Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction

Abstract

Dysfunction of the exocrine pancreas is observed in diabetes, but links between concurrent exocrine and endocrine pancreatic disease and contributing genetic factors are poorly characterized. We studied two families with diabetes and exocrine pancreatic dysfunction by genetic, physiological and in vitro functional studies. A genome-wide screen in Family 1 linked diabetes to chromosome 9q34 (maximal lod score 5.07). Using fecal elastase deficiency as a marker of exocrine pancreatic dysfunction refined the critical chromosomal region to 1.16 Mb (maximal lod score 11.6). Here, we identified a single-base deletion in the variable number of tandem repeats (VNTR)-containing exon 11 of the carboxyl ester lipase (CEL) gene, a major component of pancreatic juice and responsible for the duodenal hydrolysis of cholesterol esters. Screening subjects with maturity-onset diabetes of the young identified Family 2, with another single-base deletion in CEL and a similar phenotype with beta-cell failure and pancreatic exocrine disease. The in vitro catalytic activities of wild-type and mutant CEL protein were comparable. The mutant enzyme was, however, less stable and secreted at a lower rate. Furthermore, we found some evidence for an association between common insertions in the CEL VNTR and exocrine dysfunction in a group of 182 unrelated subjects with diabetes (odds ratio 4.2 (1.6, 11.5)). Our findings link diabetes to the disrupted function of a lipase in the pancreatic acinar cells.

Mutations at the BLK locus linked to maturity onset diabetes of the young and β-cell dysfunction

“…The availability of large families with multiple affected members has facilitated studies of this type of diabetes, leading to the identification of 8 distinct MODY genes: HNF4A, encoding hepatocyte nuclear factor 4␣ (2); GCK, encoding glucokinase (3); TCF1, encoding hepatocyte nuclear factor 1␣ (4); IPF1, encoding insulin promoter factor 1 (5); TCF2, encoding hepatocyte nuclear factor 1␤ (6); NEUROD1, encoding neurogenic differentiation 1 (7); KLF11, encoding for kruppel-like factor 11 (8); and CEL, encoding carboxyl-ester lipase (9). However, 15% or more of MODY cases are not accounted for by mutations in these genes, suggesting the existence of as yet undiscovered MODY genes in addition to those identified to date (10,11).…”

Successful discontinuation of insulin treatment after gestational diabetes is shown to be a case of MODY due to a glucokinase mutation

“…The first MODY gene was found in 1992 [3] and so far 7 genes have been identified that account for 87% of MODY [4][5][6][7][8] in the UK. MODY can be caused by mutation in one of the following genes: HNF4A encoding hepatic nuclear factor 4-α (previously described as MODY1) GCK gene encoding glucokinase (MODY 2) HNF 1A gene encoding hepatic nuclear factor 1-α (MODY 3) PDX1 (IPF1) encoding insulin promoter factor-1(MODY 4) HNF 1B gene encoding hepatic nuclear factor 1-β (MODY 5) NEUROD 1 gene encoding neurogenic differentiation 1 (MODY6) CEL gene encoding carboxy ester lipase or MODY 7 [9] …”

Monoclonal antibody 16D10 to the COOH-terminal domain of the feto-acinar pancreatic protein targets pancreatic neoplastic tissues

“…5B). Interestingly, this tumor presents two isoforms of FAPP due to a polymorphism located in the exon 11 encoding the COOHterminal domain of the protein (30). mAb16D10 also recognized peptides presenting higher migration; in part, it reacted with 40-to 60-and 25-to 35-kDa peptides.…”