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FKTN – Autosomal Recessive Limb-Girdle Muscular Dystrophy Type 2M

FKTN encodes the golgi-resident glycosyltransferase fukutin required for α-dystroglycan maturation. A single non-Japanese patient with late-onset LGMD2M presented at age 14 with rigid spine syndrome, limb-girdle weakness and cardiomyopathy, carrying a homozygous c.917A>G (p.Tyr306Cys) variant inherited from carrier parents, confirming FKTN’s role in LGMD2M (PMID:23746544).

In vitro studies demonstrate that wild-type fukutin localizes to the medial-Golgi, whereas pathogenic missense mutants mislocalize to the endoplasmic reticulum, leading to hypoglycosylation of α-dystroglycan; low-temperature and chemical chaperone treatments can restore localization and glycosylation (PMID:12471058; PMID:22275357). This supports a loss-of-function mechanism amenable to folding-amelioration therapies. Key take-home: FKTN variant analysis is essential for diagnosing LGMD2M and exploring targeted interventions.

References

  • Neuromuscular disorders • 2013 • A new mutation of the fukutin gene causing late-onset limb girdle muscular dystrophy. PMID:23746544
  • Human molecular genetics • 2002 • Functional requirements for fukutin-related protein in the Golgi apparatus. PMID:12471058
  • The Journal of biological chemistry • 2012 • Mislocalization of fukutin protein by disease-causing missense mutations can be rescued with treatments directed at folding amelioration. PMID:22275357

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Single unrelated proband with homozygous variant; carrier parents segregation; confirmed by functional data

Genetic Evidence

Limited

1 proband with homozygous c.917A>G (p.Tyr306Cys) in AR inheritance ([PMID:23746544])

Functional Evidence

Moderate

In vitro studies show Golgi localization of wild-type fukutin and ER mislocalization of pathogenic mutants causing hypoglycosylation; rescue by chaperone approaches ([PMID:12471058]; [PMID:22275357])