Two New Mutations in the CEL Gene Causing Diabetes and Hereditary Pancreatitis: How to Correctly Identify MODY8 Cases

Abstract

Objective Maturity-onset diabetes of the young, type 8 (MODY8) is associated with mutations in the CEL gene, which encodes the digestive enzyme carboxyl ester lipase. Several diabetes cases and families have in recent years been attributed to mutations in CEL without any functional or clinical evidence provided. To facilitate correct MODY8 diagnostics, we screened two cohorts of diabetes patients and delineated the phenotype. Research design Young, lean Swedish and Finnish patients with a diagnosis of type 2 diabetes (352 cases, 406 controls) were screened for mutations in the CEL gene. We also screened 58 Czech MODY cases who had tested negative for common MODY genes. For CEL mutation-positive subjects, family history was recorded, and clinical investigations and pancreatic imaging performed. Results One Swedish and one Czech case with germline mutation in CEL were identified. Clinical and radiological investigations of these two probands and their families revealed dominantly inherited insulin-dependent diabetes, pancreatic exocrine dysfunction and atrophic pancreas with lipomatosis and cysts. Notably, hereditary pancreatitis was the predominant phenotype in one pedigree. Both families carried single-base pair deletions in the proximal part of the CEL variable number of tandem repeat (VNTR) region in exon 11. The mutations are predicted to lead to aberrant protein tails that make the CEL protein susceptible to aggregation. Conclusions The diagnosis of MODY8 requires a pancreatic exocrine phenotype and a deletion in the CEL VNTR in addition to dominantly inherited diabetes. CEL screening may be warranted also in families with hereditary pancreatitis of unknown genetic etiology.

ISPAD Clinical Practice Consensus Guidelines 2022: The diagnosis and management of monogenic diabetes in children and adolescents

“…The CEL gene is highly polymorphic and extremely difficult to sequence. El Jellas et al recently described how to diagnose CEL‐MODY 219 . The disease mechanism of CEL‐MODY involves protein misfolding/aggregation, endoplasmic reticulum stress, and proteotoxicity 220–223 .…”

Identification and characterization of novel carboxyl ester lipase gene variants in patients with different subtypes of diabetes

“…Ex.8-11del and Ex.10-11del variants lead to lower levels of CEL transcripts in patients; this might be attributed to significant degradation by nonsense mRNA-mediated decay. 21 …”

Exocrine-Endocrine Crosstalk: The Influence of Pancreatic Cellular Communications on Organ Growth, Function and Disease

“…Maturity Onset Diabetes of the Young type 8 (MODY8) is a form of diabetes that results from mutations in Carboxyl Ester Lipase ( CEL ) ( 92 ). Secreted by acinar cells, CEL functions to breakdown fats and allow their proper absorption into the intestines [reviewed in ( 109 )].…”