Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus

Abstract

Type 2 or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes worldwide, affecting approximately 4% of the world's adult population. It is multifactorial in origin with both genetic and environmental factors contributing to its development. A genome-wide screen for type 2 diabetes genes carried out in Mexican Americans localized a susceptibility gene, designated NIDDM1, to chromosome 2. Here we describe the positional cloning of a gene located in the NIDDM1 region that shows association with type 2 diabetes in Mexican Americans and a Northern European population from the Botnia region of Finland. This putative diabetes-susceptibility gene encodes a ubiquitously expressed member of the calpain-like cysteine protease family, calpain-10 (CAPN10). This finding suggests a novel pathway that may contribute to the development of type 2 diabetes.

Common polymorphisms of calpain-10 are associated with abdominal obesity in subjects at high risk of type 2 diabetes

“…Thr504Ala) or may affect the levels of expression of calpain-10, e.g. SNP-43 in fat and skeletal muscle [2,4,28,29]. The novel finding of the present study was that SNP-43 affects intra-abdominal obesity and insulin sensitivity in offspring of patients with type 2 diabetes (Study I).…”

“…Abdominal obesity is a major risk factor for insulin resistance and type 2 diabetes [1]. Genetic variation in the calpain 10 gene (CAPN10) is associated with type 2 diabetes [2]. Calpain-10 is a calcium-activated protein expressed in all human tissues [3], but the biochemical and physiological mechanism(s) by which it affects the risk of type 2 diabetes remain unclear.…”

“…Calpain-10 is a calcium-activated protein expressed in all human tissues [3], but the biochemical and physiological mechanism(s) by which it affects the risk of type 2 diabetes remain unclear. The G allele of the single nucleotide polymorphism (SNP)-43, has been associated with insulin resistance [4] and type 2 diabetes in both cross-sectional [2] and prospective studies [5]. However, other studies have not found an association of the G allele with type 2 diabetes or insulin resistance [6][7][8], and other SNPs and/or haplotypes in the same locus have been proposed to be more important for glucose metabolism [6,[9][10][11].…”

Mitochondrial calpain 10 activity and expression in the kidney of multiple species

“…In 2000 a genome wide scan for type II diabetes susceptibility genes in a population of Mexican Americans identified the calpain 10 gene (CAPN10) as a putative type 2 diabetes susceptibility gene [4]. Since then, multiple other studies involving diverse populations have supported this finding, while others have not [7].…”

“…Specifically, rabbit mitochondrial calpain 10 has a mitochondrial targeting sequence and is responsible for Ca +2 -induced cleavage of Complex I proteins NDUFV2 and ND6. Horikawa et al [4] described the genetics of human CAPN10, specifically the ability of the gene to undergo alternate splicing, yielding eight potential gene products of varying size. To date there has not been conclusive evidence that the protein products of CAPN10 splice variants are expressed, although multiple investigators have identified immunoreactive bands that correspond to the predicted molecular weight of the splice variants [12;13;14].…”