Familial diabetes

Gene: CEL

Green List (high evidence)

Specific dominant negative/gain of function mutations occurring within the first 1-5 repeats of the CEL VNTR are known to cause MODY with pancreatic exocrine dysfunction (MIM609812) (PMID: 24062244, PMID: 21784842, PMID: 19760265, PMID:18544793, PMID:17989309, PMID: 16369531).Heterozygous missense variants and variants resulting in a PTC that will trigger nonsense mediated decay are not expected to cause monogenic diabetes. These VNTR-located mutations cause a shift in the reading frame and generate a highly extended protein at the C-terminus that has been shown to aggregate in pancreatic islets resulting in ER stress and apoptosis (PMID:27650499). CEL mutant proteins were observed as an aggregate at the cell surface and inside large cytoplasmic vacuoles. Many of the vacuoles were identified as components of the endosomal system, and after its secretion, the mutant CEL protein was re-internalized, transported to the lysosomes, and degraded. Internalization of CEL-MUT also led to reduced viability of pancreatic acinar and beta cells (PMID: 25160620).

Created: 15 Feb 2019, 10:28 a.m.

Publications

• 24062244
• 21784842
• 19760265
• 18544793
• 17989309
• 16369531
• 27650499
• 25160620

Green List (high evidence)

Comment on list classification: Promoted from red to green based on the new evidence provided by Jayne Houghton (Royal Devon and Exeter Foundation Trust).

Created: 1 Mar 2019, 2:20 p.m.

Comment on list classification: Promoted from red to green as advised via email communication with Jane Houghton (South West GLH).

Created: 28 Jan 2019, 9:37 a.m.

Initial gene list and info collated by Sian Ellard, University of Exeter Medical School, August 2018 on behalf of the GMS Endocrinology specialist test group. Gene Symbol submitted: CEL; Suggested intial gene rating: Green; Evidence for inclusion: none given; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given; Phenotypes: Diabetes and pancreatic exocrine dysfunction.

Created: 11 Jan 2019, 10:04 a.m.

Comment when marking as ready: Gene kept on the red list due to expert review and complication with reporting of specific variants within this gene.

Created: 7 Jun 2016, 9:59 a.m.

Red List (low evidence)

This is a very rare cause of diabetes and exocrine pancreatic dysfunction (2 families). The CEL gene is difficult to sequence and interpret due to the VNTR repeat sequences. The Exeter lab would only report frameshift mutations in the VNTR-containing exon 11 as pathogenic mutations.

Created: 23 Aug 2015, 4:32 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 16369531

Variants in this GENE are reported as part of current diagnostic practice