CEL – Maturity-Onset Diabetes of the Young

Carboxyl ester lipase (CEL) is implicated in MODY8, an autosomal dominant form of maturity-onset diabetes of the young. Heterozygous single-base deletions in the VNTR of exon 11 (DEL1, DEL4) cosegregate with diabetes and exocrine dysfunction in two multigenerational families (6/7 affected) ([PMID:19760265]). A Japanese adolescent presented with ketoacidosis and transient insulin deficiency harboring a novel frameshift, c.146_147delCT (p.Ser49CysfsTer52) in exon 2, without exocrine involvement ([PMID:35082198]). A rare high-risk allele, p.Ile488Thr, was identified by WES in an Iranian kindred and segregated with diabetes in two unrelated families ([PMID:33072637]). To date, fewer than ten unrelated probands have been reported, supporting limited genetic evidence for CEL-MODY.

Functional assays demonstrate that pathogenic CEL variants misfold, form intracellular aggregates, impair secretion, and induce endoplasmic reticulum stress in pancreatic and HEK293 cells. Coexpression of wild-type CEL attenuates proteotoxicity, consistent with a dominant-negative or gain-of-function mechanism ([PMID:31963687]; [PMID:33862081]). These data concordantly link CEL misfolding to pancreatic dysfunction. However, the low prevalence of pathogenic alleles and small sample sizes preclude a definitive classification. CEL should be included in MODY diagnostic panels for early-onset, antibody-negative diabetes given potential treatment implications.

References

• The Tohoku journal of experimental medicine • 2022 • Identification of a Novel Mutation in Carboxyl Ester Lipase Gene in a Patient with MODY-like Diabetes. PMID:35082198
• Human genetics • 2010 • Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of monogenic diabetes. PMID:19760265
• Advanced biomedical research • 2020 • Molecular Genetic Study in a Cohort of Iranian Families Suspected to Maturity-Onset Diabetes of the Young, Reveals a Recurrent Mutation and a High-Risk Variant in the CEL Gene. PMID:33072637
• Cells • 2020 • Pathogenic Carboxyl Ester Lipase (CEL) Variants Interact with the Normal CEL Protein in Pancreatic Cells. PMID:31963687
• The Journal of biological chemistry • 2021 • The position of single-base deletions in the VNTR sequence of the carboxyl ester lipase (CEL) gene determines proteotoxicity. PMID:33862081

Evidence Based Scoring (AI generated)