A biochemical, genetic, and clinical survey of autosomal recessive limb girdle muscular dystrophies in Turkey

Abstract

Autosomal recessive limb girdle muscular dystrophy (LGMD2) is a clinically and genetically heterogenous group of diseases involving at least six different loci. Five genes have already been identified: calpain-3 at LGMD2A (15q15), and four members of the sarcoglycan (SG) complex, alpha-SG at LGMD2D (17q21), beta-SG at LGMD2E (4q12), gamma-SG at LGMD2C (13q12), and delta-SG at LGMD2F (5q33-q34). The gene product at LGMD2B (2p13-p16) is still unknown and at least one other gene is still unmapped. We investigated 20 Turkish families (18 consanguineous) diagnosed as having LGMD2. Most of our patients had onset of symptoms before age 10. The phenotypes varied from severe to benign. We analyzed the SG complex by immunofluorescence and/or western blot. Genotyping was performed using markers defining the six known loci and the suspected genes were screened for mutations. Six of 17 index cases showed deficiency of the SG complex, by immunofluorescence and/or western blot. Seven cases involved one of the known genes of the SG complex (alpha, 2; beta, 1; and gamma, 4 cases), and five mutations were documented in the alpha- and gamma-SG genes. After linkage analysis, 10 families were characterized as having LGMD2A (calpain-3 deficiency), and all mutations were eventually identified. One family was classified as having LGMD2B and 1 family that has normal SGs was linked to the chromosome 5q33-q34 locus (LGMD2F). In 1 family there was no linkage to any of the known LGMD2 loci. It appears that in Turkey, there is a broad spectrum of genes and defects involved in LGMD2. It may be possible to correlate genotype to phenotype in LGMD2. All severe cases belonged to the gamma-SG-deficiency group. Nine calpain-3-deficient cases had intermediate and 1 had moderate clinical courses. The LGMD2B patient had a moderate clinical expression, whereas the LGMD2F case was truly benign.

Expanding Members and Roles of the Calpain Superfamily and Their Genetically Modified Animals

“…The positions of the mutation found in the LGMd2A patients were distributed widely within CAPN3, with more than half the mutations being missense [19,24,33,131,132,135,137]. No "hot point" was found, making diagnosis of the disease very difficult.…”

How to tackle the diagnosis of limb-girdle muscular dystrophy 2A

“…Although LGMD2I is the most common form of all LGMDs in Northern Europe, 1 LGMD2A (MIM#253600) is the most prevalent in many European countries, 2 -10 Turkey, 11,12 Brazil, 13 Japan, 14,15 Russia 16 and Australia, 17 with variable frequencies that differ depending on ethnic clusters and geographic origins. Estimates based on molecular data indicate that LGMD2A frequency ranges from about 10% of LGMD cases in the United States 18,19 to 80% in the Basque country and Russia.…”

rAAV vector-mediated sarcogylcan gene transfer in a hamster model for limb girdle muscular dystrophy

“…The disease is caused by mutations in a number of responsible genes, [13][14][15][16][17] including sarcoglycan genes ␣ (LGMD 2D), ␤ (LGMD 2E), ␥ (LGMD 2C) and ␦ (LGMD 2F), respectively. 14,[18][19][20][21][22][23][24] While the phenotype of the sarcoglycanopathies is variable, patients often show a severe progression, with fatality in the second or third decade. No effective treatment is available.…”

“…No effective treatment is available. 14,[19][20][21][22][23][24][25][26][27][28] The sarcoglycans are relatively small (cDNA Ͻ2 kb), transmembrane glycoproteins. The four commonly known sarcoglycans (␣, ␤, ␥ and ␦) associate with each other in equal stoichiometry forming a hetero-tetramer, namely the sarcoglycan complex.…”