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Functional analysis of intra-allelic variation at NACP-Rep1 in the α-synuclein gene

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Abstract

NACP-Rep1, a polymorphic microsatellite upstream of the α-synuclein gene (SNCA), consisting of the nucleotides (TC)x(T)2(TC)y(TA)z(CA)w, has five alleles originally defined by 2-bp differences in (CA)w. Different NACP-Rep1 alleles have been associated with sporadic Parkinson's disease in some, but not all, studies and can effect expression driven by the SNCA promoter over a three-fold range in the neuroblastoma cell line, SH-SY5Y. By analyzing children in CEPH families in which parents appeared to be homozygous for a NACP-Rep1 allele, we found that there are sequence differences within same-sized NACP-Rep1 alleles, contributed mainly by variation of the (TC)y(TA)z portion of the microsatellite repeat. To test whether these sequence differences might impact on promoter function we determined the effect of two sequence variant alleles, both of size "1", using the luciferase reporter system. There was only a very small expression difference between these two variant alleles. This finding implies that the overall length of the NACP-Rep1 allele plays the main role in the transcription regulation by the NACP-Rep1 element and suggests that functional differences due to sequence heterogeneity within NACP-Rep1 alleles of the same length are probably not confounding factors in association studies based on alleles defined by length.

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Acknowledgements

This work was performed within the Intramural Research Program of the National Human Genome Research Institute.

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Author notes

  1. Jeffrey W. Touchman

    Present address: Pathogen Genomics Division, The Translational Genomics Research Institute, Phoenix, AZ 85004, USA

Authors and Affiliations

  1. Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive MSC 4472, Bethesda, Maryland, 20892-4472, USA

    Ornit Chiba-Falek & Robert L. Nussbaum

  2. NIH Intramural Sequencing Center, National Institutes of Health, Gaithersburg, Maryland, 20877, USA

    Jeffrey W. Touchman

  3. School of Life Sciences, Arizona State University, Tempe, AZ 85281, USA

    Jeffrey W. Touchman

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  1. Ornit Chiba-Falek
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  2. Jeffrey W. Touchman
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  3. Robert L. Nussbaum
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Correspondence to Robert L. Nussbaum.

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Chiba-Falek, O., Touchman, J.W. & Nussbaum, R.L. Functional analysis of intra-allelic variation at NACP-Rep1 in the α-synuclein gene. Hum Genet 113, 426–431 (2003). https://doi.org/10.1007/s00439-003-1002-9

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  • DOI: https://doi.org/10.1007/s00439-003-1002-9

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