title: Identification of mutations in TRAPPC9, which encodes the NIK- and IKK-beta-binding protein, in nonsyndromic autosomal-recessive mental retardation.
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 approximately 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-beta-binding protein (NIBP), which is involved in the NF-kappaB 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.
authors.affiliation: Department of Bioscience, COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Asif
authors.initials: A
authors.lastname: Mir
authors.forename: Liana
authors.initials: L
authors.lastname: Kaufman
authors.forename: Abdul
authors.initials: A
authors.lastname: Noor
authors.forename: Mahdi M
authors.initials: MM
authors.lastname: Motazacker
authors.forename: Talal
authors.initials: T
authors.lastname: Jamil
authors.forename: Matloob
authors.initials: M
authors.lastname: Azam
authors.forename: Kimia
authors.initials: K
authors.lastname: Kahrizi
authors.forename: Muhammad Arshad
authors.initials: MA
authors.lastname: Rafiq
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.forename: Tanveer
authors.initials: T
authors.lastname: Nasr
authors.forename: Farooq
authors.initials: F
authors.lastname: Naeem
authors.forename: Andreas
authors.initials: A
authors.lastname: Tzschach
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Kuss
authors.forename: Gisele E
authors.initials: GE
authors.lastname: Ishak
authors.forename: Dan
authors.initials: D
authors.lastname: Doherty
authors.forename: H Hilger
authors.initials: HH
authors.lastname: Ropers
authors.forename: A James
authors.initials: AJ
authors.lastname: Barkovich
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ayub
authors.forename: John B
authors.initials: JB
authors.lastname: Vincent
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D008607:Intellectual Disability / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins; D008126:Lod Score; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D002352:Carrier Proteins; D051550:I-kappa B Kinase; D036341:Intercellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D000097782:NF-kappaB-Inducing Kinase; C503887:TRAPPC9 protein, human