Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability

Item Type:	Article
Title:	Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability
Creators Name:	Bögershausen, N. and Shahrzad, N. and Chong, J.X. and von Kleist-Retzow, J.C. and Stanga, D. and Li, Y. and Bernier, F.P. and Loucks, C.M. and Wirth, R. and Puffenberger, E.G. and Hegele, R.A. and Schreml, J. and Lapointe, G. and Keupp, K. and Brett, C.L. and Anderson, R. and Hahn, A. and Innes, A.M. and Suchowersky, O. and Mets, M.B. and Nürnberg, G. and McLeod, D.R. and Thiele, H. and Waggoner, D. and Altmüller, J. and Boycott, K.M. and Schoser, B. and Nürnberg, P. and Ober, C. and Heller, R. and Parboosingh, J.S. and Wollnik, B. and Sacher, M. and Lamont, R.E.
Abstract:	Myopathies are a clinically and etiologically heterogeneous group of disorders that can range from limb girdle muscular dystrophy (LGMD) to syndromic forms with associated features including intellectual disability. Here, we report the identification of mutations in transport protein particle complex 11 (TRAPPC11) in three individuals of a consanguineous Syrian family presenting with LGMD and in five individuals of Hutterite descent presenting with myopathy, infantile hyperkinetic movements, ataxia, and intellectual disability. By using a combination of whole-exome or genome sequencing with homozygosity mapping, we identified the homozygous c.2938G>A (p.Gly980Arg) missense mutation within the gryzun domain of TRAPPC11 in the Syrian LGMD family and the homozygous c.1287+5G>A splice-site mutation resulting in a 58 amino acid in-frame deletion (p.Ala372_Ser429del) in the foie gras domain of TRAPPC11 in the Hutterite families. TRAPPC11 encodes a component of the multiprotein TRAPP complex involved in membrane trafficking. We demonstrate that both mutations impair the binding ability of TRAPPC11 to other TRAPP complex components and disrupt the Golgi apparatus architecture. Marker trafficking experiments for the p.Ala372_Ser429del deletion indicated normal ER-to-Golgi trafficking but dramatically delayed exit from the Golgi to the cell surface. Moreover, we observed alterations of the lysosomal membrane glycoproteins lysosome-associated membrane protein 1 (LAMP1) and LAMP2 as a consequence of TRAPPC11 dysfunction supporting a defect in the transport of secretory proteins as the underlying pathomechanism.
Keywords:	Ataxia, Chromosome Mapping, Consanguinity, Creatine Kinase, Endoplasmic Reticulum, Exome, Golgi Apparatus, Homozygote, Intellectual Disability, Limb-Girdle Muscular Dystrophies, Lysosomal Membrane Proteins, Lysosomal-Associated Membrane Protein 2, Lysosomes, Movement Disorders, Multiprotein Complexes, Muscular Diseases, Pedigree, Protein Binding, Protein Transport, RNA Splice Sites, Sequence Deletion, Syria, Vesicular Transport Proteins, Young Adult
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	Cell Press
Volume:	93
Number:	1
Page Range:	181-190
Date:	11 July 2013
Official Publication:	https://doi.org/10.1016/j.ajhg.2013.05.028
PubMed:	View item in PubMed

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