Mutations in TRAPPC12 Manifest in Progressive Childhood Encephalopathy and Golgi Dysfunction.

Autor:	Milev MP; Department of Biology, Concordia University, Montreal, QC H4B 1R6, Canada., Grout ME; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA., Saint-Dic D; Department of Biology, Concordia University, Montreal, QC H4B 1R6, Canada., Cheng YH; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA., Glass IA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA., Hale CJ; Department of Pathology, Center for Precision Diagnostics, University of Washington, Seattle, WA 98195, USA., Hanna DS; Department of Pathology, Center for Precision Diagnostics, University of Washington, Seattle, WA 98195, USA., Dorschner MO; Department of Pathology, Center for Precision Diagnostics, University of Washington, Seattle, WA 98195, USA., Prematilake K; Department of Biology, Concordia University, Montreal, QC H4B 1R6, Canada., Shaag A; Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel., Elpeleg O; Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel., Sacher M; Department of Biology, Concordia University, Montreal, QC H4B 1R6, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 0C7, Canada. Electronic address: michael.sacher@concordia.ca., Doherty D; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. Electronic address: ddoher@uw.edu., Edvardson S; Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; Pediatric Neurology Unit, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2017 Aug 03; Vol. 101 (2), pp. 291-299.
DOI:	10.1016/j.ajhg.2017.07.006
Abstrakt:	Progressive childhood encephalopathy is an etiologically heterogeneous condition characterized by progressive central nervous system dysfunction in association with a broad range of morbidity and mortality. The causes of encephalopathy can be either non-genetic or genetic. Identifying the genetic causes and dissecting the underlying mechanisms are critical to understanding brain development and improving treatments. Here, we report that variants in TRAPPC12 result in progressive childhood encephalopathy. Three individuals from two unrelated families have either a homozygous deleterious variant (c.145delG [p.Glu49Argfs ∗ 14]) or compound-heterozygous variants (c.360dupC [p.Glu121Argfs ∗ 7] and c.1880C>T [p. Ala627Val]). The clinical phenotypes of the three individuals are strikingly similar: severe disability, microcephaly, hearing loss, spasticity, and characteristic brain imaging findings. Fibroblasts derived from all three individuals showed a fragmented Golgi that could be rescued by expression of wild-type TRAPPC12. Protein transport from the endoplasmic reticulum to and through the Golgi was delayed. TRAPPC12 is a member of the TRAPP protein complex, which functions in membrane trafficking. Variants in several other genes encoding members of the TRAPP complex have been associated with overlapping clinical presentations, indicating shared and distinct functions for each complex member. Detailed understanding of the TRAPP-opathies will illuminate the role of membrane protein transport in human disease. (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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