Alpha‐synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease

Appel‐Cresswell, Silke; Vilariño‐Güell, Carles; Encarnacion, Mary Joy; Sherman, Holly E.; Yu, Irene S.; Shah, Brinda; Weir, David W; Thompson, Christina; Szu-Tu, Chelsea; Trinh, Joanne; Aasly, Jan; Rajput, Alex; Rajput, Ali H.; Stoessl, A. Jon; Farrer, Matthew J.

doi:10.1002/mds.25421

Cited by 561 publications

(440 citation statements)

References 10 publications

(19 reference statements)

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“…Recently, the H50Q substitution in ␣Syn was identified as a familial PD-causing mutant by two different groups (30,31). In the current study NMR experiments demonstrate that the H50Q substitution, but not other examined substitutions, increased the flexibility of the ␣Syn C-terminal region.…”

mentioning

confidence: 49%

Residue Histidine 50 Plays a Key Role in Protecting α-Synuclein from Aggregation at Physiological pH

Chi

Armstrong

Jones

et al. 2014

Journal of Biological Chemistry

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Background: Mutations of ␣-synuclein (␣Syn) can cause early-onset familial Parkinson disease (PD). Results: The H50Q, H50D, or H50A substitution promotes, whereas the H50R substitution inhibits, ␣Syn aggregation in vitro. Conclusion:The recently identified PD-causing ␣Syn mutant, ␣Syn(H50Q), accelerates ␣Syn aggregation. Significance: The partial positive charge of His-50 at physiological pH likely plays a role in suppressing ␣Syn aggregation.

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mentioning

confidence: 49%

Residue Histidine 50 Plays a Key Role in Protecting α-Synuclein from Aggregation at Physiological pH

Chi

Armstrong

Jones

et al. 2014

Journal of Biological Chemistry

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“…Mutations in the human a-syn gene (A30P, E46K, H50Q, and A53T) are observed in rare autosomal-dominant forms of PD (Polymeropoulos et al 1997;Kruger et al 1998;Zarranz et al 2004;Appel-Cresswell et al 2013).…”

Section: Pd: Disease Mechanismsmentioning

confidence: 99%

Adult Neurogenesis in Neurodegenerative Diseases: Figure 1.

Winner¹,

Winkler

2015

Cold Spring Harb Perspect Biol

264

213

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“…The remaining LRRK2 variants have an unknown role in relation to PD. Coding variants in SNCA are very rare, but recently a few novel pathogenic mutations have been reported (Appel-Cresswell et al, 2013;Lesage et al, 2013;Proukakis et al, 2013). We found no SNCA variants in our sample set.…”

Section: Discussionmentioning

confidence: 40%

Effective Variant Detection by Targeted Deep Sequencing of DNA Pools: An Example from Parkinson's Disease

Pihlstrøm

Rengmark

Bjørnarå

et al. 2014

Annals of Human Genetics

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SummaryNext-generation sequencing technologies will dominate the next phase of discoveries in human genetics, but considerable costs may still represent a limitation for studies involving large sample sets. Targeted capture of genomic regions may be combined with deep sequencing of DNA pools to efficiently screen sample cohorts for disease-relevant mutations. We designed a 200 kb HaloPlex kit for PCR-based capture of all coding exons in 71 genes relevant to Parkinson's disease and other neurodegenerative disorders. DNA from 387 patients with Parkinson's disease was combined into 39 pools, each representing 10 individuals, before library preparation with barcoding and Illumina sequencing. In this study, we focused the analysis on six genes implicated in Mendelian Parkinson's disease, emphasizing quality metrics and evaluation of the method, including validation of variants against individual genotyping and Sanger sequencing. Our data showed 97% sensitivity to detect a single nonreference allele in pools, rising to 100% where pools achieved sequence depth above 80x for the relevant position. Pooled sequencing detected 18 rare nonsynonymous variants, of which 17 were validated by independent methods, corresponding to a specificity of 94%. We argue that this design represents an effective and reliable approach with possible applications for both complex and Mendelian genetics.

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Alpha‐synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease

Abstract: The substitution's evolutionary conservation and protein modeling provide additional support for pathogenicity as the amino acid perturbs the same amphipathic alpha helical structure as the previously described pathogenic mutations.

Cited by 561 publications

References 10 publications

Residue Histidine 50 Plays a Key Role in Protecting α-Synuclein from Aggregation at Physiological pH

Residue Histidine 50 Plays a Key Role in Protecting α-Synuclein from Aggregation at Physiological pH

Adult Neurogenesis in Neurodegenerative Diseases: Figure 1.

Effective Variant Detection by Targeted Deep Sequencing of DNA Pools: An Example from Parkinson's Disease

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