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

Abstract

IntroductionMutations ofCELgene 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 ofCELin patients with diabetes and confirm their pathogenicity.Research design and methodsAll 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 novelCELvariants were evaluated in HEK293 cells transfected with wild-type and mutant plasmids. Finally, we summarized allCELgene variants recorded in Human Gene Mutation Database and analyzed the mutation distribution of CEL.ResultsFive novel heterozygous variants were identified inCELgene and they were predicted to be pathogenic by bioinformatic analysis. Moreover, in vitro studies indicated that the expression of CELR540Cwas 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 reportedCELvariants 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.ConclusionOur study identified five novelCELvariants in patients with different subtypes of diabetes, expanding the gene mutation spectrum ofCELand confirmed the pathogenicity of several novel variants.