Frequency of calpain-3 c.550delA mutation in limb girdle muscular dystrophy type 2 and isolated hyperCKemia in German patients

Aims: Calpain-3 deficiency is the most common cause of autosomal-recessive limb-girdle muscular dystrophy (LGMD2). The 550delA mutation in the CAPN3 gene was frequently identified in patients from Eastern Europe.

Methods: A screening for the 550delA mutation was performed in unrelated German patients with LGMD2 (n=98) and unknown hyperCKemia (n=106). Western blot analysis was available in 76 patients with LGMD2 and 35 patients with hyperCKemia. In samples that were heterozygous for the 550delA mutation the whole coding region of the CAPN3 was analyzed by sequencing.

Results: 550delA was found in 8.1% in LGMD2 (n=1 homozygous, n=7 heterozygous) and 1.9% in hyperCkemia (n=2 heterozygous). In 8/9 heterozygous patients another CAPN3 mutation on the second allele was identified. Two mutations (Val509Phe and Gln565Stop) are novel. Pathological calpain-3 protein was found in 30% of the LGMD2 patients and 17% of the patients with hyperCKemia. Analysis of Calapin-3 protein by Western blotting was available in 9 out of the 10 patients with genetically confirmed LGMD2A and was clearly abnormal in 6 patients, suspicious in two and totally normal in one. Two patients with heterozygous 550delA mutation and onset within the first two decades had joint contractures.

Conclusion: The CAPN3 gene 550delA mutation is frequently identified in German patients with LGMD2, but also in rare cases with hyperCkemia. Thus investigation of the 550delA mutation can be a helpful screening method.