C9orf72 hexanucleotide repeat expansions in Chinese sporadic amyotrophic lateral sclerosis

He, Ji, Tang, Lu, Benyamin, Beben, Shah, Sonia, Hemani, Gib, Liu, Rong, Ye, Shan, Liu, Xiaolu, Ma, Yan, Zhang, Huagang, Cremin, Katie, Leo, Paul, Wray, Naomi R., Visscher, Peter M., Xu, Huji, Brown, Matthew A., Bartlett, Perry F., Mangelsdorf, Marie and Fan, Dongsheng (2015) C9orf72 hexanucleotide repeat expansions in Chinese sporadic amyotrophic lateral sclerosis. Neurobiology of Aging, 36 9: 2660.e1-2660.e8. doi:10.1016/j.neurobiolaging.2015.06.002

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Author He, Ji
Tang, Lu
Benyamin, Beben
Shah, Sonia
Hemani, Gib
Liu, Rong
Ye, Shan
Liu, Xiaolu
Ma, Yan
Zhang, Huagang
Cremin, Katie
Leo, Paul
Wray, Naomi R.
Visscher, Peter M.
Xu, Huji
Brown, Matthew A.
Bartlett, Perry F.
Mangelsdorf, Marie
Fan, Dongsheng
Title C9orf72 hexanucleotide repeat expansions in Chinese sporadic amyotrophic lateral sclerosis
Formatted title
C9orf72 hexanucleotide repeat expansions in Chinese sporadic amyotrophic lateral sclerosis
Journal name Neurobiology of Aging   Check publisher's open access policy
ISSN 1558-1497
0197-4580
Publication date 2015-06-09
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.neurobiolaging.2015.06.002
Open Access Status File (Author Post-print)
Volume 36
Issue 9
Start page 2660.e1
End page 2660.e8
Total pages 8
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Language eng
Subject 2800 Neuroscience
1302 Ageing
1309 Developmental Biology
2717 Geriatrics and Gerontology
2728 Clinical Neurology
Abstract A hexanucleotide repeat expansion (HRE) in the C9orf72 gene has been identified as the most common mutation in amyotrophic lateral sclerosis (ALS) among Caucasian populations. We sought to comprehensively evaluate genetic and epigenetic variants of C9orf72 and the contribution of the HRE in Chinese ALS cases. We performed fragment-length and repeat-primed polymerase chain reaction to determine GGGGCC copy number and expansion within the C9orf72 gene in 1092 sporadic ALS (sALS) and 1062 controls from China. We performed haplotype analysis of 23 single-nucleotide polymorphisms within and surrounding C9orf72. The C9orf72 HRE was found in 3 sALS patients (0.3%) but not in control subjects (p = 0.25). For 2 of the cases with the HRE, genotypes of 8 single-nucleotide polymorphisms flanking the HRE were inconsistent with the haplotype reported to be strongly associated with ALS in Caucasian populations. For these 2 individuals, we found hypermethylation of the CpG island upstream of the repeat, an observation not detected in other sALS patients (p < 10(-8)) or controls. The detailed analysis of the C9orf72 locus in a large cohort of Chinese samples provides robust evidence that may not be consistent with a single Caucasian founder event. Both the Caucasian and Chinese haplotypes associated with HRE were highly associated with repeat lengths >8 repeats implying that both haplotypes may confer instability of repeat length. (C) 2015 Elsevier Inc. All rights reserved.
Formatted abstract
A hexanucleotide repeat expansion (HRE) in the C9orf72 gene has been identified as the most common mutation in amyotrophic lateral sclerosis (ALS) among Caucasian populations. We sought to comprehensively evaluate genetic and epigenetic variants of C9orf72 and the contribution of the HRE in Chinese ALS cases. We performed fragment-length and repeat-primed polymerase chain reaction to determine GGGGCC copy number and expansion within the C9orf72 gene in 1092 sporadic ALS (sALS) and 1062 controls from China. We performed haplotype analysis of 23 single-nucleotide polymorphisms within and surrounding C9orf72. The C9orf72 HRE was found in 3 sALS patients (0.3%) but not in control subjects (p = 0.25). For 2 of the cases with the HRE, genotypes of 8 single-nucleotide polymorphisms flanking the HRE were inconsistent with the haplotype reported to be strongly associated with ALS in Caucasian populations. For these 2 individuals, we found hypermethylation of the CpG island upstream of the repeat, an observation not detected in other sALS patients (p < 10−8) or controls. The detailed analysis of the C9orf72 locus in a large cohort of Chinese samples provides robust evidence that may not be consistent with a single Caucasian founder event. Both the Caucasian and Chinese haplotypes associated with HRE were highly associated with repeat lengths >8 repeats implying that both haplotypes may confer instability of repeat length.
Keyword Amyotrophic lateral sclerosis
C9orf72 gene
Hexanucleotide repeat expansion
CpG methylation
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 81030019
LPl10200926
APP1048853
613602
Institutional Status UQ
Additional Notes Article in press corrected proof.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2016 Collection
UQ Diamantina Institute Publications
 
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