Deletion of the<i>parkin</i>and<i>PACRG</i>gene promoter in early-onset parkinsonism

Lesage, Suzanne; Periquet, Magali; Lohmann, Ebba; Lacomblez, Lucette; Teive, Hélio Afonso Ghizoni; Janin, Sabine; Cousin, Pierre-Yves; Dürr, Alexandra; Brice, Alexis

doi:10.1002/humu.20436

Cited by 39 publications

(30 citation statements)

References 35 publications

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“…To address the first hypothesis, we screened all patients and controls for rearrangements of the parkin promoter and all exons. This technique has recently allowed the identification of a novel deletion of the common promoter and exon 1 of both parkin and the adjacent parkin coregulated gene ( PACRG , OMIM 608427), in 1 family out of 23 with members who were heterozygous parkin carriers 15. No promoter rearrangements were detected in the present series, but it is still possible that a second disease-causing mutation in the very large parkin gene has escaped detection.…”

Section: Discussionmentioning

confidence: 67%

Rare heterozygous parkin variants in French early-onset Parkinson disease patients and controls

Lesage¹,

Lohmann²,

Tison³

et al. 2007

Journal of Medical Genetics

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Section: Discussionmentioning

confidence: 67%

Rare heterozygous parkin variants in French early-onset Parkinson disease patients and controls

Lesage¹,

Lohmann²,

Tison³

et al. 2007

Journal of Medical Genetics

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“…Although studies have linked PACRG to certain genetic diseases, such as parkinsonism (21,22), leprosy (23,24), and even cancer (25,26), further investigation conclusively established its role in ciliogenesis. Proteomics and biochemical studies revealed that it is a component of Chlamydomonas reinhardtii centriole/basal bodies (27,28).…”

Section: Discussionmentioning

confidence: 99%

MEIG1 is essential for spermiogenesis in mice

Zhang

Shen²,

Gude

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Spermatogenesis can be divided into three stages: spermatogonial mitosis, meiosis of spermatocytes, and spermiogenesis. During spermiogenesis, spermatids undergo dramatic morphological changes including formation of a flagellum and chromosomal packaging and condensation of the nucleus into the sperm head. The genes regulating the latter processes are largely unknown. We previously discovered that a bi-functional gene, Spag16, is essential for spermatogenesis. SPAG16S, the 35 kDa, testis-specific isoform derived from the Spag16 gene, was found to bind to meiosis expressed gene 1 product (MEIG1), a protein originally thought to play a role in meiosis. We inactivated the Meig1 gene and, unexpectedly, found that Meig1 mutant male mice had no obvious defect in meiosis, but were sterile as a result of impaired spermatogenesis at the stage of elongation and condensation. Transmission electron microscopy revealed that the manchette, a microtubular organelle essential for sperm head and flagellar formation was disrupted in spermatids of MEIG1-deficient mice. We also found that MEIG1 associates with the Parkin co-regulated gene (PACRG) protein, and that testicular PACRG protein is reduced in MEIG1-deficient mice. PACRG is thought to play a key role in assembly of the axonemes/flagella and the reproductive phenotype of Pacrg-deficient mice mirrors that of the Meig1 mutant mice. Our findings reveal a critical role for the MEIG1/PARCG partnership in manchette structure and function and the control of spermiogenesis. Spermatogenesis can be divided into three stages: spermatogonial mitosis, meiosis of spermatocytes, and spermiogenesis, the final step of spermatogenesis. During this stage, the haploid round spermatids differentiate into species-specific shaped spermatozoon, with dramatic morphological changes, including elongation and condensation of the nucleus, and formation of the flagellum (1, 2). Even though some genes have been reported to be indispensable for this process (3, 4), the underlying mechanisms remains largely unknown and need to be elucidated.Mouse meiosis expressed gene 1 (Meig1) was originally identified in a search for mammalian genes potentially involved in meiosis. Two Meig1 transcripts, 11a2 and 2a2, were identified previously, both containing three exons. The two transcripts share the same ORF and 3Ј UTR, but differ in their 5Ј UTRs. Each has a unique non-translated exon 1. The 11a2 message was expressed in somatic cells in the testis, including Leydig cells, whereas the predominant 2a2 isoform was reported to be germ cell-specific. The 2a2 transcript begins to accumulate in the testis at day (d)8-9 of postnatal (pn) development, coinciding with the entry of germ cells into meiosis, and is expressed most abundantly at pn d14 and subsequent stages, when spermatocytes enter the pachytene stage. In situ hybridization analysis showed that Meig1 expression level was low in leptotene cells and increased as the cells progressed through zygotene and pachytene stages. In addition, Meig1 message was also detecte...

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“…Although PARK2 is known as an autosomal recessive gene, many studies reported heterozygous mutations, both simple mutations as well as CNVs [Kann et al, 2002;Lucking et al, 2000;Mata et al, 2005a;Periquet et al, 2003]. But reports that compared the mutation frequencies obtained in patients vs. control individuals [Clark et al, 2006;Kay et al, 2007;Lesage et al, 2007;Lincoln et al, 2003;Mata et al, 2005a;Oliveira et al, 2003], were unable to answer questions about the true nature of the PARK2 heterozygous mutations and their contribution to PD pathogenesis.…”

Section: Introductionmentioning

confidence: 90%

Relative contribution of simple mutations vs. copy number variations in five Parkinson disease genes in the Belgian population

et al. 2009

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The relative contribution of simple mutations and copy number variations (CNVs) in SNCA, PARK2, PINK1, PARK7, and LRRK2 to the genetic etiology of Parkinson disease (PD) is still unclear because most studies did not completely analyze each gene. In a large group of Belgian PD patients (N = 310) and control individuals (N = 270), we determined the mutation frequency of both simple mutations and CNVs in these five PD genes, using direct sequencing, multiplex amplicon quantification (MAQ), and real-time PCR assays. Overall, we identified 14 novel heterozygous variants, of which 11 were absent in control individuals. We observed eight PARK2 (multiple) exon multiplications in PD patients and one exon deletion in a control individual. Furthermore, we identified one SNCA whole-gene duplication. The PARK2 and LRRK2 mutation frequencies in Belgian PD patients were similar to those reported in other studies. However, at this stage the true pathogenic nature of some heterozygous mutations in recessive genes remains elusive. Furthermore, though mutations is SNCA, PINK1, and PARK7 are rare, our identification of a SNCA duplication confirmed that screening of these genes remains meaningful.

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Deletion of theparkinandPACRGgene promoter in early-onset parkinsonism

Cited by 39 publications

References 35 publications

Rare heterozygous parkin variants in French early-onset Parkinson disease patients and controls

Rare heterozygous parkin variants in French early-onset Parkinson disease patients and controls

MEIG1 is essential for spermiogenesis in mice

Relative contribution of simple mutations vs. copy number variations in five Parkinson disease genes in the Belgian population

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