TY - JOUR
T1 - A Truncating Mutation of TRAPPC9 Is Associated with Autosomal-Recessive Intellectual Disability and Postnatal Microcephaly
AU - Mochida, Ganeshwaran H.
AU - Mahajnah, Muhammad
AU - Hill, Anthony D.
AU - Basel-Vanagaite, Lina
AU - Gleason, Danielle
AU - Hill, R. Sean
AU - Bodell, Adria
AU - Crosier, Moira
AU - Straussberg, Rachel
AU - Walsh, Christopher A.
N1 - Funding Information:
We would like to thank the patients and family for their participation in this research. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. We thank Jennifer Partlow and Brenda Barry for coordinating patient studies, James Barkovich for help in interpretation of brain MRI of Patient 2, Jillian Felie and Dan Rakiec for technical assistance in DNA sequencing, the Partners HealthCare Center for Personalized Genetic Medicine for establishing the lymphoblast cell lines, and Urs Berger for help with in situ hybridization using the mouse brain. The authors would like to thank Jacques Michaud for sharing DNA samples. The human embryonic and fetal material was provided by the joint MRC-Wellcome Trust Human Developmental Biology Resource at the Institute of Human Genetics, Newcastle-upon-Tyne, UK. We thank the consenting women who made this study possible and A. Farnworth, who gained consent on our behalf. This research was supported by grants from the NINDS (2R01NS035129-12) to C.A.W. and by the Nancy Lurie Marks Family Foundation, the Dubai Harvard Foundation for Medical Research, the Simons Foundation, and the Manton Center for Orphan Disease Research. G.H.M. was supported by the Young Investigator Award of NARSAD as a NARSAD Lieber Investigator. C.A.W. is an Investigator of the Howard Hughes Medical Institute.
PY - 2009/12/11
Y1 - 2009/12/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=71149100261&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2009.10.027
DO - 10.1016/j.ajhg.2009.10.027
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C2 - 20004763
AN - SCOPUS:71149100261
SN - 0002-9297
VL - 85
SP - 897
EP - 902
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -