The Experts below are selected from a list of 477 Experts worldwide ranked by ideXlab platform
Paul J. Lockhart - One of the best experts on this subject based on the ideXlab platform.
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Generation and characterisation of a parkin-PACRG knockout mouse line and a PACRG knockout mouse line.
Scientific Reports, 2018Co-Authors: Sarah E. M. Stephenson, Juliet M. Taylor, Tim D. Aumann, Jessica R. Riseley, Jeffrey R. Mann, Doris Tomas, Paul J. LockhartAbstract:Mutations in PARK2 (parkin) can result in Parkinson’s disease (PD). Parkin shares a bidirectional promoter with parkin coregulated gene (PACRG) and the transcriptional start sites are separated by only ~200 bp. Bidirectionally regulated genes have been shown to function in common biological pathways. Mice lacking parkin have largely failed to recapitulate the dopaminergic neuronal loss and movement impairments seen in individuals with parkin-mediated PD. We aimed to investigate the function of PACRG and test the hypothesis that parkin and PACRG function in a common pathway by generating and characterizing two novel knockout mouse lines harbouring loss of both parkin and PACRG or PACRG alone. Successful modification of the targeted allele was confirmed at the genomic, transcriptional and steady state protein levels for both genes. At 18–20 months of age, there were no significant differences in the behaviour of parental and mutant lines when assessed by openfield, rotarod and balance beam. Subsequent neuropathological examination suggested there was no gross abnormality of the dopaminergic system in the substantia nigra and no significant difference in the number of dopaminergic neurons in either knockout model compared to wildtype mice.
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Parkin co-regulated gene is involved in aggresome formation and autophagy in response to proteasomal impairment.
Experimental Cell Research, 2012Co-Authors: Juliet M. Taylor, Kate M. Brody, Paul J. LockhartAbstract:PArkin Co-Regulated Gene is a gene that shares a bidirectional promoter with the Parkinson's disease associated gene parkin. The encoded protein (PACRG) is found in Lewy bodies and glial cytoplasmic inclusions, the pathological hallmarks of parkinsonian disorders. To investigate the function and regulation of PACRG, cells were treated with the proteasomal inhibitor, MG-132. As previously reported with parkin, inhibition of the proteasome resulted in the formation of aggresomes that contained endogenous PACRG. Increased levels of exogenous PACRG resulted in an increase in aggresome formation, and conferred significant resistance to aggresome disruption and cell death mediated by microtubule depolymerisation. In contrast, shRNA mediated knockdown of PACRG significantly reduced aggresome numbers. Elevated levels of PACRG also resulted in increased autophagy, as demonstrated by biochemical and quantitative analysis of autophagic vesicles, whereas lowered levels of PACRG resulted in reduced autophagy. These results suggest a role for PACRG in aggresome formation and establish a further link between the UPS and autophagy.
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Deletion of the Parkin co-regulated gene causes defects in ependymal ciliary motility and hydrocephalus in the quakingviable mutant mouse
Human Molecular Genetics, 2010Co-Authors: Gabrielle R. Wilson, Martin B. Delatycki, Hong X Wang, Gary F Egan, Moira K O'bryan, Philip J. Robinson, Paul J. LockhartAbstract:The quakingviable mouse (qkv) is a spontaneous recessive mouse mutant with a deletion of approximately 1.1 Mb in the proximal region of chromosome 17. The deletion affects the expression of three genes; quaking (Qk), Parkin-coregulated gene (PACRG) and parkin (Park2). The resulting phenotype, which includes dysmyelination of the central nervous system and male sterility, is due to reduced expression of Qk and a complete lack of PACRG expression, respectively. PACRG is required for correct development of the spermatozoan flagella, a specialized type of motile cilia. In vertebrates, motile cilia are required for multiple functions related to cellular movement or movement of media over a stationary cell surface. To investigate the potential role of PACRG in motile cilia we analysed qkv mutant mice for evidence of cilial dysfunction. Histological and magnetic resonance imaging analyses demonstrated that qkv mutant mice were affected by acquired, communicating hydrocephalus (HC). Structural analysis of ependymal cilia demonstrated that the 9 + 2 arrangement of axonemal microtubules was intact and that both the density of ciliated cells and cilia length was similar to wild-type littermates. Cilia function studies showed a reduction in ependymal cilial beat frequency and cilial mediated flow in qkv mutant mice compared with wild-type littermate controls. Moreover, transgenic expression of PACRG was necessary and sufficient to correct this deficit and rescue the HC phenotype in the qkv mutant. This study provides novel in vivo evidence that PACRG is required for motile cilia function and may be involved in the pathogenesis of human ciliopathies, such as HC, asthenospermia and primary ciliary dyskinesia.
