title: Recurrent deletions of ULK4 in schizophrenia: a gene crucial for neuritogenesis and neuronal motility.
abstract: Although many pathogenic copy number variations (CNVs) are associated with neuropsychiatric diseases, few of them have been functionally characterised. Here we report multiple schizophrenia cases with CNV abnormalities specific to unc-51-like kinase 4 (ULK4), a serine/threonine kinase gene. Deletions spanning exons 21-34 of ULK4 were present in 4 out of 3391 schizophrenia patients from the International Schizophrenia Consortium, but absent in 3181 controls. Deletions removing exons 33 and 34 of the large splice variant of ULK4 also were enriched in Icelandic schizophrenia and bipolar patients compared with 98,022 controls (P = 0.0007 for schizophrenia plus bipolar disorder). Combining the two cohorts gives a P-value less than 0.0001 for schizophrenia, or for schizophrenia plus bipolar disorder. The expression of ULK4 is neuron-specific and developmentally regulated. ULK4 modulates multiple signalling pathways that include ERK, p38, PKC and JNK, which are involved in stress responses and implicated in schizophrenia. Knockdown of ULK4 disrupts the composition of microtubules and compromises neuritogenesis and cell motility. Targeted Ulk4 deletion causes corpus callosum agenesis in mice. Our findings indicate that ULK4 is a rare susceptibility gene for schizophrenia.
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.
authors.forename: Bing
authors.initials: B
authors.lastname: Lang
authors.forename: Jin
authors.initials: J
authors.lastname: Pu
authors.forename: Irene
authors.initials: I
authors.lastname: Hunter
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Cristina
authors.initials: C
authors.lastname: Martin-Granados
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Reilly
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Gao
authors.forename: Zhen-Long
authors.initials: ZL
authors.lastname: Guan
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Li
authors.forename: Yong-Yong
authors.initials: YY
authors.lastname: Shi
authors.forename: Guang
authors.initials: G
authors.lastname: He
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.forename: Hreinn
authors.initials: H
authors.lastname: Stefánsson
authors.forename: David
authors.initials: D
authors.lastname: St Clair
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Blackwood
authors.forename: Colin D
authors.initials: CD
authors.lastname: McCaig
authors.forename: Sanbing
authors.initials: S
authors.lastname: Shen
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D016501:Neurites / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012559:Schizophrenia / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion
chemical_list: D017346:Protein Serine-Threonine Kinases; C570299:Ulk4 protein, human
keywords: Neurite branching; Schizophrenia; ULK4; serine/threonine kinase