Founder Mutation In The γ-Sarcoglycan Gene Causes Milder Phenotype Of Limb-Girdle Muscular Dystrophy Type 2C (LGMD2C) in the Hispanic Population of Puerto Rico (S46.002)

OBJECTIVE: To ascertain a potential founder effect of the E263K mutation in the γ-sarcoglycan (SGCG) gene in Puerto Rican Hispanics by performing haplotype analysis on four unrelated families from this population. We also compared clinical and immunohistochemical analyses of the phenotype associated with this mutation. BACKGROUND: Limb-girdle muscular dystrophy type 2C (LGMD2C) is inherited as an autosomal recessive mutation in the SGCG gene causing deficiency of the γ-sarcoglycan protein. Clinically LGMD2C demonstrates progressive muscle weakness, calf hypertrophy and early loss of ambulation. LGMD2C prevalence is dependent on geographical distribution of founder mutations in the SGCG gene. The North African (del521T) and European Gypsy (C283Y) founder mutations both result in a severe form of childhood-onset LGMD2C. In a previous report, a novel missense mutation (E263K) in the SGCG gene in two unrelated patients of Puerto Rican ancestry raised suspicions of a founder effect in this island that were not confirmed. METHODS:Two unrelated Puerto Rican patients (Patients 1 and 2) with LGMD2C and a confirmed E263K mutation underwent a thorough clinical and histological evaluation. DNA was obtained from the two previously reported families (Duncan et al., Neurology ® 2006)and haplotype analysis for six polymorphic microsatellite markers internal to (D13S232) and flanking (D13S175, D13S292, D13S787, D13S1243, D13S283) the SGCG gene was performed on all four families. RESULTS:Patients 1 and 2 both had preserved ambulation in the second decade of life suggesting a milder LGMD2C phenotype. Muscle biopsies demonstrated γ-sarcoglycan deficiency. Two markers, D13S232 and D13S292, confirmed that the haplotype of the mutant allele is shared by all four families. CONCLUSIONS:The E263K missense mutation in the SGCG gene is a founder mutation in the Hispanic Puerto Rican population that is associated with a milder phenotype of LGMD2C. The clinical presentation and the capacity for targeted diagnostic testing stress the importance of this finding. Study Supported by: NIH Ruth L. Kirschtein (T32) Training Grant through the Research Institute at Nationwide Children’s Hospital. Disclosure: Dr. Al-Zaidy has nothing to disclose. Dr. Malik has nothing to disclose. Dr. Kneile has nothing to disclose. Dr. Rosales has nothing to disclose. Dr. Gastier-Fosteer has received personal compensation for activities with Inova Health Sciences as a participant in a discussion group. Dr. Kang has received personal compensation for activities with Brookes Publishing and ISIS Pharmaceuticals. Dr. Kang has received research support from ISIS Pharmaceuticals. Dr. Darras has received personal compensation for activities with UpToDate Inc., Isis Pharmaceuticals, and Athena Diagnostics. Dr. Darras has received research support from PTC Therapeutics Inc. Dr. Kunkel has nothing to disclose. Dr. Moore has nothing to disclose. Dr. Pyatt has nothing to disclose. Dr. Mendell has received research support from Sarepta Therapeutics Inc.