Abstract:
:Parkinson disease (PD) is a common neurodegenerative disorder caused by environmental and genetic factors. We have previously shown linkage of PD to chromosome 8p. Subsequently, fibroblast growth factor 20 (FGF20) at 8p21.3-22 was identified as a risk factor in several association studies. To identify the risk-conferring polymorphism in FGF20, we performed genetic and functional analysis of single-nucleotide polymorphisms within the gene. In a sample of 729 nuclear families with 1089 affected and 1165 unaffected individuals, the strongest evidence of association came from rs12720208 in the 3' untranslated region of FGF20. We show in several functional assays that the risk allele for rs12720208 disrupts a binding site for microRNA-433, increasing translation of FGF20 in vitro and in vivo. In a cell-based system and in PD brains, this increase in translation of FGF20 is correlated with increased alpha-synuclein expression, which has previously been shown to cause PD through both overexpression and point mutations. We suggest a novel mechanism of action for PD risk in which the modulation of the susceptibility gene's translation by common variations interfere with the regulation mechanisms of microRNA. We propose this is likely to be a common mechanism of genetic modulation of individual susceptibility to complex disease.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Wang G,van der Walt JM,Mayhew G,Li YJ,Züchner S,Scott WK,Martin ER,Vance JMdoi
10.1016/j.ajhg.2007.09.021subject
Has Abstractpub_date
2008-02-01 00:00:00pages
283-9issue
2eissn
0002-9297issn
1537-6605pii
S0002-9297(08)00078-5journal_volume
82pub_type
杂志文章abstract::The exploration of copy-number variation (CNV), notably of somatic cells, is an understudied aspect of genome biology. Any differences in the genetic makeup between twins derived from the same zygote represent an irrefutable example of somatic mosaicism. We studied 19 pairs of monozygotic twins with either concordant ...
journal_title:American journal of human genetics
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journal_title:American journal of human genetics
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journal_title:American journal of human genetics
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journal_title:American journal of human genetics
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更新日期:1982-09-01 00:00:00
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更新日期:1986-12-01 00:00:00
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1975-01-01 00:00:00
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更新日期:1996-05-01 00:00:00
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