Fukuyama Congenital Muscular Dystrophy via the FKTN Japanese Founder Mutation

Mutations in FKTN cause muscular dystrophies in the dystroglycanopathy spectrum, the most severe of which is Walker-Warburg syndrome (WWS, OMIM 236670; Beltran-Valero de Bernabe et al. J. Med. Genet. 40:845-848, 2003). Patients with WWS typically die at birth or shortly thereafter due to complications from severe CNS structural abnormalities. Fukuyama congenital muscular dystrophy (FCMD, OMIM 253800) is a less severe phenotype and is the second most common muscular dystrophy among Japanese people (Kobayashi et al. Nature 394:388-392, 1998). In the vast majority of cases the causative mutation is an inserted 3 kb retrotransposon at the 3’ UTR of the FKTN gene. Patients who are compound heterozygous for the Japanese founder mutation and an FKTN coding mutation may have more severe WWS-like features than homozygous founder mutation patients (Kondo-Iida, et al. Hum. Molec. Genet. 8:2303-2309, 1999). A third reported variant is limb girdle muscular dystrophy due to FKTN mutations (Godfrey et al. Ann Neurol 60;603-610, 2006). These patients are responsive to steroid treatment and, unlike WWS and FCMD patients, are able to ambulate and have normal intelligence and normal brain structure.

The FKTN-related disorders are inherited in an autosomal recessive manner. Although the retrotransposon mutation is the most commonly reported pathogenic variant, mutations of other forms are found throughout the gene. Mutations in FKTN lead to reduced glycosylation of alpha-dystroglycan (ADG), a component of the dystrophin-glycoprotein complex (Ervasti et al. Nature 345:315-319). Evaluation of a patient’s muscle biopsy by immunofluorescence can detect abnormal glycosylation of ADG and can, therefore, help direct a diagnostic evaluation. It should be noted that at least six other genes (POMT1, POMT2, ISPD, POMGnT1, FKRP, LARGE) encode proteins required for processing of ADG, and that overlap exists between clinical phenotypes resulting from mutations in these genes.

Fukutin is coded by exons 2-10 of the FKTN gene located on chromosome 9q31. Testing for the presence/absence of the Japanese ancestral retrotransposon is accomplished by polymerase chain reaction.