title: A truncating mutation of TRAPPC9 is associated with autosomal-recessive intellectual disability and postnatal microcephaly.
abstract: Although autosomal genes are increasingly recognized as important causes of intellectual disability, very few of them are known. We identified a genetic locus for autosomal-recessive nonsyndromic intellectual disability associated with variable postnatal microcephaly through homozygosity mapping of a consanguineous Israeli Arab family. Sequence analysis of genes in the candidate interval identified a nonsense nucleotide change in the gene that encodes TRAPPC9 (trafficking protein particle complex 9, also known as NIBP), which has been implicated in NF-kappaB activation and possibly in intracellular protein trafficking. TRAPPC9 is highly expressed in the postmitotic neurons of the cerebral cortex, and MRI analysis of affected patients shows defects in axonal connectivity. This suggests essential roles of TRAPPC9 in human brain development, possibly through its effect on NF-kappaB activation and protein trafficking in the postmitotic neurons of the cerebral cortex.
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ganeshwaran H
authors.initials: GH
authors.lastname: Mochida
authors.forename: Muhammad
authors.initials: M
authors.lastname: Mahajnah
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Hill
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
authors.forename: Danielle
authors.initials: D
authors.lastname: Gleason
authors.forename: R Sean
authors.initials: RS
authors.lastname: Hill
authors.forename: Adria
authors.initials: A
authors.lastname: Bodell
authors.forename: Moira
authors.initials: M
authors.lastname: Crosier
authors.forename: Rachel
authors.initials: R
authors.lastname: Straussberg
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D002874:Chromosome Mapping; D003241:Consanguinity; D018507:Gene Expression Regulation, Developmental; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008831:Microcephaly / Q000235:genetics*; D008938:Mitosis; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics; D009474:Neurons / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; C503887:TRAPPC9 protein, human