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Molecular analysis of the PArkin co-regulated gene and association with male infertility
Fertility and Sterility, 2010Co-Authors: Gabrielle R. Wilson, Juliet M. Taylor, Kate M. Brody, Martin B. Delatycki, Marcus L-j Sim, Robert I Mclachlan, Moira K O'bryan, Paul J. LockhartAbstract:Objective To investigate the potential role of PArkin co-regulated gene ( PACRG ) in human male infertility. Design Case-control study. Setting Academic reproductive biology department. Patient(s) Blood samples were obtained from 610 patients and 156 normal control subjects. Intervention(s) Genomic DNA was used as template for polymerase chain reaction amplification of the PACRG promoter and coding exons. The amplified fragments were tested for DNA sequence variations by direct sequencing and restriction enzyme analysis. Main Outcome Measure(s) Gene structure and sequence alterations of PACRG in infertile male patients. Result(s) The structure of PACRG was determined to comprise 5 coding exons, generating a single transcript in the testis which encoded a predicted protein of 257 amino acids. No pathogenic mutations were identified; however, a variant in the promoter of PACRG was shown to be significantly associated with azoospermia, but not oligospermia, in the case-control cohort. Conclusion(s) Mutation of PACRG was not identified as a cause of male infertility, but variation in the promoter was demonstrated to be a risk factor associated with azoospermia.
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Expression and localization of the Parkin co-regulated gene in mouse CNS suggests a role in ependymal cilia function.
Neuroscience Letters, 2009Co-Authors: Gabrielle R. Wilson, Juliet M. Taylor, Kate M. Brody, Jacqueline T. Tan, Martin B. Delatycki, Paul J. LockhartAbstract:Parkin Co-Regulated Gene (PACRG) is a gene that shares a bi-directional promoter with the Parkinson's disease associated gene parkin. The functional role of PACRG is not well understood, although the gene has been associated with parkinsonian syndromes and more recently with eukaryotic cilia and flagella. We investigated the expression of PACRG in the mouse brain by in situ hybridization and observed robust expression of PACRG in the cells associated with the lateral, third and fourth ventricle, in addition to the aqueduct of Sylvius and choroid plexus. For all regions of PACRG expression identified, strong expression was observed in the newborn period and this was maintained into adulthood. Immunohistochemical analysis showed that PACRG was a component of the ependymal cells and cilia lining the ventricles. Based on our results and the previous association of PACRG homologues with cilia and flagella, we propose that PACRG is a component of the ependymal cilia and may play an important role in motile cilia development and/or function in the CNS.
Yao-zong Guan - One of the best experts on this subject based on the ideXlab platform.
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Associations of PRKN-PACRG SNPs and G × G and G × E interactions with the risk of hyperlipidaemia.
Scientific Reports, 2020Co-Authors: Peng-fei Zheng, Rui-xing Yin, Bi-liu Wei, Chun-xiao Liu, Guo-xiong Deng, Yao-zong GuanAbstract:This research aimed to assess the associations of 7 parkin RBR E3 ubiquitin protein ligase (PRKN) and 4 parkin coregulated gene (PACRG) single-nucleotide polymorphisms (SNPs), their haplotypes, gene-gene (G × G) and gene-environment (G × E) interactions with hyperlipidaemia in the Chinese Maonan minority. The genotypes of the 11 SNPs in 912 normal and 736 hyperlipidaemic subjects were detected with next-generation sequencing technology. The genotypic and allelic frequencies of the rs1105056, rs10755582, rs2155510, rs9365344, rs11966842, rs6904305 and rs11966948 SNPs were different between the normal and hyperlipidaemic groups (P 15%) and PACRG A-T-A-T (> 40%). The PRKN C-G-C-A-T-T-C and PRKN-PACRG C-G-T-G-T-T-C-A-T-A-T haplotypes were associated with an increased risk of hyperlipidaemia, whereas the PRKN-PACRG C-G-T-G-C-T-C-A-T-C-T and C-G-T-G-T-T-C-A-T-C-T haplotypes provided a protective effect. Association analysis based on the haplotypes and G × G interaction could improve the power to detect the risk of hyperlipidaemia over the analysis of any one SNP alone. The differences in serum lipid parameters between the hyperlipidaemic and normal groups might partly be due to the effects of the PRKN-PACRG SNPs and their haplotypes.
