2. Academic Validation
  3. Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability

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

  • Am J Hum Genet. 2013 Jul 11;93(1):181-90. doi: 10.1016/j.ajhg.2013.05.028.
Nina Bögershausen 1,  Nassim Shahrzad,  Jessica X Chong,  Jürgen-Christoph von Kleist-Retzow,  Daniela Stanga,  Yun Li,  Francois P Bernier,  Catrina M Loucks,  Radu Wirth,  Eric G Puffenberger,  Robert A Hegele,  Julia Schreml,  Gabriel Lapointe,  Katharina Keupp,  Christopher L Brett,  Rebecca Anderson,  Andreas Hahn,  A Micheil Innes,  Oksana Suchowersky,  Marilyn B Mets,  Gudrun Nürnberg,  D Ross McLeod,  Holger Thiele,  Darrel Waggoner,  Janine Altmüller,  Kym M Boycott,  Benedikt Schoser,  Peter Nürnberg,  Carole Ober,  Raoul Heller,  Jillian S Parboosingh,  Bernd Wollnik,  Michael Sacher,  Ryan E Lamont
Affiliations

Affiliation

  • 1 Institute of Human Genetics, University Hospital Cologne, 50931 Cologne, Germany.
PMID: 23830518 DOI: 10.1016/j.ajhg.2013.05.028
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.

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