Polymorphism Screening of PIP5K2A: A Candidate Gene for Chromosome 10p‐Linked Psychiatric Disorders

Stopková, Pavla; Saito, Takuya; Fann, Cathy S.J.; Papolos, Demitri F.; Vevera, Jan; Paclt, Ivo; Zukov, Ilja; Stryjer, Rafael; Strous, Rael D.; Lachman, Herbert M.

doi:10.1002/ajmg.b.20012

Cited by 47 publications

(39 citation statements)

References 58 publications

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“…It has the highest catalytic activity among the three isoforms. PIP4K2A is responsible for the clearance of PI(5)P upon oxidative stress (16) and its mutations are associated with leukemia (17)(18)(19) and schizophrenia (20)(21)(22).…”

Section: Pip4k2a Is Required For Intracellular Cholesterol Transportmentioning

confidence: 99%

PIP4K2A regulates intracellular cholesterol transport through modulating PI(4,5)P2 homeostasis

Zhao

et al. 2018

Journal of Lipid Research

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The transport of LDL-derived cholesterol from lysosomes to peroxisomes is mediated by membrane contacts, which are facilitated by the lysosomal protein synaptotagmin VII and the peroxisomal lipid phosphatidylinositol 4, 5-bisphosphate (PI(4,5)P 2 ). Here, we used RNA interference to search for regulators of PI(4,5)P 2 and to study the effects of altered PI(4,5)P 2 homeostasis on cholesterol transport. We found that knockdown of phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A) reduced peroxisomal PI(4,5)P 2 levels, decreased lysosome-peroxisome membrane contacts, and increased accumulation of lysosomal cholesterol in human SV-589 fibroblasts. Forced expression of peroxisome-localized, kinase-active PIP4K2A in the knockdown cells reduced cholesterol accumulation, and in vitro addition of recombinant PIP4K2A restored membrane contacts.These results suggest that PIP4K2A plays a critical role in intracellular cholesterol transport by up-regulating PI(4,5)P 2 in the peroxisome membrane. Further research into PIP4K2A activity may inform future therapeutic interventions for managing lysosomal storage disorders.

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Section: Pip4k2a Is Required For Intracellular Cholesterol Transportmentioning

confidence: 99%

PIP4K2A regulates intracellular cholesterol transport through modulating PI(4,5)P2 homeostasis

Zhao

et al. 2018

Journal of Lipid Research

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“…In addition to the Dutch study mentioned above, 65 this polymorphism was tested in another case-control sample comprising 176 patients with schizophrenia and 178 controls from North America with European background and from Israel, as well as in a sample comprising 198 bipolar patients and 212 controls from USA and the Czech Republic, 77 following up our preliminary report on association of the N251S polymorphism in schizophrenia at the IXth World Congress for Psychiatric Genetics 2001. 64 Association was not detected with this particular variant, but a modest difference was found in the distribution of alleles from the CT repeat pik53 þ 54 (M45), which was also associated in our sample (Table 1, P = 0.026).…”

Section: -36mentioning

confidence: 99%

Evidence for association of DNA sequence variants in the phosphatidylinositol-4-phosphate 5-kinase IIα gene (PIP5K2A) with schizophrenia

et al. 2006

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Linkage studies in schizophrenia have identified a candidate region on chromosome 10p14-11 as reported for several independent samples. We investigated association of DNA sequence variants in a plausible candidate gene located in this region, the gene for phosphatidylinositol-4-phosphate 5-kinase IIa (PIP5K2A), in a sample of 65 sib-pair families for which linkage had been reported. Evidence for association was obtained for 15 polymorphisms spanning 73.6 kb in the genomic region of the gene between intron 4 and the 3 0 untranslated region, a region with high degree of linkage disequilibrium. Single nucleotide polymorphism (SNP) rs10828317 located in exon 7 and causing a non-synonymous amino-acid exchange (asparagine/serine) produced a P-value of 0.001 (experiment-wide significance level 0.00275) for over-transmission of the major allele coding for serine, analysed by transmission disequilibrium test using FAMHAP. Association of this SNP with schizophrenia has been also described in a sample of 273 Dutch schizophrenic patients and 580 controls (P = 0.0004). PIP5K2A is involved in the biosynthesis of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P 2 ), one of the key metabolic crossroads in phosphoinositide signalling. PI(4,5)P 2 plays a role in membrane transduction of neurotransmitter signals as well as in intracellular signalling, pathways that may be impaired in schizophrenia.

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“…Its product is involved in the phosphoinositide signal transduction system, and it is also harbored by 10p12, a chromosomal region showing linkage to schizophrenia and bipolar disorder, although less consistently than other linkage regions [Stopkova et al, 2003]. Two association studies have reported several SNPs in PIP5K2A to be associated with schizophrenia [Stopkova et al, 2005;Schwab et al, 2006].…”

Section: Introductionmentioning

confidence: 98%

Association study of NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A with schizophrenia and symptom severity in a Hungarian sample

Réthelyi

Bakker

Polgár

et al. 2009

American J of Med Genetics Pt B

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Genetic association studies have yielded extensive but frequently inconclusive data about genetic risk factors for schizophrenia. Clinical and genetic heterogeneity are possible factors explaining the inconsistent findings. The objective of this study was to test the association of commonly incriminated candidate genes with two clinically divergent subgroups, non-deficit (SZ-ND) and deficit-schizophrenia (SZ-D), and symptom severity, in order to test for replication of previously reported results. A homogeneous sample of 280 schizophrenia patients and 230 healthy controls of Hungarian, Caucasian descent were genotyped for polymorphisms in schizophrenia candidate genes NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A. Patients were divided into the diagnostic subgroups of SZ-ND and SZ-D using the Schedule for Deficit Syndrome (SDS), and assessed clinically by the Positive and Negative Symptom Scale (PANSS). SNP8NRG241930 in NRG1 and rs1011313 in DTNBP1 were associated with SZ-ND (P = 0.04 and 0.03, respectively). Polymorphisms in RGS4, G72/G30, and PIP5K2A were neither associated with SZ-ND nor with SZ-D. SNP8NRG241930 showed association with the PANSS cognitive and hostility/excitability factors, rs1011313 with the negative factor and SDS total score, and rs10917670 in RGS4 was associated with the depression factor. Although these results replicate earlier findings about the genetic background of SZ-ND and SZ-D only partially, our data seem to confirm previously reported association of NRG1 with schizophrenia without prominent negative symptoms. It was possible to detect associations of small-to-medium effect size between the investigated candidate genes and symptom severity. Such studies have the potential to unravel the possible connection between genetic and clinical heterogeneity in schizophrenia.

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Polymorphism Screening of PIP5K2A: A Candidate Gene for Chromosome 10p‐Linked Psychiatric Disorders

Cited by 47 publications

References 58 publications

PIP4K2A regulates intracellular cholesterol transport through modulating PI(4,5)P2 homeostasis

PIP4K2A regulates intracellular cholesterol transport through modulating PI(4,5)P2 homeostasis

Evidence for association of DNA sequence variants in the phosphatidylinositol-4-phosphate 5-kinase IIα gene (PIP5K2A) with schizophrenia

Association study of NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A with schizophrenia and symptom severity in a Hungarian sample

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