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. Epub 2013 Jul 3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Ataxia / genetics
  • Chromosome Mapping
  • Consanguinity
  • Creatine Kinase / blood
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / pathology
  • Exome
  • Female
  • Golgi Apparatus / genetics
  • Golgi Apparatus / metabolism
  • Golgi Apparatus / pathology
  • Homozygote
  • Humans
  • Intellectual Disability / genetics*
  • Lysosomal-Associated Membrane Protein 2
  • Lysosome-Associated Membrane Glycoproteins / genetics
  • Lysosome-Associated Membrane Glycoproteins / metabolism
  • Lysosomes / metabolism
  • Male
  • Movement Disorders / genetics*
  • Movement Disorders / pathology
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Muscular Diseases / genetics*
  • Muscular Diseases / pathology
  • Muscular Dystrophies, Limb-Girdle / genetics*
  • Muscular Dystrophies, Limb-Girdle / pathology
  • Pedigree
  • Protein Binding
  • Protein Transport
  • RNA Splice Sites
  • Sequence Deletion*
  • Syria
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*
  • Young Adult

Substances

  • LAMP1 protein, human
  • LAMP2 protein, human
  • Lysosomal-Associated Membrane Protein 2
  • Lysosome-Associated Membrane Glycoproteins
  • Multiprotein Complexes
  • RNA Splice Sites
  • Vesicular Transport Proteins
  • Creatine Kinase