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Background: Limb-girdle muscular dystrophy type 2I is caused by mutations in the fukutin-related protein gene (FKRP). FKRP encodes a putative glycosyltransferase protein that is involved in α-dystroglycan glycosylation. Objectives: To identify patients with limb-girdle muscular dystrophy type 2I and to derive genotype-phenotype correlations. Design: Two hundred fourteen patients who showed muscle histopathologic features consistent with muscular dystrophy or myopathy of unknown etiology were studied. The entire 1.5-kilobase FKRP coding sequence from patient DNA was analyzed using denaturing high-performance liquid chromatography of overlapping polymerase chain reaction products, followed by direct sequencing of heteroduplexes. Results: Thirteen patients with limb-girdle muscular dystrophy type 2I (6%of all patients tested) were identified by FKRP muta tion analysis, and 7 additional patients were identified by family screening. Six missense mutations (1 novel) were identified. The 826C >A nucleotide change was a common mutation, present in 35%of the mutated chromosomes. Clinical presentations included asymptomatic hyperCKemia, severe early-onset muscular dystrophy, and mild late-onset muscular dystrophy. Dilated cardiomyopathy and ventilatory impairment were frequent features. Significant intrafamilial and interfamilial clinical variability was observed. Conclusions: FKRP mutations are a frequent cause of limb-girdle muscular dystrophies. The degree of respiratory and cardiac insufficiency in patients did not correlate with the severity of muscle involve ment. The finding of 2 asymptomatic patients with FKRP mutations suggests that modulating factors may ameliorate the clinical phenotype.
Background: Limb-girdle muscular dystrophy type 2I is caused by mutations in the fukutin-related protein gene (FKRP). FKRP encodes a putative glycosyltransferase protein that is involved in α-dystroglycan glycosylation. Objectives: To identify patients with limb-girdle muscular dystrophy type 2I and to derive genotype-phenotype correlations. Design: Two hundred fourteen patients who showed muscle histopathologic features consistent with muscular dystrophy or myopathy of unknown etiology were studied. The entire 1.5-kilobase FKRP coding sequence from patient DNA was analyzed using denaturing high- performance liquid chromatography of overlapping polymerase chain reaction products, followed by direct sequencing of heteroduplexes. Results: Thirteen patients with limb-girdle muscular dystrophy type 2I (6% of all patients tested) were identified by FKRP muta- tion analysis, and 7 additional patients were identified by family screening. Six missense mutations (1 novel) were identified. The 826 C> A nucleotide change was a common mutation, present in 35% of the mutated chromosomes. Clinical presentations included asymptomatic hyperCKemia, severe early-onset muscular dystrophy, and mild late-onset muscular dystrophy. Dilated cardiomyopathy and ventilatory impairment were frequent features. Significant The degree of respiratory and cardiac insufficiency in patients did not correlate with the severity of muscle involve ment. The finding of 2 asymptomatic patients with FKRP mutant suggests that modulating factors may ameliorate the clinical phenotype.