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Identification of Mutations in TRAPPC9, which Encodes the NIK- and IKK-β-Binding Protein, in Nonsyndromic Autosomal-Recessive Mental Retardation

Mir, A.; Kaufman, L.; Noor, A.; Motazacker, M.M.; Jamil, T.; Azam, M.; Kahrizi, K.; Rafiq, M.A.; Weksberg, R.; Nasr, T.; Naeem, F.; Tzschach, A.; Kuss, A.W.; Ishak, G.E.; Doherty, D.; Ropers, H.H.; Barkovich, A.J.; Najmabadi, H.; Ayub, M.; Vincent, J.B.

Authors

A. Mir

L. Kaufman

A. Noor

M.M. Motazacker

T. Jamil

M. Azam

K. Kahrizi

M.A. Rafiq

R. Weksberg

T. Nasr

F. Naeem

A. Tzschach

A.W. Kuss

G.E. Ishak

D. Doherty

H.H. Ropers

A.J. Barkovich

H. Najmabadi

M. Ayub

J.B. Vincent



Abstract

Mental retardation/intellectual disability is a devastating neurodevelopmental disorder with serious impact on affected individuals and their families, as well as on health and social services. It occurs with a prevalence of 2%, is an etiologically heterogeneous condition, and is frequently the result of genetic aberrations. Autosomal-recessive forms of nonsyndromic MR (NS-ARMR) are believed to be common, yet only five genes have been identified. We have used homozygosity mapping to search for the gene responsible for NS-ARMR in a large Pakistani pedigree. Using Affymetrix 5.0 single nucleotide polymorphism (SNP) microarrays, we identified a 3.2 Mb region on 8q24 with a continuous run of 606 homozygous SNPs shared among all affected members of the family. Additional genotype data from microsatellite markers verified this, allowing us to calculate a two-point LOD score of 5.18. Within this region, we identified a truncating homozygous mutation, R475X, in exon 7 of the gene TRAPPC9. In a second large NS-ARMR/ID family, previously linked to 8q24 in a study of Iranian families, we identified a 4 bp deletion within exon 14 of TRAPPC9, also segregating with the phenotype and truncating the protein. This gene encodes NIK- and IKK-β-binding protein (NIBP), which is involved in the NF-B signaling pathway and directly interacts with IKK-β and MAP3K14. Brain magnetic resonance imaging of affected individuals indicates the presence of mild cerebral white matter hypoplasia. Microcephaly is present in some but not all affected individuals. Thus, to our knowledge, this is the sixth gene for NS-ARMR to be discovered.

Citation

Mir, A., Kaufman, L., Noor, A., Motazacker, M., Jamil, T., Azam, M., …Vincent, J. (2009). Identification of Mutations in TRAPPC9, which Encodes the NIK- and IKK-β-Binding Protein, in Nonsyndromic Autosomal-Recessive Mental Retardation. American Journal of Human Genetics, 85(6), 909-915. https://doi.org/10.1016/j.ajhg.2009.11.009

Journal Article Type Article
Publication Date Dec 1, 2009
Deposit Date Jun 22, 2011
Journal American Journal of Human Genetics
Print ISSN 0002-9297
Publisher Cell Press
Peer Reviewed Peer Reviewed
Volume 85
Issue 6
Pages 909-915
DOI https://doi.org/10.1016/j.ajhg.2009.11.009

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