DOES THE SEVERITY OF THE LGMD2A PHENOTYPE IN COMPOUND HETEROZYGOTES DEPEND ON THE COMBINATION OF MUTATIONS?
Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by a deficiency of calpain-3/p94. Although the symptoms in most LGMD2A patients are generally homogeneous, some variation in the severity and progression of the disease has been reported.
Methods: We describe 2 patients who carry the same combination of compound heterozygous mutations (pG222R/pR748Q) and whose symptoms are exceptionally benign compared to homozygotes with each missense mutation.
Results: The benign phenotype observed in association with the combined pG222R and pR748Q mutations suggested that it may result from a compensatory effect of compound heterozygosity rather than the individual mutations themselves. Our analyses revealed that these two mutations exert different effects on the protease activity of calpain-3, suggesting ‘molecular complementation’ in these patients.
Conclusion: We propose several hypotheses to explain how this specific combination of mutations may rescue the normal proteolytic activity of calpain-3, resulting in an exceptionally benign phenotype.
AMETS SÁENZ, PhD,YASUKO ONO, PhD, HIROYUKI SORIMACHI, PhD, MARIA GOICOECHEA, PhD,FRANCE LETURCQ, PhD,LOREA BLÁZQUEZ, PhD, FEDERICO GARCÍA-BRAGADO, MD, PhD, ALBERTO MARINA, PhD,JUAN JOSÉ POZA, MD, PhD, MARGARITA AZPITARTE, MD,NAOKO DOI, MSc, MIGUEL URTASUN, MD, PhD,JEAN-CLAUDE KAPLAN, MD, PhD and ADOLFO LÓPEZ DE MUNAIN, MD, PhD.
Abstract from Muscle Nerve 44: 710–714, 2011