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associations of prkn PACRG snps and g g and g e interactions with the risk of hyperlipidaemia
Scientific Reports, 2020Co-Authors: Peng-fei Zheng, Rui-xing Yin, Bi-liu Wei, Chun-xiao Liu, Guo-xiong Deng, Yao-zong GuanAbstract:This research aimed to assess the associations of 7 parkin RBR E3 ubiquitin protein ligase (PRKN) and 4 parkin coregulated gene (PACRG) single-nucleotide polymorphisms (SNPs), their haplotypes, gene-gene (G × G) and gene-environment (G × E) interactions with hyperlipidaemia in the Chinese Maonan minority. The genotypes of the 11 SNPs in 912 normal and 736 hyperlipidaemic subjects were detected with next-generation sequencing technology. The genotypic and allelic frequencies of the rs1105056, rs10755582, rs2155510, rs9365344, rs11966842, rs6904305 and rs11966948 SNPs were different between the normal and hyperlipidaemic groups (P 15%) and PACRG A-T-A-T (> 40%). The PRKN C-G-C-A-T-T-C and PRKN-PACRG C-G-T-G-T-T-C-A-T-A-T haplotypes were associated with an increased risk of hyperlipidaemia, whereas the PRKN-PACRG C-G-T-G-C-T-C-A-T-C-T and C-G-T-G-T-T-C-A-T-C-T haplotypes provided a protective effect. Association analysis based on the haplotypes and G × G interaction could improve the power to detect the risk of hyperlipidaemia over the analysis of any one SNP alone. The differences in serum lipid parameters between the hyperlipidaemic and normal groups might partly be due to the effects of the PRKN-PACRG SNPs and their haplotypes.
Ramesh Bamezai - One of the best experts on this subject based on the ideXlab platform.
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Association study of major risk single nucleotide polymorphisms in the common regulatory region of PARK2 and PACRG genes with leprosy in an Indian population
European Journal of Human Genetics, 2006Co-Authors: Dheeraj Malhotra, Katayoon Darvishi, Manmohan Lohra, Himanshu Kumar, Chander Grover, Soni Sood, Belum Siva Nagi Reddy, Ramesh BamezaiAbstract:Single nucleotide polymorphisms (SNPs) in the regulatory region shared by PARK2 and PACRG have been identified as major risk factors for leprosy susceptibility in two ethnically distinct populations. We investigated the association of six SNPs present in this regulatory region with leprosy susceptibility in an Indian population. Genotyping was performed by direct PCR sequencing in 286 leprosy patients and 350 healthy controls. Our results showed that T allele of SNPs PARK2_e01 (−2599) and 28 kb target_2_1 was significantly associated with susceptibility to leprosy per se ( P =0.03 and 0.03, respectively). The T allele of SNPs PARK2_e01 (−2599) showed a significant recessive effect ( P =0.04) in susceptibility to leprosy in Indian population as against the dominant effect of haplotype T-C of the major risk SNPs PARK2_e01 (−2599) and rs1040079 in Brazilian and Vietnamese population. However, after bonferroni corrections, these significant differences disappeared. Haplotype analysis also showed a lack of significant association of any haplotype with cases or controls. The noninvolvement of major risk SNPs in the regulatory region of PARK2 and PACRG locus with leprosy susceptibility in Indian population highlights the differential effect of these SNPs in regulating genetic susceptibility to leprosy in different populations.
