title: 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.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Joshi
authors.initials: J
authors.lastname: Stephen
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.|Division of Medical Genomics, Inova Translational Medicine Institute, Fairfax, VA, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Vilboux
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology and Nutrition, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.|Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Yael
authors.initials: Y
authors.lastname: Haberman
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Hadass
authors.initials: H
authors.lastname: Pri-Chen
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.|The Dr Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Ben
authors.initials: B
authors.lastname: Pode-Shakked
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sina
authors.initials: S
authors.lastname: Mazaheri
authors.affiliation: Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Marek-Yagel
authors.affiliation: Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Ortal
authors.initials: O
authors.lastname: Barel
authors.affiliation: Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Di Segni
authors.affiliation: Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Eyal
authors.affiliation: Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Goni
authors.initials: G
authors.lastname: Hout-Siloni
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology and Nutrition, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Avishay
authors.initials: A
authors.lastname: Lahad
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology and Nutrition, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Tzippora
authors.initials: T
authors.lastname: Shalem
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.|NIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: May Christine V
authors.initials: MC
authors.lastname: Malicdan
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology and Nutrition, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Batia
authors.initials: B
authors.lastname: Weiss
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.|NIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.|Office of the Clinical Director, NHGRI, National Institutes of Health, Bethesda, MD, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D002648:Child; D051048:Diacylglycerol O-Acyltransferase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D007223:Infant; D008052:Lipid Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D000072417:Protein Domains; D011504:Protein-Losing Enteropathies / Q000175:diagnosis / Q000235:genetics*; D012326:RNA Splicing
chemical_list: C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase