Alphasynuclein p.H50Q, a novel pathogenic mutation ...

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Silke Appel-Cresswell, MD,1* Carles Vilarino-Guell, PhD,2. Mary Encarnacion, BSc,2 .... put); and the Greystone Classic for Parkinson's, Inc. (to Alex Rajput and.


Alpha-Synuclein p.H50Q, a Novel Pathogenic Mutation for Parkinson’s Disease Silke Appel-Cresswell, MD,1* Carles Vilarino-Guell, PhD,2 Mary Encarnacion, BSc,2 Holly Sherman, BSc,2 Irene Yu, MSc,2 Brinda Shah, MSc,2 David Weir, MSc,1 Christina Thompson, BSc,2 Chelsea Szu-Tu, MSc,2 Joanne Trinh, BSc,2 Jan O. Aasly, MD,3 Alex Rajput, MD,4 Ali H. Rajput, MD,4 A. Jon Stoessl, MD,1 and Matthew J. Farrer, PhD1,2 1

Department of Medicine (Neurology), Pacific Parkinson’s Research Centre, University of British Columbia, Vancouver, British Columbia, Canada; 2Department of Medical Genetics, Centre for Applied Neurogenetics, University of British Columbia, Vancouver, British Columbia, Canada; 3Department of Neurology, St. Olav’s Hospital, Trondheim, Norway; 4Division of Neurology, University of Saskatchewan and Saskatoon Health Region, Saskatoon, Saskatchewan, Canada

ABSTRACT Background: Alpha-synuclein plays a central role in the pathophysiology of Parkinson’s disease. Three missense mutations in SNCA, the gene encoding alpha-synuclein, as well as genomic multiplications have been identified as causes for autosomal-dominantly inherited Parkinsonism. Methods: Here, we describe a novel missense mutation in exon 4 of SNCA encoding a H50Q substitution in a patient with dopa-responsive Parkinson’s disease with a family history of parkinsonism and dementia. Results: The variant was not observed in public databases or identified in unrelated subjects. Conclusions: 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 C 2013 Movement described pathogenic mutations. V Disorder Society Key Words: parkinson disease; genetic; alphasynuclein

The identification of the alpha-synuclein gene mutation, SNCA c.209G>A (p.A53T), in families with autosomal dominantly inherited parkinsonism led to its discovery as the main component of Lewy bodies, the pathological hallmark of Parkinson’s disease


(PD).1–3 Polymorphic SNCA variability is now associated with idiopathic PD worldwide (for cumulative meta-analysis, see Other alpha-synuclein substitutions (p.A30P and p.E46K) and pathogenic genomic multiplications have been described4–6 and have led to physiologically relevant translational neuroscience directed towards diseasemodifying therapeutics. Sanger sequencing of SNCA coding exons in a patient with PD, with a family history of parkinsonism and dementia, and for whom all other known PD mutations had been excluded led to the identification of a c.150T>G mutation encoding a histidine-to-glutamine substitution (p.H50Q). The affected carrier was 1 of 110 subjects fully sequenced, of whom 66 (59%) had a family history of parkinsonism (2 or more affected subjects within a degree of relationship). This amino acid is evolutionarily conserved and is likely to perturb the same amphipathic alpha helical structure as p.E46K and p.A53T (Fig. 1), suggesting the disease mechanism for these mutations is similar. TaqMan probe genotyping of SNCA c.150T>G in 1105 PD patients (21% familial) and 875 controls of white ethnicity from specialty movement disorders clinics in Canada and Norway failed to identify any additional carriers. This missense mutation has not been reported in publicly available next-generation sequencing databases (, indicating it is unlikely to be a benign albeit rare variant. The research protocols were approved by the relevant local ethics committees, and all subjects provided written informed consent.

-----------------------------------------------------------*Correspondence to: Dr. Silke Appel-Cresswell, Pacific Parkinson’s Research Centre, Department of Medicine (Neurology), University of British Columbia, Vancouver, BC, Canada, V6T 2B5; [email protected]

Funding agencies: This study was supported by Canada Excellence Research Chairs program (to Matthew J. Farrer); Canada Research Chairs (to A. Jon Stoessl); the Cundill Foundation (to A. Jon Stoessl and Matthew J. Farrer); Leading Edge Endowment Funds provided by the Province of British Columbia, LifeLabs, and Genome BC, which support the Dr. Donald Rix BC Leadership Chair (to Matthew J. Farrer); the Pacific Parkinson’s Research Institute (to Silke Appel-Cresswell); Canadian Institutes of Health Research (to A. Jon Stoessl); the Pacific Alzheimer Research Foundation (to A. Jon Stoessl and Silke AppelCresswell); the Regina Curling Classic (to Alex Rajput and Ali H. Rajput); the Royal University Hospital Foundation (to Alex Rajput and Ali H. Rajput); and the Greystone Classic for Parkinson’s, Inc. (to Alex Rajput and Ali H. Rajput). Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 11 September 2012; Revised: 31 December 2012; Accepted: 27 January 2013 Published online in Wiley Online Library ( DOI: 10.1002/mds.25421

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FIG. 1. Pedigree, protein structure, and conservation. A: Pedigree. B: Protein conservation. SNCA mutations (p.A30P, p.E46K, p.H50Q, and p.A53T) are boxed in black; positions not evolutionary conserved are boxed in gray. C: Model of protein structure, E46K, H50Q and A53T are on the same face of the amphipathic helix. [Color figure can be viewed in the online issue, which is available at]

The patient developed a bilateral action tremor at age 60, followed by micrographia and decreased walking speed with shuffling and problems turning. When walking, his toes curled up in painful dystonic flexion. Fine motor skills declined. His voice became hypophonic, his speech was faster and marked by a newonset stutter. Subsequently, he developed apathy, reduced energy, and heightened anxiety levels as well as mild memory problems and difficulties making decisions. He denied any symptoms suggestive of hyposmia, REM sleep behavior disorder, constipation, genitourinary dysfunction, postural hypotension, postural instability, dysphagia, or hallucinations. Examination at age 62 revealed hypomimia, hypophonia, micrographia, and mild bilateral rest and postural tremor. Rigidity and bradykinesia were moderate and mostly present on the right side. His gait was very slow, with reduced arm swing and turning-en-bloc. Blood pressure levels supine and after 1 minute of standing were 148/76 and 144/84 mm Hg, respectively. There were no pyramidal or cerebellar signs or postural instability. On levodopa/carbidopa, his UPDRS Part III score improved from 30 to 11 points. At age 63, he scored 23 of 30 points on the Montreal Cognitive Assessment. At the last review at age 64, he had developed some end-of-dose deterioration but otherwise continued to respond well to levodopa. At this time, MRI of the brain showed mild generalized atrophy and mild small-vessel disease. The patient reported a family history of neurodegeneration. His mother developed problems walking and visual and speech problems at age 56. She had tremor and appeared “parkinsonian”; she continued to decline, was eventually bedridden and demented, and died at age 61. According to the proband, the mother’s sister had dementia and died in her early 80s, and her brother, aged 78, has dementia. The patient’s sister, aged 52, is reported to have multiple sclerosis. His


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2 sons, aged 38 and 36, are asymptomatic. The maternal family is of English/Welsh origin. SNCA p.H50Q was first presented at the Movement Disorders Society 16th International Congress, Dublin, where it was also described in the brain of a British patient with Lewy body disease7,8 Importantly, microsatellite marker alleles spanning > 1.77 Mb of the SNCA locus about the c.150T>G (p.H50Q) mutation are shared by both individuals, consistent with their common ancestral founder (data available on request). Clinically, of alpha-synuclein missense mutations, the p.A53T families have the earliest-onset parkinsonism (47 6 11 years; range, 36–58 years; n 5 10), often leading to cognitive decline and dementia.1,9 The p.A30P substitution is associated with later-onset parkinsonism (60 6 11 years; range, 54–76 years; n 5 5) with mild dementia.4,10 The p.E46K mutation, in turn, is associated with parkinsonism (59 6 6 years; range, 50–65 years; n 5 4) and more often dementia and visual hallucinations (dementia with Lewy bodies [DLB]).5 The phenotype in SNCA multiplication depends on dose; triplication carriers (4 copies) develop fulminant parkinsonism-dementia by the fourth and fifth decades, whereas duplication carriers (3 copies) may manifest a variety of later-onset Lewy body spectrum disorders clinically described as PD, DLB, or multiple system atrophy.6 SNCA p.H50Q is located between the previously reported p.E46K and p.A53T pathogenic substitutions and similarly disrupts the protein’s amphipathic helix. The index subject developed dopa-responsive parkinsonism at age 60 years and showed a combination of motor and cognitive decline. The rapidly progressive course of motor problems and dementia in the subject’s mother, with a history of dementia in 2 of her siblings, is similar to the clinical description of p.E46K and p.A53T families. We were not able to perform mutation segregation analysis with disease but

a- S Y N U C L E I N

nonetheless postulate that SNCA p.H50Q is a novel cause of parkinsonism and dementia in this kindred. Acknowledgements: We are grateful to all individuals who generously participated in this research.

p . H 5 0 Q ,

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