A slowly progressive form of limb-girdle muscular dystrophy type 2C associated with founder mutation in the SGCG gene in Puerto Rican Hispanics

Abstract

Limb-girdle muscular dystrophy type 2C (LGMD2C) is considered one of the severe forms of childhood-onset muscular dystrophy. The geographical distribution of founder mutations in the SGCG gene has a prominent effect on the prevalence of LGMD2C in certain populations. The aim of this study was to confirm the hypothesis that the c.787G>A (p.E263K) mutation in the SGCG gene is a founder mutation among Puerto Rican Hispanics and to characterize the associated clinical and immunohistochemical phenotype. Genotyping of six polymorphic microsatellite markers internal to (D13S232) and flanking (D13S175, D13S292, D13S787, D13S1243, D13S283) the SGCG gene was performed on four unrelated Puerto Rican patients with LGMD2C. Preserved ambulation to the second decade of life was observed in at least two subjects. Immunostaining of skeletal muscle demonstrated absence of γ-sarcoglycan in all affected subjects. Two markers, D13S232 and D13S292, were highly informative and confirmed that all four families share the haplotype of the mutant allele. Our findings confirm that the E263K missense mutation in the SGCG gene is a founder mutation in Puerto Rican Hispanics. A slowly progressive disease course with prolonged preservation of ambulation can be seen in association with this mutation, providing evidence for phenotypic variability.

Keywords: Founder mutation; LGMD2C; Puerto Rico; SGCG; gamma-sarcoglycan.

Figure 1

Family structure, genotyping, and haplotype analysis. Two-generation pedigrees for families 1, 2, 3, and 4 are shown. Probands and family members were screened for the E263K mutation. Genotyping for six polymorphic microsatellite markers on chromosome 13 internal to (D13S232) and flanking (D13S175, D13S292, D13S787, D13S1243, D13S283) the SGCG gene revealed a common disease-bearing haplotype (shaded in gray).

Figure 2

Immunostaining of quadriceps muscle samples for Patients 1 and 2. Complete absence of staining (K and M) for γ-sarcoglycan antibody is demonstrated in both patients. Patient 1′s muscle tissue (E, H, and N) shows partial reduction in staining of α-, β-, and δ-sarcoglycan, while tissue on Patient 2 (F, I, and O) demonstrates loss of expression of α- and β-sarcoglycan and reduction in δ-sarcoglycan.