Investigation of the PARK10 Gene in Parkinson Disease

Abstract

SummaryTwo recent association mapping studies in Parkinson disease (PD) reported three candidate genes for the PARK10 locus: EIF2B3 as a modifier of age-at-onset of PD (min P= 0.0004) and HIVEP3 as a PD risk gene (P ≤ 0.006) (Oliveira et al. 2005); and LOC200008 (CDCP2) identified by the whole genome association (WGA) study of PD of Maraganore et al. (2005). However, evaluation of the on-line PD WGA results revealed two significant SNPs in HIVEP3 in the two datasets, Tier 1 and Tier 2, used by Maraganore et al. (P ≤ 0.008 for Tier 1 and P=0.03 for Tier 2 dataset). Here, we revisited both the HIVEP3 and CDCP2 loci by examining 47 SNPs, mostly tagging, in an expanded PD family dataset (293 multiplex and 467 singleton families). A discordant sibpair (DSP) dataset (one DSP per family), with similar data structure as the WGA Tier 1 dataset, was also tested. We confirmed our and other previous negative findings for CDCP2. However, five significant SNPs in HIVEP3 (min P=0.004) were observed, although the two significant HIVEP3 SNPs from the PD WGA study were not significant in our datasets. Even though the sets of significant HIVEP3 markers differ between studies, these findings strongly support HIVEP3 as a candidate for PARK10. Further testing of HIVEP3 by other groups is encouraged.

Gene Expression in the Addicted Brain

“…They include CDR1 , a cerebellar degeneration-related protein; LRCH4 , a leucine-rich repeat-containing neuronal protein; CACNB2 , a subunit of voltage-gated calcium channel and involved in neuronal functions; and FAM123A ( AMER2 ), a member of the gene family involved in neurogenesis (Comai, Boutet, Neirijnck, & Schedl, 2010). Other commonly and most significantly affected genes also encode for proteins critical in cellular functions such as histone ( HIST1H4E ), transcription regulations ( ZGPAT , ERF , and HIVEP3 ) (Li et al, 2007), and mitochrondrial poly(A) polymerase ( PAPD1 ). A subsequent pathway-targeted analysis of GABAergic genes also revealed common expression changes in the cocaine addicts and alcoholics from our study, such as the downregulation of GABBR1 , GABRG2 , and GPHN , a gene encoding the associated scaffolding protein gephyrin (Enoch et al, 2012).…”

Fine-mapping and candidate gene investigation within the PARK10 locus

“…In a recent study by the same group, the association between HIVEP3 SNPs and PD was still present when genotyping an extended series that included the original samples. 6 We found no association between HIVEP3 SNPs and PD (Table 1), including the most significant SNP from Li et al, 6 rs1105414 (previously known as rs3856255). Hence, our data do not support a role for HIVEP3 in the etiology of PD.…”

Cortical gene expression: prognostic value for seizure outcome following temporal lobectomy and amygdalohippocampectomy

“…By examining CDCP2 SNPs in an expanded PD family dataset (293 multiplex and 467 singleton families) and a discordant sib-pair dataset, Li et al found no significant association of CDCP2 with PD [21]. They noted that the results confirmed previous negative findings for CDCP2 as a candidate PARK10 gene [21]. CDCP2 may influence seizure outcomes in numerous ways.…”

“…Maraganore et al stated that the CDCP2 protein had inferred oxidoreductase activity and was potentially involved in cholesterol biosynthesis and electron transport and mapped the CDCP2 gene to chromosome 1p32 [20]. By examining CDCP2 SNPs in an expanded PD family dataset (293 multiplex and 467 singleton families) and a discordant sib-pair dataset, Li et al found no significant association of CDCP2 with PD [21]. They noted that the results confirmed previous negative findings for CDCP2 as a candidate PARK10 gene [21].…”