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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.

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Figure 1: Pedigree of studied branches of Family 1.
Figure 2: Identification of the chromosomal region and gene causing autosomal dominant diabetes and pancreatic exocrine deficiency in Family 1.
Figure 3: Structure and variants of the CEL protein.
Figure 4: Defining pancreatic function in affected subjects in Family 1.
Figure 5: Pancreas structure and morphology.
Figure 6: Studies of the mutant CEL protein.

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Acknowledgements

We thank L. Bindoff, G. Eide, G. Fluge and H. Immervoll for discussions; L. Marselli and G. Weir for sharing unpublished information; S. Aanderud and E. Husebye for providing outpatients; B.H. Berge and L. Aasmul for technical assistance; E. Aubert-Jousset for catalytic constant determinations; B. Mallet and L. Benkoel for assays of C-reactive protein, and orosomucoid and immunohistochemistry experiments, respectively; and the families involved in the study. This work was supported in part by funds from Helse Vest, Haukeland University Hospital and Innovest (to the Department of Pediatrics, Haukeland University Hospital, Bergen), from the University of Bergen, the Meltzer Foundation, Norwegian Diabetes Association and Health & Rehabilitation (to the Institute of Clinical Medicine, University of Bergen, Bergen, Norway) and from INSERM and the Université de la Méditerranée (to the INSERM U-559, Marseille, France).

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Correspondence to Pål Rasmus Njølstad.

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Supplementary information

Supplementary Fig. 1

Pedigree of studied branches of Family 2. (PDF 20 kb)

Supplementary Fig. 2

Pancreas morphology investigated by abdominal CT. (PDF 116 kb)

Supplementary Fig. 3

Sequencing a CEL polymorphism to investigate mutant CEL expression in fibroblasts. (PDF 63 kb)

Supplementary Table 1

Markers with two-point lod scores >1.17 (P < 0.01) in the genome scan of the core pedigree of 61 subjects in Family 1. (PDF 16 kb)

Supplementary Table 2

Two-point lod scores at different theta values between diabetes or elastase deficiency and chromosome 9 saturation markers in the extended pedigree of 184 subjects in Family 1. (PDF 74 kb)

Supplementary Table 3

Clinical characteristics of patients in Family 1 with mutation in CEL. (PDF 21 kb)

Supplementary Table 4

Clinical characteristics of patients in Family 2 with mutation in CEL. (PDF 22 kb)

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Ræder, H., Johansson, S., Holm, P. et al. Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat Genet 38, 54–62 (2006). https://doi.org/10.1038/ng1708

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