Identification of mutations in TRAPPC9, which encodes the NIK- and IKK-beta-binding protein, in nonsyndromic autosomal-recessive mental retardation.
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.
Mir
Asif
A
Department of Bioscience, COMSATS Institute of Information Technology, Islamabad, Pakistan.
Kaufman
Liana
L
Noor
Abdul
A
Motazacker
Mahdi M
MM
Jamil
Talal
T
Azam
Matloob
M
Kahrizi
Kimia
K
Rafiq
Muhammad Arshad
MA
Weksberg
Rosanna
R
Nasr
Tanveer
T
Naeem
Farooq
F
Tzschach
Andreas
A
Kuss
Andreas W
AW
Ishak
Gisele E
GE
Doherty
Dan
D
Ropers
H Hilger
HH
Barkovich
A James
AJ
Najmabadi
Hossein
H
Ayub
Muhammad
M
Vincent
John B
JB
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
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