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Henry Houlden

Bio: Henry Houlden is an academic researcher from UCL Institute of Neurology. The author has contributed to research in topics: Medicine & Exome sequencing. The author has an hindex of 86, co-authored 661 publications receiving 35754 citations. Previous affiliations of Henry Houlden include Great Ormond Street Hospital for Children NHS Foundation Trust & Mayo Clinic.


Papers
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Journal ArticleDOI
18 Jun 1998-Nature
TL;DR: In this paper, the authors sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon in
Abstract: Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)(1-9), historically termed Pick's disease(10) Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics(1-8,12) Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q2111; the tau gene also lies within this region We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon in The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10 (ref 13) This causes more frequent usage of the 5' splice site and an increased proportion of tan transcripts that include exon 10 The increase in exon 10(+) messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17 (refs 12, 14)

3,366 citations

Journal ArticleDOI
TL;DR: It is demonstrated that an unequivocal role for common genetic variants in the etiology of typical PD and population-specific genetic heterogeneity in this disease is suggested, and supporting evidence that common variation around LRRK2 modulates risk for PD is provided.
Abstract: We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding a-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 x 10(-16)) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 x 10(-16)). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS1, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 x 10(-8)) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 x 10(-5)). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.

1,793 citations

Journal ArticleDOI
TL;DR: This article conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls.
Abstract: We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55–4.30; P = 2 × 10−16). We also show six risk loci associated with proximal gene expression or DNA methylation.

1,636 citations

Journal ArticleDOI
TL;DR: A double mutation at codons 670 and 671 (APP 770 transcript) in exon 16 which co–segregates with the disease in two large (probably related) early–onset Alzheimer's disease families from Sweden is identified.
Abstract: Mutations at codon 717 in exon 17 of the beta-amyloid precursor protein (APP) gene have previously been shown to segregate with early onset Alzheimer's disease in some families. We have identified a double mutation at codons 670 and 671 (APP 770 transcript) in exon 16 which co-segregates with the disease in two large (probably related) early-onset Alzheimer's disease families from Sweden. Two base pair transversions (G to T, A to C) from the normal sequence predict Lys to Asn and Met to Leu amino acid substitutions at codons 670 and 671 of the APP transcript. This mutation occurs at the amino terminal of beta-amyloid and may be pathogenic because it occurs at or close to the endosomal/lysosomal cleavage site of the molecule. Thus, pathogenic mutations in APP frame the beta-amyloid sequence.

1,626 citations

Journal ArticleDOI
31 Oct 1991-Nature
TL;DR: The occurrence of a second allelic variant at codon 717 linked to the Alzheimer's phenotype supports the hypothesis that they are pathogenic mutations.
Abstract: A MUTATION at codon 717 of the β-amyloid precursor protein gene has been found to cosegregate with familial Alzheimer's disease in a single family1. This mutation has been reported in a further five out of ∼ 100 families multiply affected by Alzheimer's disease1–4. We have identified another family, F19, in which we have detected linkage between the β-amyloid precursor protein gene and Alzheimer's disease. Direct sequencing of exon 17 (ref. 5) in affected individuals from this family has revealed a base change producing a Val → Gly substitution, also at codon 717. The occurrence of a second allelic variant at codon 717 linked to the Alzheimer's phenotype supports the hypothesis that they are pathogenic mutations.

1,286 citations


Cited by
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28 Jul 2005
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1(PfPMP1)与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员,通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

18,940 citations

Journal ArticleDOI
TL;DR: The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available.
Abstract: The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

13,710 citations

Journal ArticleDOI
19 Jul 2002-Science
TL;DR: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide in plaques in brain tissue and the rest of the disease process is proposed to result from an imbalance between Aβ production and Aβ clearance.
Abstract: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer9s disease (AD) may be caused by deposition of amyloid β-peptide (Aβ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Aβ production and Aβ clearance.

12,652 citations

Journal ArticleDOI
10 Apr 1992-Science
TL;DR: An extensive catalog of genes that act in a migrating cell is provided, unique molecular functions involved in nematode cell migration are identified, and similar functions in humans are suggested.
Abstract: In both metazoan development and metastatic cancer, migrating cells must carry out a detailed, complex program of sensing cues, binding substrates, and moving their cytoskeletons. The linker cell in Caenorhabditis elegans males undergoes a stereotyped migration that guides gonad organogenesis, occurs with precise timing, and requires the nuclear hormone receptor NHR-67. To better understand how this occurs, we performed RNA-seq of individually staged and dissected linker cells, comparing transcriptomes from linker cells of third-stage (L3) larvae, fourth-stage (L4) larvae, and nhr-67-RNAi–treated L4 larvae. We observed expression of 8,000–10,000 genes in the linker cell, 22–25% of which were up- or down-regulated 20-fold during development by NHR-67. Of genes that we tested by RNAi, 22% (45 of 204) were required for normal shape and migration, suggesting that many NHR-67–dependent, linker cell-enriched genes play roles in this migration. One unexpected class of genes up-regulated by NHR-67 was tandem pore potassium channels, which are required for normal linker-cell migration. We also found phenotypes for genes with human orthologs but no previously described migratory function. Our results provide an extensive catalog of genes that act in a migrating cell, identify unique molecular functions involved in nematode cell migration, and suggest similar functions in humans.

6,144 citations