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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.

SUBMITTER: Stephen J

PROVIDER: S-EPMC4989215 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Stephen Joshi J Vilboux Thierry T Haberman Yael Y Pri-Chen Hadass H Pode-Shakked Ben B Mazaheri Sina S Marek-Yagel Dina D Barel Ortal O Di Segni Ayelet A Eyal Eran E Hout-Siloni Goni G Lahad Avishay A Shalem Tzippora T Rechavi Gideon G Malicdan May Christine V MC Weiss Batia B Gahl William A WA Anikster Yair Y

European journal of human genetics : EJHG 20160217 9

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 ch ...[more]

PMID: 26883093

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Dataset Information

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

Publications

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

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