title: Identification and characterization of a novelDGAT1missense mutation associated with congenital diarrhea.
abstract: Acyl-CoA:diacylglycerol acyltransferase (DGAT)1 and DGAT2 catalyze triglyceride (TG) biosynthesis in humans. Biallelic loss-of-function mutations in humanDGAT1result 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 unknownDGAT1mutation 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 inDGAT1, 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 ofDGAT1, 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 thatDGAT1mutations result in a spectrum of diseases.
authors.affiliation: Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA 02115.|Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115.|Harvard Medical School, Boston, MA 02115.
authors.forename: Nina L
authors.initials: NL
authors.lastname: Gluchowski
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115.|Harvard Medical School, Boston, MA 02115.
authors.forename: Chandramohan
authors.initials: C
authors.lastname: Chitraju
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Columbia University Medical Center, New York, NY 10027.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Picoraro
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115.|Harvard Medical School, Boston, MA 02115.
authors.forename: Niklas
authors.initials: N
authors.lastname: Mejhert
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ 07033.
authors.forename: Shirly
authors.initials: S
authors.lastname: Pinto
authors.affiliation: Harvard Medical School, Boston, MA 02115.|Department of Neurology, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Winnie
authors.initials: W
authors.lastname: Xin
authors.affiliation: Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA 02115.|Harvard Medical School, Boston, MA 02115.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Kamin
authors.affiliation: Harvard Medical School, Boston, MA 02115.|Division of Gastroenterology, MassGeneral Hospital for Children, Boston, MA 02114.
authors.forename: Harland S
authors.initials: HS
authors.lastname: Winter
authors.affiliation: Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY 10027.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115 twalther@hsph.harvard.edu robert@hsph.harvard.edu.|Harvard Medical School, Boston, MA 02115.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142.|Howard Hughes Medical Institute, Boston, MA 02115.
authors.forename: Tobias C
authors.initials: TC
authors.lastname: Walther
authors.affiliation: Harvard Medical School, Boston, MA 02115 twalther@hsph.harvard.edu robert@hsph.harvard.edu.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
mesh_terms: D000483:Alleles; D045744:Cell Line, Tumor; D002675:Child, Preschool; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics*; D003967:Diarrhea / Q000151:congenital* / Q000201:enzymology / Q000235:genetics*; D005260:Female; D006720:Homozygote; D006801:Humans; D000073658:Loss of Function Mutation; D008297:Male; D020125:Mutation, Missense; D011247:Pregnancy
chemical_list: C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase
keywords: acyl CoA:diacylglycerol acyltransferase; diet and dietary lipids; genetics; intestine; lipid droplets; protein-losing enteropathy; triglycerides