title: A novelTRAPPC11mutation in two Turkish families associated with cerebral atrophy, global retardation, scoliosis, achalasia and alacrima.
abstract: Triple A syndrome (MIM #231550) is associated with mutations in theAAASgene. However, about 30% of patients with triple A syndrome symptoms but an unresolved diagnosis do not harbour mutations inAAAS.
  
  
  
  Search for novel genetic defects in families with a triple A-like phenotype in whomAAASmutations are not detected.
  
  
  
  Genome-wide linkage analysis, whole-exome sequencing and functional analyses were used to discover and verify a novel genetic defect in two families with achalasia, alacrima, myopathy and further symptoms. Effect and pathogenicity of the mutation were verified by cell biological studies.
  
  
  
  We identified a homozygous splice mutation inTRAPPC11(c.1893+3A>G, [NM_021942.5], g.4:184,607,904A>G [hg19]) in four patients from two unrelated families leading to incomplete exon skipping and reduction in full-length mRNA levels.TRAPPC11encodes for trafficking protein particle complex subunit 11 (TRAPPC11), a protein of the transport protein particle (TRAPP) complex. Western blot analysis revealed a dramatic decrease in full-length TRAPPC11 protein levels and hypoglycosylation of LAMP1. Trafficking experiments in patient fibroblasts revealed a delayed arrival of marker proteins in the Golgi and a delay in their release from the Golgi to the plasma membrane. Mutations inTRAPPC11have previously been described to cause limb-girdle muscular dystrophy type 2S (MIM #615356). Indeed, muscle histology of our patients also revealed mild dystrophic changes. Immunohistochemically, β-sarcoglycan was absent from focal patches.
  
  
  
  The identified novelTRAPPC11mutation represents an expansion of the myopathy phenotype described before and is characterised particularly by achalasia, alacrima, neurological and muscular phenotypes.
authors.affiliation: Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Koehler
authors.affiliation: Department of Biology, Concordia University, Montreal, Quebec, Canada.
authors.forename: Miroslav P
authors.initials: MP
authors.lastname: Milev
authors.affiliation: Department of Biology, Concordia University, Montreal, Quebec, Canada.
authors.forename: Keshika
authors.initials: K
authors.lastname: Prematilake
authors.affiliation: Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Reschke
authors.affiliation: Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Kutzner
authors.affiliation: Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Jühlen
authors.affiliation: Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Dana
authors.initials: D
authors.lastname: Landgraf
authors.affiliation: Pediatric Genetics Department, Ihsan Dogramaci Children's Hospital, Hacettepe University, Ankara, Turkey.
authors.forename: Eda
authors.initials: E
authors.lastname: Utine
authors.affiliation: Department of Medical Genetics, Dr. Behçet Uz Children's Hospital, Izmir, Turkey.
authors.forename: Filiz
authors.initials: F
authors.lastname: Hazan
authors.affiliation: Neuromuscular Diseases Centre, Tepecik Research Hospital, Izmir, Turkey.
authors.forename: Gulden
authors.initials: G
authors.lastname: Diniz
authors.affiliation: Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schuelke
authors.affiliation: Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Huebner
authors.affiliation: Department of Biology, Concordia University, Montreal, Quebec, Canada.|Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Sacher
mesh_terms: D000293:Adolescent; D000309:Adrenal Insufficiency / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D003241:Consanguinity; D004931:Esophageal Achalasia / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D005091:Exons / Q000235:genetics; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics; D014421:Turkey / Q000453:epidemiology; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: D022821:RNA Splice Sites; C000613447:TRAPPC11 protein, human; D033921:Vesicular Transport Proteins
keywords: Achalasia; Alacrimia; Scoliosis; Transport protein particle complex; Triple A syndrome