Two New Mutations in the CEL Gene Causing Diabetes and Hereditary Pancreatitis : How to Correctly Identify MODY8 Cases
(2022) In Journal of Clinical Endocrinology and Metabolism 107(4). p.1455-1466- Abstract
Context: 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. Objective: To facilitate correct MODY8 diagnostics, we screened 2 cohorts of diabetes patients and delineated the phenotype. Methods: 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,... (More)
Context: 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. Objective: To facilitate correct MODY8 diagnostics, we screened 2 cohorts of diabetes patients and delineated the phenotype. Methods: 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: Two cases (1 Swedish and 1 Czech) with germline mutation in CEL were identified. Clinical and radiological investigations of these 2 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 1 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. Conclusion: 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.
(Less)
- author
- organization
- publishing date
- 2022-04-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- chronic pancreatitis, MODY8, monogenic diabetes, mutation screening, pancreatic exocrine function, pancreatic imaging
- in
- Journal of Clinical Endocrinology and Metabolism
- volume
- 107
- issue
- 4
- pages
- 1455 - 1466
- publisher
- Oxford University Press
- external identifiers
-
- pmid:34850019
- scopus:85127906982
- ISSN
- 0021-972X
- DOI
- 10.1210/clinem/dgab864
- language
- English
- LU publication?
- yes
- id
- c44491af-9667-41d2-ac2f-4d661e46eb07
- date added to LUP
- 2022-06-10 09:33:41
- date last changed
- 2024-04-18 12:07:27
@article{c44491af-9667-41d2-ac2f-4d661e46eb07,
abstract = {{<p>Context: 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. Objective: To facilitate correct MODY8 diagnostics, we screened 2 cohorts of diabetes patients and delineated the phenotype. Methods: 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: Two cases (1 Swedish and 1 Czech) with germline mutation in CEL were identified. Clinical and radiological investigations of these 2 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 1 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. Conclusion: 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. </p>}},
author = {{El Jellas, Khadija and Dušátková, Petra and Haldorsen, Ingfrid S. and Molnes, Janne and Tjora, Erling and Johansson, Bente B. and Fjeld, Karianne and Johansson, Stefan and Průhová, Štěpánka and Groop, Leif and Löhr, J. Matthias and Njølstad, Pål R. and Molven, Anders}},
issn = {{0021-972X}},
keywords = {{chronic pancreatitis; MODY8; monogenic diabetes; mutation screening; pancreatic exocrine function; pancreatic imaging}},
language = {{eng}},
month = {{04}},
number = {{4}},
pages = {{1455--1466}},
publisher = {{Oxford University Press}},
series = {{Journal of Clinical Endocrinology and Metabolism}},
title = {{Two New Mutations in the CEL Gene Causing Diabetes and Hereditary Pancreatitis : How to Correctly Identify MODY8 Cases}},
url = {{http://dx.doi.org/10.1210/clinem/dgab864}},
doi = {{10.1210/clinem/dgab864}},
volume = {{107}},
year = {{2022}},
}