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

Joshi Stephen, Thierry Vilboux, Yael Haberman, Hadass Pri-Chen, Ben Pode-Shakked, Sina Mazaheri, Dina Marek-Yagel, Ortal Barel, Ayelet Di Segni, Eran Eyal, Goni Hout-Siloni, Avishay Lahad, Tzippora Shalem, Gideon Rechavi, May Christine V. Malicdan*, Batia Weiss, William A. Gahl, Yair Anikster

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1268-1273
Number of pages6
JournalEuropean Journal of Human Genetics
Issue number9
StatePublished - 1 Aug 2016


FundersFunder number
National Institute of Diabetes and Digestive and Kidney DiseasesP30DK078392


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