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Association study of major risk single nucleotide polymorphisms in the common regulatory region of PARK2 and PACRG genes with leprosy in an Indian population.
European Journal of Human Genetics, 2005Co-Authors: Dheeraj Malhotra, Katayoon Darvishi, Manmohan Lohra, Himanshu Kumar, Chander Grover, Soni Sood, Belum Siva Nagi Reddy, Ramesh BamezaiAbstract:Association study of major risk single nucleotide polymorphisms in the common regulatory region of PARK2 and PACRG genes with leprosy in an Indian population
Peng-fei Zheng - One of the best experts on this subject based on the ideXlab platform.
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Associations of PRKN-PACRG SNPs and G × G and G × E interactions with the risk of hyperlipidaemia.
Scientific Reports, 2020Co-Authors: Peng-fei Zheng, Rui-xing Yin, Bi-liu Wei, Chun-xiao Liu, Guo-xiong Deng, Yao-zong GuanAbstract:This research aimed to assess the associations of 7 parkin RBR E3 ubiquitin protein ligase (PRKN) and 4 parkin coregulated gene (PACRG) single-nucleotide polymorphisms (SNPs), their haplotypes, gene-gene (G × G) and gene-environment (G × E) interactions with hyperlipidaemia in the Chinese Maonan minority. The genotypes of the 11 SNPs in 912 normal and 736 hyperlipidaemic subjects were detected with next-generation sequencing technology. The genotypic and allelic frequencies of the rs1105056, rs10755582, rs2155510, rs9365344, rs11966842, rs6904305 and rs11966948 SNPs were different between the normal and hyperlipidaemic groups (P 15%) and PACRG A-T-A-T (> 40%). The PRKN C-G-C-A-T-T-C and PRKN-PACRG C-G-T-G-T-T-C-A-T-A-T haplotypes were associated with an increased risk of hyperlipidaemia, whereas the PRKN-PACRG C-G-T-G-C-T-C-A-T-C-T and C-G-T-G-T-T-C-A-T-C-T haplotypes provided a protective effect. Association analysis based on the haplotypes and G × G interaction could improve the power to detect the risk of hyperlipidaemia over the analysis of any one SNP alone. The differences in serum lipid parameters between the hyperlipidaemic and normal groups might partly be due to the effects of the PRKN-PACRG SNPs and their haplotypes.
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associations of prkn PACRG snps and g g and g e interactions with the risk of hyperlipidaemia
Scientific Reports, 2020Co-Authors: Peng-fei Zheng, Rui-xing Yin, Bi-liu Wei, Chun-xiao Liu, Guo-xiong Deng, Yao-zong GuanAbstract:This research aimed to assess the associations of 7 parkin RBR E3 ubiquitin protein ligase (PRKN) and 4 parkin coregulated gene (PACRG) single-nucleotide polymorphisms (SNPs), their haplotypes, gene-gene (G × G) and gene-environment (G × E) interactions with hyperlipidaemia in the Chinese Maonan minority. The genotypes of the 11 SNPs in 912 normal and 736 hyperlipidaemic subjects were detected with next-generation sequencing technology. The genotypic and allelic frequencies of the rs1105056, rs10755582, rs2155510, rs9365344, rs11966842, rs6904305 and rs11966948 SNPs were different between the normal and hyperlipidaemic groups (P 15%) and PACRG A-T-A-T (> 40%). The PRKN C-G-C-A-T-T-C and PRKN-PACRG C-G-T-G-T-T-C-A-T-A-T haplotypes were associated with an increased risk of hyperlipidaemia, whereas the PRKN-PACRG C-G-T-G-C-T-C-A-T-C-T and C-G-T-G-T-T-C-A-T-C-T haplotypes provided a protective effect. Association analysis based on the haplotypes and G × G interaction could improve the power to detect the risk of hyperlipidaemia over the analysis of any one SNP alone. The differences in serum lipid parameters between the hyperlipidaemic and normal groups might partly be due to the effects of the PRKN-PACRG SNPs and their haplotypes.
Martin B. Delatycki - One of the best experts on this subject based on the ideXlab platform.
