title: Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability.
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.
authors.affiliation: Institute of Human Genetics, University Hospital Cologne, 50931 Cologne, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Bögershausen
authors.forename: Nassim
authors.initials: N
authors.lastname: Shahrzad
authors.forename: Jessica X
authors.initials: JX
authors.lastname: Chong
authors.forename: Jürgen-Christoph
authors.initials: JC
authors.lastname: von Kleist-Retzow
authors.forename: Daniela
authors.initials: D
authors.lastname: Stanga
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Francois P
authors.initials: FP
authors.lastname: Bernier
authors.forename: Catrina M
authors.initials: CM
authors.lastname: Loucks
authors.forename: Radu
authors.initials: R
authors.lastname: Wirth
authors.forename: Eric G
authors.initials: EG
authors.lastname: Puffenberger
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.forename: Julia
authors.initials: J
authors.lastname: Schreml
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lapointe
authors.forename: Katharina
authors.initials: K
authors.lastname: Keupp
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Brett
authors.forename: Rebecca
authors.initials: R
authors.lastname: Anderson
authors.forename: Andreas
authors.initials: A
authors.lastname: Hahn
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.forename: Oksana
authors.initials: O
authors.lastname: Suchowersky
authors.forename: Marilyn B
authors.initials: MB
authors.lastname: Mets
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: D Ross
authors.initials: DR
authors.lastname: McLeod
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Darrel
authors.initials: D
authors.lastname: Waggoner
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.forename: Benedikt
authors.initials: B
authors.lastname: Schoser
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Carole
authors.initials: C
authors.lastname: Ober
authors.forename: Raoul
authors.initials: R
authors.lastname: Heller
authors.forename: Jillian S
authors.initials: JS
authors.lastname: Parboosingh
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.forename: Michael
authors.initials: M
authors.lastname: Sacher
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Lamont
mesh_terms: D000293:Adolescent; D000328:Adult; D001259:Ataxia / Q000235:genetics; D002874:Chromosome Mapping; D003241:Consanguinity; D003402:Creatine Kinase / Q000097:blood; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059472:Exome; D005260:Female; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D009069:Movement Disorders / Q000235:genetics* / Q000473:pathology; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D011485:Protein Binding; D021381:Protein Transport; D022821:RNA Splice Sites; D017384:Sequence Deletion; D013593:Syria; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D003402:Creatine Kinase; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D046912:Multiprotein Complexes; D022821:RNA Splice Sites; D033921:Vesicular Transport Proteins; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C497811:LAMP2 protein, human