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

TitleClinical, genetic, and pathologic characterization of Mexican founder mutation c.1387A>G.
Publication TypeJournal Article
Year of Publication2019
AuthorsLee, AJ, Jones, KA, Butterfield, RJ, Cox, MO, Konersman, CG, Grosmann, C, Abdenur, JE, Boyer, M, Beson, B, Wang, C, Dowling, JJ, Gibbons, MA, Ballard, A, Janas, JS, Leshner, RT, Donkervoort, S, Bönnemann, CG, Malicki, DM, Weiss, RB, Moore, SA, Mathews, KD
JournalNeurol Genet
Date Published2019 Apr

Objective: To characterize the clinical phenotype, genetic origin, and muscle pathology of patients with the c.1387A>G mutation.

Methods: Standardized clinical data were collected for all patients known to the authors with c.1387A>G mutations in . 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 . Onset of symptoms was G patients revealed a 500-kb region of shared homozygosity at 19q13.32, including . All 4 muscle biopsies available for review showed end-stage dystrophic pathology, near absence of glycosylated α-dystroglycan (α-DG) by immunofluorescence, and reduced molecular weight of α-DG compared with controls and patients with homozygous c.826C>A limb-girdle muscular dystrophy.

Conclusions: The clinical features and muscle pathology in these newly reported patients homozygous for c.1387A>G confirm that this mutation causes congenital muscular dystrophy. The clinical severity might be explained by the greater reduction in α-DG glycosylation compared with that seen with the c.826C>A mutation. The shared region of homozygosity at 19q13.32 indicates that c.1387A>G is a founder mutation with an estimated age of 60 generations (∼1,200-1,500 years).

Alternate JournalNeurol Genet
PubMed ID31041397
PubMed Central IDPMC6454397
Grant ListU01 DD001108 / DD / NCBDD CDC HHS / United States
U54 NS053672 / NS / NINDS NIH HHS / United States
UM1 HG008900 / HG / NHGRI NIH HHS / United States