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Deletion of the Parkin co-regulated gene causes defects in ependymal ciliary motility and hydrocephalus in the quakingviable mutant mouse
Human Molecular Genetics, 2010Co-Authors: Gabrielle R. Wilson, Martin B. Delatycki, Hong X Wang, Gary F Egan, Moira K O'bryan, Philip J. Robinson, Paul J. LockhartAbstract:The quakingviable mouse (qkv) is a spontaneous recessive mouse mutant with a deletion of approximately 1.1 Mb in the proximal region of chromosome 17. The deletion affects the expression of three genes; quaking (Qk), Parkin-coregulated gene (PACRG) and parkin (Park2). The resulting phenotype, which includes dysmyelination of the central nervous system and male sterility, is due to reduced expression of Qk and a complete lack of PACRG expression, respectively. PACRG is required for correct development of the spermatozoan flagella, a specialized type of motile cilia. In vertebrates, motile cilia are required for multiple functions related to cellular movement or movement of media over a stationary cell surface. To investigate the potential role of PACRG in motile cilia we analysed qkv mutant mice for evidence of cilial dysfunction. Histological and magnetic resonance imaging analyses demonstrated that qkv mutant mice were affected by acquired, communicating hydrocephalus (HC). Structural analysis of ependymal cilia demonstrated that the 9 + 2 arrangement of axonemal microtubules was intact and that both the density of ciliated cells and cilia length was similar to wild-type littermates. Cilia function studies showed a reduction in ependymal cilial beat frequency and cilial mediated flow in qkv mutant mice compared with wild-type littermate controls. Moreover, transgenic expression of PACRG was necessary and sufficient to correct this deficit and rescue the HC phenotype in the qkv mutant. This study provides novel in vivo evidence that PACRG is required for motile cilia function and may be involved in the pathogenesis of human ciliopathies, such as HC, asthenospermia and primary ciliary dyskinesia.
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Molecular analysis of the PArkin co-regulated gene and association with male infertility
Fertility and Sterility, 2010Co-Authors: Gabrielle R. Wilson, Juliet M. Taylor, Kate M. Brody, Martin B. Delatycki, Marcus L-j Sim, Robert I Mclachlan, Moira K O'bryan, Paul J. LockhartAbstract:Objective To investigate the potential role of PArkin co-regulated gene ( PACRG ) in human male infertility. Design Case-control study. Setting Academic reproductive biology department. Patient(s) Blood samples were obtained from 610 patients and 156 normal control subjects. Intervention(s) Genomic DNA was used as template for polymerase chain reaction amplification of the PACRG promoter and coding exons. The amplified fragments were tested for DNA sequence variations by direct sequencing and restriction enzyme analysis. Main Outcome Measure(s) Gene structure and sequence alterations of PACRG in infertile male patients. Result(s) The structure of PACRG was determined to comprise 5 coding exons, generating a single transcript in the testis which encoded a predicted protein of 257 amino acids. No pathogenic mutations were identified; however, a variant in the promoter of PACRG was shown to be significantly associated with azoospermia, but not oligospermia, in the case-control cohort. Conclusion(s) Mutation of PACRG was not identified as a cause of male infertility, but variation in the promoter was demonstrated to be a risk factor associated with azoospermia.
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Expression and localization of the Parkin co-regulated gene in mouse CNS suggests a role in ependymal cilia function.
Neuroscience Letters, 2009Co-Authors: Gabrielle R. Wilson, Juliet M. Taylor, Kate M. Brody, Jacqueline T. Tan, Martin B. Delatycki, Paul J. LockhartAbstract:Parkin Co-Regulated Gene (PACRG) is a gene that shares a bi-directional promoter with the Parkinson's disease associated gene parkin. The functional role of PACRG is not well understood, although the gene has been associated with parkinsonian syndromes and more recently with eukaryotic cilia and flagella. We investigated the expression of PACRG in the mouse brain by in situ hybridization and observed robust expression of PACRG in the cells associated with the lateral, third and fourth ventricle, in addition to the aqueduct of Sylvius and choroid plexus. For all regions of PACRG expression identified, strong expression was observed in the newborn period and this was maintained into adulthood. Immunohistochemical analysis showed that PACRG was a component of the ependymal cells and cilia lining the ventricles. Based on our results and the previous association of PACRG homologues with cilia and flagella, we propose that PACRG is a component of the ependymal cilia and may play an important role in motile cilia development and/or function in the CNS.
