Calpainopathy—A Survey of Mutations and Polymorphisms

Abstract

Limb-girdle muscular dystrophy type 2A (LGMD2A) is an autosomal recessive disorder characterized mainly by symmetrical and selective atrophy of the proximal limb muscles. It derives from defects in the human CAPN3 gene, which encodes the skeletal muscle-specific member of the calpain family. This report represents a compilation of the mutations and variants identified so far in this gene. To date, 97 distinct pathogenic calpain 3 mutations have been identified (4 nonsense mutations, 32 deletions/insertions, 8 splice-site mutations, and 53 missense mutations), 56 of which have not been described previously, together with 12 polymorphisms and 5 nonclassified variants. The mutations are distributed along the entire length of the CAPN3 gene. Thus far, most mutations identified represent private variants, although particular mutations have been found more frequently. Knowledge of the mutation spectrum occurring in the CAPN3 gene may contribute significantly to structure/function and pathogenesis studies. It may also help in the design of efficient mutation-screening strategies for calpainopathies.

Natural history of LGMD2A for delineating outcome measures in clinical trials

“…In terms of clinical presentation, our study confirms and further delineates the picture previously reported in several earlier studies 2, 3, 21, 22, 23, 24, 25, 26. Muscle weakness, which is remarkably symmetrical, is predominant in the axial muscles of the trunk and proximal muscles of the lower limb.…”

“…Moreover, the fact that predominant mutations are null mutations prevents our cohort to truly represent the real genetic spectrum of calpainopathy. Indeed, the percentage of null alleles in Centers 2 (78%) and 3 (90%) exceeds what was previously reported (about a third of calpain 3 null alleles in the Leiden database (www.dmd.nl) and 45% in a previous report 21. Since null mutations seem to have a higher deleterious effect than missense mutations, it is possible that clinical presentation reported here is more severe than the mainstream presentation of LGMD2A patients.…”

“…Among the previous studies aimed at describing the clinical features of the disease, only the initial publications reported a follow‐up of the progression2, 3, 21, 22 that was roughly evaluated using the Gardner–Medwin and Walton scale 37. The interindividual variability as measured by MMT, QMT, and MFM was significant, both at baseline and over the follow‐up, yielding small to modest SRM in most of the variables used.…”

Clinical variability in calpainopathy: What makes the difference?

“…This great inter and intra family variability has already been described not only in LGMD2A patients 16 but also in LGMD patients in general. 1,2,5 Here we confirmed this observation in a large calpainopathy sample including a total of 42 patients that carry the same recurrent mutations.…”

“…16 Most of them (70%) represent private variants although particular mutations were found more frequently in some populations. In addition six other mutations were identified exclusively in LGMD2A patients from Japan.…”