Association study of major risk single nucleotide polymorphisms in the common regulatory region of PARK2 and PACRG genes with leprosy in an Indian population

Malhotra, Dheeraj; Darvishi, Katayoon; Lohra, Manmohan; Kumar, Himanshu; Grover, Chander; Sood, Soni; Reddy, B. Naresh Kumar; Bamezai, R.

doi:10.1038/sj.ejhg.5201563

Cited by 46 publications

(24 citation statements)

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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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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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“…Several candidate genes including IL10, TLR1, TAP, SLC11A1, have been associated with susceptibility to leprosy and the development of its clinical forms (Malhotra et al 2005;Rajalingam et al 1997;Santos et al 2002;Wong et al 2010a). The association, however, with several loci, such as PARK2-PACRG, LTA and MICA, has not been replicated in many ethnically distinct leprosy affected populations (Hill 2006;Malhotra et al 2006;Wong et al 2010a;Zhang et al 2009). Genome-wide linkage and association studies also have suggested an involvement of multiple risk loci within Histocompatibility antigen (HLA) complex located in 6p21.3 region.…”

Section: Introductionmentioning

confidence: 92%

Association of variants in BAT1-LTA-TNF-BTNL2 genes within 6p21.3 region show graded risk to leprosy in unrelated cohorts of Indian population

et al. 2011

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Host immune response against Mycobacterium leprae plays an important role in providing resistance to infection and disease progression. Genome-wide linkage and association studies suggest the possibility of multiple risk loci within HLA (6p21.3) region. Any systematic study of relevance within the histocompatibility complex of importance in host immune response would be pertinent because of non-replication of the known loci and unavailable information on some of the unexplored genes and regions. A systematic scan was performed of the selected region involving LTA-TNF-LTB genes within 6p21.3 with a resolution of 1SNP/127 bp; and the SNPs in flanking BAT1, NFKBIL and BTNL2-DRA genes on the basis of their tag status or their presence in promoter/exonic regions with MAF of >5%. Nine SNPs located in BAT1, LTA, TNF genes and BTNL2-DRA interval showed strong association with leprosy susceptibility in two independent sets of North Indian population which was replicated in a geographically distinct East Indian population. Conditional logistic regression showed at least one functional SNP remaining significant in each gene, suggesting an independent role of each of the disease associated SNPs. In vitro reporter assay revealed that two SNPs located at BAT1 promoter and 13 kb upstream to LTA gene affected the transcription factor binding site, hence the gene expression. We unravel the role of unexplored immunologically important genes, BAT1 and BTNL2, in addition to known LTA and TNF genes, and the haplotypes of the significantly associated SNPs therein, to understand susceptibility to the disease, leprosy and its differential severity.

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“…Abnormalities in the promoter region of Parkin/Park2 and PACRG are implicated in various human diseases that include leprosy [12,16,17], typhoid and paratyphoid fever [18], and leukemia [19], as well as in male sterility [5] and ParkinsonÕs disease [3,4]. Considering such a wide range of abnormalities for which PACRG may be responsible, PACRG can be involved in some fundamental cellular function.…”

Section: Discussionmentioning

confidence: 99%

“…Total RNA was prepared from wild-type C. reinhardtii cells using TRIzol Reagent (Invitrogen) and first strand cDNA was synthesized by SuperScript II reverse transcriptase (Invitrogen) using an oligo(dT) [12][13][14][15][16][17][18] primer. Using it as the template, the cDNAs encoding the full-length and truncated coding sequences of PACRG were amplified by PCR using the primer sets, PACRG_BamHI_F 0 ] (DC2), and PACRG301 + ATG_BamHI_F and PAC-RG693 + 6His_EcoRI_R (DNC2).…”

Section: Expression and Purification Of Recombinant Pacrg Proteinsmentioning

confidence: 99%

Parkin‐co‐regulated gene (PACRG) product interacts with tubulin and microtubules

Ikeda

2008

FEBS Letters

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Parkin-co-regulated gene (PACRG) is a gene that shares a bidirectional promoter with ParkinsonÕs disease-related Parkin/Park2 gene. Recently, the PACRG gene product was implicated in the function of flagella. However, its exact function remains unknown. Here, I assessed the interaction between PACRG and tubulin. Co-sedimentation experiments revealed that PACRG directly binds to microtubules and a/b-tubulin heterodimers with high affinity. Microscopic studies showed that PACRG bundles microtubules and forms branched aggregates with unpolymerized tubulin dimers. The amino acid sequence of the microtubule-binding region of PACRG is highly conserved among various organisms, suggesting that tubulin binding is a basic property of PACRG.

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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

Cited by 46 publications

References 8 publications

MEIG1 is essential for spermiogenesis in mice

MEIG1 is essential for spermiogenesis in mice

Association of variants in BAT1-LTA-TNF-BTNL2 genes within 6p21.3 region show graded risk to leprosy in unrelated cohorts of Indian population

Parkin‐co‐regulated gene (PACRG) product interacts with tubulin and microtubules

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