TY - JOUR T1 - Identification and characterization of novel carboxyl ester lipase gene variants in patients with different subtypes of diabetes JF - BMJ Open Diabetes Research & Care JO - BMJ Open Diab Res Care DO - 10.1136/bmjdrc-2022-003127 VL - 11 IS - 1 SP - e003127 AU - Huixiao Wu AU - Meng Shu AU - Changmei Liu AU - Wanyi Zhao AU - Qiu Li AU - Yuling Song AU - Ting Zhang AU - Xinyu Chen AU - Yingzhou Shi AU - Ping Shi AU - Li Fang AU - Runbo Wang AU - Chao Xu Y1 - 2023/01/01 UR - http://drc.bmj.com/content/11/1/e003127.abstract N2 - Introduction Mutations of CEL gene were first reported to cause a new type of maturity-onset diabetes of the young (MODY) denoted as MODY8 and then were also found in patients with type 1 (T1D) and type 2 diabetes (T2D). However, its genotype-phenotype relationship has not been fully determined and how carboxyl ester lipase (CEL) variants result in diabetes remains unclear. The aim of our study was to identify pathogenic variants of CEL in patients with diabetes and confirm their pathogenicity.Research design and methods All five patients enrolled in our study were admitted to Shandong Provincial Hospital and diagnosed with diabetes in the past year. Whole-exome sequencing was performed to identify pathogenic variants in three patients with MODY-like diabetes, one newborn baby with T1D and one patient with atypical T2D, as well as their immediate family members. Then the consequences of the identified variants were predicted by bioinformatic analysis. Furthermore, pathogenic effects of two novel CEL variants were evaluated in HEK293 cells transfected with wild-type and mutant plasmids. Finally, we summarized all CEL gene variants recorded in Human Gene Mutation Database and analyzed the mutation distribution of CEL.Results Five novel heterozygous variants were identified in CEL gene and they were predicted to be pathogenic by bioinformatic analysis. Moreover, in vitro studies indicated that the expression of CELR540C was remarkably increased, while p.G729_T739del variant did not significantly affect the expression of CEL. Both novel variants obviously abrogated the secretion of CEL. Furthermore, we summarized all reported CEL variants and found that 74.3% of missense mutations were located in exons 1, 3, 4, 10 and 11 and most missense variants clustered near catalytic triad, Arg-83 and Arg-443.Conclusion Our study identified five novel CEL variants in patients with different subtypes of diabetes, expanding the gene mutation spectrum of CEL and confirmed the pathogenicity of several novel variants.All data relevant to the study are included in the article or uploaded as supplementary information. ER -