A Truncating Mutation of TRAPPC9 Is Associated with Autosomal-Recessive Intellectual Disability and Postnatal Microcephaly

Ganeshwaran H. Mochida, Muhammad Mahajnah, Anthony D. Hill, Lina Basel-Vanagaite, Danielle Gleason, R. Sean Hill, Adria Bodell, Moira Crosier, Rachel Straussberg, Christopher A. Walsh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

122 Scopus citations

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-κB 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-κB activation and protein trafficking in the postmitotic neurons of the cerebral cortex.

Original languageEnglish
Pages (from-to)897-902
Number of pages6
JournalAmerican Journal of Human Genetics
Volume85
Issue number6
DOIs
StatePublished - 11 Dec 2009

Funding

FundersFunder number
National Institutes of Health
National Institute of Neurological Disorders and StrokeR01NS035129
National Institute of Neurological Disorders and Stroke
Simons Foundation
Nancy Lurie Marks Family Foundation
Johns Hopkins UniversityHHSN268200782096C
Johns Hopkins University
National Alliance for Research on Schizophrenia and Depression
Dubai Harvard Foundation for Medical Research
Manton Center for Orphan Disease Research, Boston Children's Hospital

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