Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations

Abstract

Protein-losing enteropathy (PLE) is a clinical disorder of protein loss from the gastrointestinal system that results in hypoproteinemia and malnutrition. This condition is associated with a wide range of gastrointestinal disorders. Recently, a unique syndrome of congenital PLE associated with biallelic mutations in the DGAT1 gene has been reported in a single family. We hypothesize that mutations in this gene are responsible for undiagnosed cases of PLE in infancy. Here we investigated three children in two families presenting with severe diarrhea, hypoalbuminemia and PLE, using clinical studies, homozygosity mapping, and exome sequencing. In one family, homozygosity mapping using SNP arrays revealed the DGAT1 gene as the best candidate gene for the proband. Sequencing of all the exons including flanking regions and promoter regions of the gene identified a novel homozygous missense variant, p.(Leu295Pro), in the highly conserved membrane-bound O-acyl transferase (MBOAT) domain of the DGAT1 protein. Expression studies verified reduced amounts of DGAT1 in patient fibroblasts. In a second family, exome sequencing identified a previously reported splice site mutation in intron 8. These cases of DGAT1 deficiency extend the molecular and phenotypic spectrum of PLE, suggesting a re-evaluation of the use of DGAT1 inhibitors for metabolic disorders including obesity and diabetes.

Triglyceride Synthesis by DGAT1 Protects Adipocytes from Lipid-Induced ER Stress during Lipolysis

“…Further, we found a negative correlation of DGAT1 mRNA levels with many UPR genes in adipose tissue of fasted human subjects. In previous studies, we and others found that homozygous DGAT1 loss-of-function mutations in humans leads to a severe congenital diarrheal disorder involving enterocyte dysfunction, which is triggered by a fat-containing diet (Gluchowski et al, 2017; Haas et al, 2012; Stephen et al, 2016). Similarly, DGAT1 inhibition caused dose-related diarrhea in clinical studies of humans (Denison et al, 2014; Meyers et al, 2015).…”

Reversible deficits in apical transporter trafficking associated with deficiency in diacylglycerol acyltransferase

“…Deficiency in DGAT1 is a recently recognized, serious cause of neonatal diarrhea. Since its description in 2012, three genetic mutations have been identified resulting in variable phenotypes of this disease, and suggesting that, like many cases of congenital diarrhea diagnoses, there remains much to learn regarding the presentation, prevalence and etiology of DGAT1 mutation-driven diarrhea 5–7 . Despite the growing recognition of congenital diarrheal pathologies, and the increasing diversity of diagnosis resulting in significant diarrheal disease, the establishment of in vitro models to study the physiology behind these and other diseases remains elusive in the literature.…”

Dgat1 and Dgat2 regulate enterocyte triacylglycerol distribution and alter proteins associated with cytoplasmic lipid droplets in response to dietary fat

“…Dgat2 is present at significantly lower levels compared to Dgat1 in the intestine of mice, and whether DGAT2 is expressed in human intestine is questionable [6]. One of the reasons for this is that a DGAT1 loss of function mutation has been identified in humans and observed to cause congenital diarrheal disorder resulting in severe outcomes [68, 69]. Dgat1 − / − mice, on the other hand, have no obvious increase in fecal fat or diarrhea, and their intestine phenotype contributes to their beneficial resistance to diet induced obesity [16, 18, 19].…”