Arg143Ser is the most frequent variant in Limb Girdle Muscular Dystrophy-R9 in southern Italy

Fukutin related protein (FKRP) is a glycosyltransferase involved in the glycosylation of α-dystroglycan essential component in linking the intracellular cytoskeleton with the extracellular matrix. Recessive mutations in the FKRP gene are associated with a broad range of dystroglycanopathies, from severe forms of Congenital Muscular Dystrophy (MDCIC) to Limb Girdle Muscular Dystrophy-R9 (LGMDR9, previously known as LGMD2I). IperCKmia, cardiomyopathy, proximal muscles weakness and atrophy, calf hypertrophy, respiratory failure are common clinical features in the LGMDR9 as well in the dystrophinopathies. Several LGMDR9 patients follow a mild Becker-like course without showing severe gait impairment until late in their adulthood. The most frequently reported FKRP mutation in LGMDR9 is 826C>A (L276I), especially in western and northern Europe. We decided to perform mutation screening of FKRP gene in patients from southern Italy with a Duchenne (DMD)/Becker (BMD) like phenotype of unknown genetic etiology. The study was performed on 110 sporadic cases resulted negative for exonic deletion/duplication of the DMD gene. The molecular analysis of the entire 1.5-kilobase coding sequence of the FKRP gene was conducted by PCR and direct sequencing. The mutational screening revealed seven patients heterozygous for 427C>A (Arg143Ser) (6,3%) and four patients homozygous or compound heterozygous for L276I (3,6%). Finally, four patients were compound heterozygous for Ala114Gly (3,6%). Discussion and conclusions: Mutations in the FKRP gene have been identified in patients with Duchenne/Becker like phenotype and dystrophin reduction on muscle biopsy. Mutational screening of the FKRP gene was conducted on 110 DMD/BMD like phenotype sporadic patients from south Italy with no rearrangement of the dystrophin gene. Arg143Ser was the most frequent mutation identified in heterozygosity in seven patients, only in one patient was identified the second mutated allele. Our data are in agreement with what reported in the literature. In fact the Arg143Ser was previously identified in six Italian patients with clinical presentation consistent of LGMDR9 but only in one patient was identified the second mutated allele1,2. Arg143Ser mutation was validated in 200 control chromosome. This variant involves an evolutionary conserved residue and the loss of a positively charged amino acid in the mutated protein could have a dramatic effect on protein function. Manifesting carriers of FKRP mutation seem to be common among patients with LGMDR9. This finding suggests the possibility that Arg143Ser mutation on one allele is sufficient for the onset of the pathology or that the second mutation falls outside the FKRP gene.