Clinical, genetic, and pathologic characterization of FKRP Mexican founder mutation c.1387A>G.

ABSTRACT: Objective:To characterize the clinical phenotype, genetic origin, and muscle pathology of patients with the FKRP c.1387A>G mutation. Methods:Standardized clinical data were collected for all patients known to the authors with c.1387A>G mutations in FKRP. Muscle biopsies were reviewed and used for histopathology, immunostaining, Western blotting, and DNA extraction. Genetic analysis was performed on extracted DNA. Results:We report the clinical phenotypes of 6 patients homozygous for the c.1387A>G mutation in FKRP. Onset of symptoms was <2 years, and 5 of the 6 patients never learned to walk. Brain MRIs were normal. Cognition was normal to mildly impaired. Microarray analysis of 5 homozygous FKRP c.1387A>G patients revealed a 500-kb region of shared homozygosity at 19q13.32, including FKRP. All 4 muscle biopsies available for review showed end-stage dystrophic pathology, near absence of glycosylated ?-dystroglycan (?-DG) by immunofluorescence, and reduced molecular weight of ?-DG compared with controls and patients with homozygous FKRP c.826C>A limb-girdle muscular dystrophy. Conclusions:The clinical features and muscle pathology in these newly reported patients homozygous for FKRP c.1387A>G confirm that this mutation causes congenital muscular dystrophy. The clinical severity might be explained by the greater reduction in ?-DG glycosylation compared with that seen with the c.826C>A mutation. The shared region of homozygosity at 19q13.32 indicates that FKRP c.1387A>G is a founder mutation with an estimated age of 60 generations (?1,200-1,500 years).

SUBMITTER: Lee AJ 

PROVIDER: S-EPMC6454397 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature