with ocular anomalies. The inheritance is autosomal recessive, with affected individuals homozygous or compound heterozygous for pathogenic FKTN variants.

Genetic evidence includes linkage of FCMD to chromosome 9q31-33 in 21 families (Zmax 16.93) (PMID:8275093), and multiple case reports outside Japan identifying homozygous founder SVA insertions and diverse point mutations such as c.919C>G (p.Arg307Gly) in non-Japanese patients (PMID:19396839). Over 100 probands have been described, including consanguineous sibships and unrelated patients from Korea, China, Italy and Mexico, supporting a definitive gene–disease relationship.

Segregation analysis in large cohorts and family studies demonstrates co-segregation of FKTN variants with the disease phenotype. Haplotype–phenotype correlation studies in 56 Japanese FCMD families showed that compound heterozygosity for the ancestral founder haplotype and a second allele correlates with severe, typical and mild clinical subtypes (PMID:10817652).

Functional assays confirm that fukutin localizes to the medial-Golgi via its N-terminal transmembrane domain and is required for α-dystroglycan glycan processing. Mutant proteins mislocalize to the endoplasmic reticulum and fail to restore laminin-binding glycans in patient-derived cells and animal models, consistent with a loss-of-function mechanism (PMID:12471058).

Phenotypic spectrum ranges from severe Walker-Warburg syndrome to isolated cardiomyopathy without central nervous system involvement. Deep-intronic variants such as c.647+2084G>T create pseudoexons; antisense oligonucleotide correction restores normal splicing and partially rescues α-dystroglycan glycosylation in patient myotubes, illustrating therapeutic potential (PMID:36426838).

Integration of robust genetic, segregation and functional data over three decades supports a definitive clinical validity for FKTN in FCMD type A4. Genetic testing for FKTN variants is clinically useful for early diagnosis, carrier detection, prenatal diagnosis, and guiding management of respiratory and cardiac complications.

Key Take-home: FKTN testing enables precise diagnosis and informs clinical management of Fukuyama congenital muscular dystrophy type A4, with evolving therapeutic strategies targeting aberrant splicing.

References

• Brain & development • 1992 • Clinical variation within sibships in Fukuyama-type congenital muscular dystrophy. PMID:1456390
• Nature Genetics • 1993 • Localization of a gene for Fukuyama type congenital muscular dystrophy to chromosome 9q31-33. PMID:8275093
• Human Molecular Genetics • 2002 • Functional requirements for fukutin-related protein in the Golgi apparatus. PMID:12471058
• American Journal of Medical Genetics • 2000 • Haplotype-phenotype correlation in Fukuyama congenital muscular dystrophy. PMID:10817652
• Journal of Human Genetics • 2017 • Deep-intronic variant of fukutin is the most prevalent point mutation of Fukuyama congenital muscular dystrophy in Japan. PMID:28680109
• 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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