Identification and characterization of a novel DGAT1 missense mutation associated with congenital diarrhea.

Autor:	Gluchowski NL; 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., Chitraju C; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115.; Harvard Medical School, Boston, MA 02115., Picoraro JA; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Columbia University Medical Center, New York, NY 10027., Mejhert N; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115.; Harvard Medical School, Boston, MA 02115., Pinto S; Merck & Co., Inc., Kenilworth, NJ 07033., Xin W; Harvard Medical School, Boston, MA 02115.; Department of Neurology, Massachusetts General Hospital, Boston, MA 02114., Kamin DS; Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA 02115.; Harvard Medical School, Boston, MA 02115., Winter HS; Harvard Medical School, Boston, MA 02115.; Division of Gastroenterology, MassGeneral Hospital for Children, Boston, MA 02114., Chung WK; Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY 10027., Walther TC; 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., Farese RV Jr; 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.
Jazyk:	angličtina
Zdroj:	Journal of lipid research [J Lipid Res] 2017 Jun; Vol. 58 (6), pp. 1230-1237. Date of Electronic Publication: 2017 Apr 03.
DOI:	10.1194/jlr.P075119
Abstrakt:	Acyl-CoA:diacylglycerol acyltransferase (DGAT)1 and DGAT2 catalyze triglyceride (TG) biosynthesis in humans. Biallelic loss-of-function mutations in human DGAT1 result 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 unknown DGAT1 mutation 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 in DGAT1 , 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 of DGAT1 , 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 that DGAT1 mutations result in a spectrum of diseases. (Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.)
Databáze:	MEDLINE
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