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

被引：119

作者：

Mir, Asif ^{[2
]}

Kaufman, Liana ^{[1
]}

Noor, Abdul ^{[1
]}

Motazacker, Mahdi M. ^{[3
]}

Jamil, Talal ^{[2
]}

Azam, Matloob ^{[4
]}

Kahrizi, Kimia ^{[5
]}

Rafiq, Muhammad Arshad ^{[1
]}

Weksberg, Rosanna ^{[6
]}

Nasr, Tanveer ^{[7
,8
]}

Naeem, Farooq ^{[9
,10
]}

Tzschach, Andreas ^{[3
]}

Kuss, Andreas W. ^{[3
]}

Ishak, Gisele E. ^{[11
]}

Doherty, Dan ^{[12
]}

Ropers, H. Hilger ^{[3
]}

Barkovich, A. James ^{[13
]}

Najmabadi, Hossein ^{[5
]}

Ayub, Muhammad ^{[7
,14
]}

Vincent, John B. ^{[1
,15
]}

机构：

[1] Ctr Addict & Mental Hlth, Neuropsychiat & Dev Lab, Neurogenet Sect, Toronto, ON M5T 1R8, Canada

[2] COMSATS Inst Informat Technol, Dept Biosci, Islamabad, Pakistan

[3] Max Planck Inst Mol Genet, D-14195 Berlin, Germany

[4] Pakistan Inst Med Sci, Islamabad, Pakistan

[5] Univ Social Welf & Rehabil Sci, Genet Res Ctr, Tehran, Iran

[6] Hosp Sick Children, Program Genet & Genom Biol, Toronto, ON M5G 1L7, Canada

[7] Mayo Hosp, Lahore 54000, Pakistan

[8] Chaudhry Hosp, Gujranwala 52250, Pakistan

[9] Univ Southampton, Sch Med, Southampton SO16 5ST, Hants, England

[10] Lahore Inst Res & Dev, Lahore 54000, Pakistan

[11] Univ Washington, Dept Radiol, Seattle Childrens Hosp, Seattle, WA 98105 USA

[12] Univ Washington, Div Genet & Dev Med, Seattle Childrens Hosp, Seattle, WA 98105 USA

[13] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA

[14] St Lukes Hosp, Middlesbrough TS4 3AF, Cleveland, England

[15] Univ Toronto, Dept Psychiat, Toronto, ON M5T 1R8, Canada

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2009年 / 85卷 / 06期

关键词：

NF-KAPPA-B; HEAD CIRCUMFERENCE; GENE; SUBUNITS; BIRTH;

D O I：

10.1016/j.ajhg.2009.11.009

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Mental retardation/intellectual disability is a devastating neurodevelopmental disorder with serious impact oil affected individuals and their families, as well as on health and social services. It occurs with a prevalence of similar to 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 Lis to calculate a two-point LOD score of 5.18. Within this region, we identified a truncating homozygous mutation, R47SX, 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-beta-binding protein (NIBP), which is involved in the NF-kappa B signaling pathway and directly interacts with IKK-beta 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.

引用

页码：909 / 915

页数：7