A null mutation in TNIK defines a novel locus for intellectual disability.
Intellectual disability (ID) is one of the most common disabilities and, although many genes have been implicated in its etiology, the genetic heterogeneity of ID continues to expand. The purpose of the study was to describe a novel autosomal recessive non-syndromic ID locus. Autozygome and linkage analysis, and exome sequencing followed by RNA and protein analysis of the candidate disease gene were performed. We describe two multiplex consanguineous families with non-syndromic ID phenotype, which maps to a critical linkage locus on 3q26. Exome sequencing of the index in each family revealed the same homozygous truncating mutation in TNIK that results in complete loss of the protein. TNIK is a kinase with a well-established role in dendrite development and synaptic transmission. The phenotype we observe in human patients who lack TNIK is consistent with the previously published Tnik (-/-) phenotype in the murine model. Our data strongly implicate TNIK deficiency in the causation of ID in humans.
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Shams
S
Anazi
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Hanan E
HE
Shamseldin
University Diabetes Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Dhekra
D
AlNaqeb
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
Mohamed
M
Abouelhoda
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
Dorota
D
Monies
Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Mustafa A
MA
Salih
University Diabetes Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia. krubeaan@dscenter.org.
Khalid
K
Al-Rubeaan
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.|Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
Fowzan S
FS
Alkuraya
D000818:Animals; D003241:Consanguinity; D004195:Disease Models, Animal; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D000081410:Germinal Center Kinases; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
D000081410:Germinal Center Kinases; D017346:Protein Serine-Threonine Kinases; C000631454:TNIK protein, human