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Analysis of PArkin Co-Regulated Gene in a Taiwanese-ethnic Chinese cohort with early-onset Parkinson's disease.
Parkinsonism & Related Disorders, 2009Co-Authors: Juliet M. Taylor, Martin B. Delatycki, Matthew J. Farrer, Paul J. LockhartAbstract:Abstract PArkin Co-Regulated Gene (PACRG) is a novel gene which is transcriptionally co-regulated with the parkin gene (PRKN) by a shared bi-directional promoter. To determine whether mutations in PACRG are associated with early-onset Parkinson's disease (EO-PD), we performed sequence and dosage analysis of 76 EO-PD patients from a Taiwanese–Ethnic Chinese cohort. This analysis identified two novel nucleotide variants in the non-coding region of PACRG. One patient had an IVS2 + 247851T > C heterozygous change and two patients had an IVS4 + 78A > G heterozygous alteration. Neither of these variants was present in the 91 controls tested. A third intronic polymorphism (IVS1 + 85744insC) was present in cases and controls at an equivalent frequency (∼0.25). To facilitate gene dosage analysis, we identified cell lines with a heterozygous deletion or duplication of the entire PACRG locus. Three patients with heterozygous dosage alterations were identified, including two patients with an exon 2 duplication and one patient with an exon 3 deletion of PACRG. No dosage alterations were observed in the 91 controls analyzed (χ2 = 3.66, P = 0.056). Our results suggest that point mutations in PACRG are not a common cause of EO-PD but haploinsufficiency for PACRG may be associated with disease.
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219 parkin co regulated gene PACRG is an axonemal protein involved in sperm tail and ependymal cell function and is a candidate primary ciliary dyskinesia gene
Reproduction Fertility and Development, 2008Co-Authors: Gabrielle R. Wilson, Martin B. Delatycki, Hong X Wang, Gary F Egan, M K O Bryan, Paul J. LockhartAbstract:A leading cause of male infertility is genetic variation in genes required for sperm formation or function. Considerable evidence suggests PACRG is involved in spermiogeneis. The loss of PACRG function causes infertility in mice (Lorenzetti et al. 2004) and we have shown an association between variability in the 5′ untranslated region of PACRG and human male infertility (Wilson et al. in preparation). Evidence from studies in C.reinhardtii and T.brucei indicate PACRG is crucial for axonome formation and microtubule stability. To assess this possibility in mammals, we generated and characterised PACRG knockout (Quaking viable, Qkv), wildtype and PACRG transgenic mice (Qkv-Tg). Using confocal and immunoelectron microscopy we showed that PACRG was localised to the axonemal microtubule doublets of sperm, tracheal and ependymal cilia. The absence of PACRG was associated with compromised sperm flagella formation and MRI analyses revealed the occurrence of hydrocephalus. Specifically, Qkv mice showed an inward expansion of the lateral ventricles, resulting in a significant reduction in distance between ventricles (1.0 ± 0.6 mm, mean ± s.d., n = 5) and a ~250% increase in ventricle area (70 ± 13 arbitrary units, mean ± s.d., n = 5) compared with wildtype littermates (1.38 ± 0.09 mm; area 26 ± 12, n = 3). Transgenic expression of PACRG was necessary and sufficient to correct the hydrocephalus (1.45 ± 0.05 mm; area 26 ± 9, n = 2) and infertility phenotypes (evidenced by daily sperm counts and litter sizes). In conclusion, we have shown PACRG is a novel axoneme associated protein in a subset of motile cilia/flagella and loss of PACRG function results in spermiogenic defects and hydrocephalus in mice. Further, we have shown that variations in the human PACRG promoter are a risk factor in human male infertility. Collectively these data suggest PACRG is a candidate gene in the human syndrome of primary ciliary dyskinesia. (1) Lorenzetti D, Bishop CE, Justice MJ. 2004. Deletion of the Parkin coregulated gene causes male sterility in the quaking (viable) mouse mutant. Proc Natl Acad Sci U S A 101(22):8402–8407
