TY - JOUR
T1 - Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability
AU - Bögershausen, Nina
AU - Shahrzad, Nassim
AU - Chong, Jessica X.
AU - Von Kleist-Retzow, Jürgen Christoph
AU - Stanga, Daniela
AU - Li, Yun
AU - Bernier, Francois P.
AU - Loucks, Catrina M.
AU - Wirth, Radu
AU - Puffenberger, Eric G.
AU - Hegele, Robert A.
AU - Schreml, Julia
AU - Lapointe, Gabriel
AU - Keupp, Katharina
AU - Brett, Christopher L.
AU - Anderson, Rebecca
AU - Hahn, Andreas
AU - Innes, A. Micheil
AU - Suchowersky, Oksana
AU - Mets, Marilyn B.
AU - Nürnberg, Gudrun
AU - McLeod, D. Ross
AU - Thiele, Holger
AU - Waggoner, Darrel
AU - Altmüller, Janine
AU - Boycott, Kym M.
AU - Schoser, Benedikt
AU - Nürnberg, Peter
AU - Ober, Carole
AU - Heller, Raoul
AU - Parboosingh, Jillian S.
AU - Wollnik, Bernd
AU - Sacher, Michael
AU - Lamont, Ryan E.
N1 - Funding Information:
We are grateful to all family members that participated in this study and to Karin Boss and Bob Argiropolous for critically reading the manuscript, Leo Dimnik for assistance with NGS data, and Kelley Moremon for the manII antibody. This work was supported by the German Federal Ministry of Education and Research (BMBF) by grant number 01GM1211A (E-RARE network CRANIRARE-2) to B.W., by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Council of Canada to M.S., research grant #5-FY09-529 from the March of Dimes Foundation to K.M.B., and the National Institutes of Health grants R01HD21244 and R01HL085197 to C.O. R.E.L. was supported by a Remax clinical fellowship from the Alberta Children’s Hospital Foundation and K.M.B. is supported by a Clinical Investigatorship Award from the Canadian Institutes of Health Research, Institute of Genetics. M.S. is a member of the Groupe de Recherche Axé sur la Structure des Protéines (GRASP) network.
PY - 2013/7/11
Y1 - 2013/7/11
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2013.05.028
DO - 10.1016/j.ajhg.2013.05.028
M3 - Article
C2 - 23830518
AN - SCOPUS:84880266535
VL - 93
SP - 181
EP - 190
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 1
ER -