Centrosomal proteins Nde1 and Su48 form a complex regulated by phosphorylation

Hirohashi, Yoshihiko; Wang, Qiang; Liu, Q; Li, B; Du, Xiulian; Zhang, Hongtao; Furuuchi, Keiji; Masuda, Kenta; Sato, Noriyuki; Greene, Mark I.

doi:10.1038/sj.onc.1209637

Cited by 37 publications

(30 citation statements)

References 20 publications

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“…NDE1 exon 7 is located C-terminalα-helix where many phosphorylation sites are located (figures 1A and 1B), and predicted to regulate the NDE1 structure and interactions with other proteins. 31,49 Moreover, it was suggested disease associated mutations cluster within protein interacting domains. 50 In the current study, we could detect a significant association (OR = 7.1, P = .039) between SCZ and S214F in the sample comprising 8734 Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Although the contribution of R234C mutation to neurodevelopment remains unclear, the change of the axon length by R234C might relate to NDE1 structure or protein-protein interactions. In fact, several proteins besides YWHAE bind to this region of NDE1, including the S214 and R234 resides; CENPF, 52 Su48, 31 and Katanin p60 are among these. 53 Furthermore, in silico analysis with Splice Aid 2 54 indicates that the nucleotide change causing R234C may be located within an exon-splicing enhancer (ESE) motif 54 and may decrease mRNA transcription because the alternative splicing might result in exon skipping during transcription.…”

Section: Discussionmentioning

confidence: 99%

“…29 NDE1 protein has an N-terminal region with coiled-coil motif known to bind to lissencephaly 1, 30 and a C-terminal region known to harbor several phosphorylation sites involved in subcellular localization, protein-protein interactions and the cell cycle. 31,32 In humans, homozygous loss of function mutations at C-terminal regions have been associated with extreme microlissencephaly, 28,32 suggesting that NDE1 is required for neurogenesis and neuronal migration. NDE1 was also identified as a SCZ susceptibility locus by a genome-wide linkage study on common risk variants of disrupted in schizophrenia 1 (DISC1), 33 which is a scaffold protein indicated in neurodevelopment and synaptic regulation with several interacting proteins and is a suggested risk factor for SCZ, ASD, and BD.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Rare, Single-Nucleotide Mutations in NDE1 and Their Contributions to Schizophrenia Susceptibility

Kimura

Tsuboi

Wang

et al. 2014

Schizophrenia Bulletin

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Background: Nuclear distribution E homolog 1 (NDE1), located within chromosome 16p13.11, plays an essential role in microtubule organization, mitosis, and neuronal migration and has been suggested by several studies of rare copy number variants to be a promising schizophrenia (SCZ) candidate gene. Recently, increasing attention has been paid to rare single-nucleotide variants (SNVs) discovered by deep sequencing of candidate genes, because such SNVs may have large effect sizes and their functional analysis may clarify etiopathology. Methods and Results: We conducted mutation screening of NDE1 coding exons using 433 SCZ and 145 pervasive developmental disorders samples in order to identify rare single nucleotide variants with a minor allele frequency ≤5%. We then performed genetic association analysis using a large number of unrelated individuals (3554 SCZ, 1041 bipolar disorder [BD], and 4746 controls). Among the discovered novel rare variants, we detected significant associations between SCZ and S214F (P = .039), and between BD and R234C (P = .032). Furthermore, functional assays showed that S214F affected axonal outgrowth and the interaction between NDE1 and YWHAE (14-3-3 epsilon; a neurodevelopmental regulator). Conclusions: This study strengthens the evidence for association between rare variants within NDE1 and SCZ, and may shed light into the molecular mechanisms underlying this severe psychiatric disorder.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of Rare, Single-Nucleotide Mutations in NDE1 and Their Contributions to Schizophrenia Susceptibility

Kimura

Tsuboi

Wang

et al. 2014

Schizophrenia Bulletin

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“…DISC1 binding to DBZ influences neurite extension in PC12 cells. 89 Intriguingly, Su48 complexes with NDE1 at the centrosome 232 and a number of studies provide suggestive evidence that this gene may be involved in major mental illness. [233][234][235][236][237] Finally, a novel function for DISC1 is suggested by its interaction with EIF3S3, a component of the eukaryotic initiation factor 3 complex.…”

Section: Disc1 Interaction With Atf4 and Atf5mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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“…For example, ZNF365A is the only isoform observed in rodents, but this isoform is highly conserved among higher-order species, including humans. The ZNF365A/Su48 protein has been implicated as a centrosomal protein in mitosis and is expressed in human brain, heart, lung and pancreas 15 16. In contrast, ZNF365 isoform D appears to have emerged during primate evolution, as it has not been identified in rodents, but is present in monkeys and has been detected in hominoids 15 17.…”

Section: Introductionmentioning

confidence: 99%

Variants in ZNF365 isoform D are associated with Crohn's disease

Haritunians

Jones

McGovern

et al. 2011

Gut

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Objective Genome-wide association studies (GWAS) have identified multiple Crohn’s disease (CD) susceptibility loci, including association with non-coding intergenic single nucleotide polymorphisms (SNPs) at 10q21. Design To fine-map the 10q21 locus, we genotyped 86 SNPs in 1632 CD cases and 961 controls and performed single marker and conditional analyses using logistic regression. Results We observed association with CD risk spanning eleven SNPs (p< 0.001). The most significant association observed was at the nonsynonymous SNP rs7076156 (Ala62Thr) in ZNF365. The alanine allele was over-represented in CD (p= 5.23×10−7; OR= 1.39 [1.22–1.58]); allele frequency 76% CD, 69.7% controls). Conditional analysis on rs7076156 nullified all other significant associations, suggesting that this is the causative variant at this locus. Four isoforms of ZNF365 have previously been identified and rs7076156 is located in an exon unique to ZNF365 isoform D. We demonstrated, using RT-PCR, expression of ZNF365D in intestinal resections from both CD subjects and controls. We identified markedly reduced ZNF365D mean expression levels in EBV-transformed lymphoblastoid cell lines (ELCLs) from CD subjects homozygous for the risk allele (Ala). A whole-genome microarray expression study further suggested that the Ala62Thr change in ZNF365 isoform D is related to differential expression of the genes ARL4A, MKKS, RRAGD, SUMF2, TDR1 and ZNF148 in CD. Conclusions Collectively our data support the hypothesis that the nonsynonymous Ala62Thr SNP rs7076156 underlies the association between 10q21 and CD risk and suggests that this SNP acts by altering expression of genes under the control of ZNF365 isoform D.

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Centrosomal proteins Nde1 and Su48 form a complex regulated by phosphorylation

Cited by 37 publications

References 20 publications

Identification of Rare, Single-Nucleotide Mutations in NDE1 and Their Contributions to Schizophrenia Susceptibility

Identification of Rare, Single-Nucleotide Mutations in NDE1 and Their Contributions to Schizophrenia Susceptibility

The DISC locus in psychiatric illness

Variants in ZNF365 isoform D are associated with Crohn's disease

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