CEL – Maturity-Onset Diabetes of the Young Type 8

Maturity-onset diabetes of the young type 8 (MODY8) is an autosomal dominant disorder caused by pathogenic variants in the carboxyl ester lipase gene (CEL) expressed in pancreatic acinar cells. A total of 21 unrelated probands carrying heterozygous frameshift mutations in exon 11 have been described, each presenting with exocrine pancreatic dysfunction in childhood followed by insulin-dependent diabetes in adulthood ([PMID:37726640]). Segregation of these variants with disease has been observed in multiple families, and no alternative genetic causes have been identified, supporting a strong gene–disease relationship.

Genetic evidence is underpinned by recurrent single-base deletions in the variable number tandem repeat (VNTR) region of CEL, notably DEL1 and DEL4, which lead to C-terminal frameshift tails and proteotoxic aggregation. Functional studies in human embryonic kidney cells show that these DEL1/DEL4 variants exhibit significantly reduced secretion, increased intracellular aggregation, and endoplasmic reticulum stress compared with wild-type CEL ([PMID:33862081]). Additional novel variants, such as c.1618C>T (p.Arg540Cys), have been identified in small cohorts, and in vitro assays confirm impaired secretion and stability, expanding the mutational spectrum.

Mechanistic experiments reveal that mutant CEL proteins are transferred from acinar to β-cells, where they form stable intracellular aggregates that disrupt insulin secretion and promote β-cell loss ([PMID:35058633]). Co-expression of pathogenic CEL variants with wild-type protein in pancreatic cell lines further demonstrates dominant-negative effects on secretion and cell viability ([PMID:31963687]). These data are consistent with a proteotoxic mechanism driving both exocrine and endocrine pancreatic pathology.

Despite the association of ER stress-inducing CEL variants with other pancreatic disorders, a case–control study of pancreatic ductal adenocarcinoma found no significant enrichment of MODY8-associated variants in cancer cases versus controls (P = 0.055), indicating that CEL-MODY pathogenic variants specifically predispose to MODY8 rather than neoplastic transformation ([PMID:35995657]).

In summary, heterozygous frameshift mutations in the VNTR of CEL cause misfolding, aggregation, and ER stress in acinar cells with subsequent β-cell toxicity, firmly establishing CEL as a strong monogenic cause of MODY8. Identification of exocrine dysfunction and targeted genetic testing are critical for accurate diagnosis and management. Key take-home: CEL-MODY8 should be considered in nonobese early-onset diabetes with exocrine pancreatic signs for precise genetic diagnosis and tailored care.

References

• Nature Metabolism • 2022 • Abnormal exocrine-endocrine cell cross-talk promotes β-cell dysfunction and loss in MODY8 PMID:35058633
• 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
• Endocrine • 2024 • Clinical and genetic characteristics of CEL-MODY (MODY8): a literature review and screening in Chinese individuals diagnosed with early-onset type 2 diabetes. PMID:37726640
• Cells • 2020 • Pathogenic Carboxyl Ester Lipase (CEL) Variants Interact with the Normal CEL Protein in Pancreatic Cells. PMID:31963687
• Pancreatology • 2022 • Endoplasmic stress-inducing variants in carboxyl ester lipase and pancreatic cancer risk. PMID:35995657

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