Identification and characterization of a novel missense mutation associated with congenital diarrhea.

Acyl-CoA:diacylglycerol acyltransferase (DGAT)1 and DGAT2 catalyze triglyceride (TG) biosynthesis in humans. Biallelic loss-of-function mutations in human result in severe congenital diarrhea and protein-losing enteropathy. Additionally， pharmacologic inhibition of DGAT1 led to dose-related diarrhea in human clinical trials. Here we identify a previously unknown mutation in identical twins of South Asian descent. These male patients developed watery diarrhea shortly after birth， with protein-losing enteropathy and failure to thrive. Exome sequencing revealed a homozygous recessive mutation in ， c.314T>C， p.L105P. We show here that the p.L105P DGAT1 enzyme produced from the mutant allele is less abundant， resulting in partial loss of TG synthesis activity and decreased formation of lipid droplets in patient-derived primary dermal fibroblasts. Thus， in contrast with complete loss-of-function alleles of ， the p.L105P missense allele partially reduces TG synthesis activity and causes a less severe clinical phenotype. Our findings add to the growing recognition of DGAT1 deficiency as a cause of congenital diarrhea with protein-losing enteropathy and indicate that mutations result in a spectrum of diseases.