TY - JOUR
T1 - Congenital protein losing enteropathy
T2 - An inborn error of lipid metabolism due to DGAT1 mutations
AU - Stephen, Joshi
AU - Vilboux, Thierry
AU - Haberman, Yael
AU - Pri-Chen, Hadass
AU - Pode-Shakked, Ben
AU - Mazaheri, Sina
AU - Marek-Yagel, Dina
AU - Barel, Ortal
AU - Di Segni, Ayelet
AU - Eyal, Eran
AU - Hout-Siloni, Goni
AU - Lahad, Avishay
AU - Shalem, Tzippora
AU - Rechavi, Gideon
AU - Malicdan, May Christine V.
AU - Weiss, Batia
AU - Gahl, William A.
AU - Anikster, Yair
N1 - Publisher Copyright:
© 2016 Macmillan Publishers Limited, part of Springer Nature.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84958780885&partnerID=8YFLogxK
U2 - 10.1038/ejhg.2016.5
DO - 10.1038/ejhg.2016.5
M3 - Article
C2 - 26883093
AN - SCOPUS:84958780885
SN - 1018-4813
VL - 24
SP - 1268
EP - 1273
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 9
ER -