Sequence variants of the sarco(endo)plasmic reticulum Ca 2+ -transport ATPase 3 gene (SERCA3) in Caucasian Type II diabetic patients (UK Prospective Diabetes Study 48)

Abstract

Genetic factors play an important part in the pathogenesis of Type II (non-insulin-dependent) diabetes mellitus, a heterogeneous disorder characterised by defects in insulin action as well as insulin secretion [1]. Investigations of candidate genes for Type II diabetes have led to the identification of polymorphisms of several genes. Major genetic causes of this disease, however, remain elusive.Glucose-dependent sequestration of Ca 2+ into endoplasmic reticulum and its subsequent release play an important part in the control of intracellular Ca 2+ concentration, which regulates insulin secretion in pancreatic beta cells [2]. The active uptake of cytosolic Ca 2+ into endoplasmic reticulum is mediated by sarco(endo)plasmic reticulum Ca 2+ -transport ATPases (SERCAs) Abstract Aims/hypothesis. Type II (non-insulin-dependent) diabetes mellitus is a common heterogeneous metabolic disorder of largely unknown genetic aetiology. The sarco(endo)plasmic reticulum Ca 2+ -transport ATPase (SERCA) plays an important part in the glucose-activated beta-cell Ca 2+ signalling that regulates insulin secretion. Impaired function and expression of SERCA have been shown in islets of Langerhans from diabetic animal models and have also been associated with beta-cell apoptosis. Thus, the SERCA3 encoding gene is a plausible candidate for a primary pancreatic beta-cell defect. Methods. In this study, the entire coding and the promoter regions of SERCA3 gene were screened by single-strand conformation polymorphism analysis in white Caucasian Type II diabetic patients. Results. We found four rare missense mutations [Exon 4: Gln 108 ®His (CAG®CAT), Exon 14: Val 648 ®Met (GTG®ATG) and Arg 674 ®Cys (CGC® TGC), and Exon 15: Ile 753 ®Leu (ATC®CTC)]. The patients with Gln 108 ®His, Val 648 ®Met and Arg 674 ®Cys mutations, which may affect the E1P-E2P transition of SERCA3 during its enzyme cycle, had normal body weight with marked hyperglycaemia and beta-cell dysfunction. That is an unusual phenotype only found in 6 % of the Type II diabetic patients recruited for the UK Prospective Diabetes Study. In addition, five silent polymorphisms, six intron variants and two polymorphisms in the 3' untranslated region of exon 22 were found with similar frequency in diabetic and control subjects. Conclusion/interpretation. Our result suggests that in white Caucasians, the SERCA3 locus possibly contributes to the genetic susceptibility to Type II diabetes [Diabetologia (1999.

Three Novel Sarco/endoplasmic Reticulum Ca2+-ATPase (SERCA) 3 Isoforms

“…1 The abbreviations used are: ER, endoplasmic reticulum; SERCA, sarco/endoplasmic reticulum Ca 2ϩ -ATPase; PMCA, plasma membrane Ca 2ϩ -ATPase; RT, reverse transcriptase; InsP 3 -R, inositol 1,4,5-trisphosphate receptor; PMA, 4␤-phorbol 12-myristate 13-acetate; ATRA, all-trans-retinoic acid; WKY, Wistar Kyoto; SHR, spontaneously hypertensive rat(s); PKC, protein kinase C; h3, human SERCA3; h3a-e, human SERCA3a, -3b, -3c, -3d, and -3e isoforms; r3a, rat SERCA3a; r3b/c, rat SERCA3b/c; aa, amino acid(s); HEK, human embryonic kidney; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. the SERCA3 gene are described in type II diabetic patients (10). In contrast, knockout of SERCA2 and SERCA3 genes leads to impaired cardiac performance (11), followed by squamous cell tumors (12) and defects in endothelium-and epithelium-dependent relaxation of vascular (13) and tracheal (14) smooth muscles, respectively.…”

“…In recent years, there have been enormous advances in our understanding of SERCAs, including new insight into their structure (8) and their relevant physiological functions in human diseases (4,9,10). SERCA1 gene mutations have been reported in some patients with Brody disease, a muscle disease.…”

Dissection of the Functional Differences between Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA) 1 and 3 Isoforms by Steady-state and Transient Kinetic Analyses

“…SERCA3 is always co-expressed along with SERCA2b, and the expression level of SERCA3 varies dramatically from tissue to tissue (16, 18 -22). Specific changes to SERCA3 expression and mutations in the SERCA3 gene have been linked with pathological conditions such as type II diabetes (23,24), hyperten-sion (25,26), defective endothelium-and epithelium-dependent relaxation of smooth muscles (27,28), and, most recently, carcinoma of colon and gastric epithelial cells (29). The human SERCA3a has been cloned from a Jurkat cell line, and the localization of the SERCA3 gene (ATP2A3) on human chromosome 17p13.3, as well as the complete structure of the human SERCA3 gene, has been documented (12,13).…”

Basal Transcription of the Mouse Sarco(endo)plasmic Reticulum Ca2+-ATPase Type 3 Gene in Endothelial Cells Is Controlled by Ets-1 and Sp1

“…It affects the endotheliumand epithelium-dependent relaxation of smooth muscles suggesting its action on synthesis and/or secretion of vasoactive peptides such as nitric oxide (16,17). Mutations of the SERCA3 gene have been reported in some forms of type 2 diabetes (18). The structure of the human SERCA3 gene has been documented (14), but data concerning the mechanisms involved in the transcription of this gene remain scarce.…”