Deletion at ITPR1 Underlies Ataxia in Mice and Spinocerebellar Ataxia 15 in Humans

We observed a severe autosomal recessive movement disorder in mice used within our laboratory. We pursued a series of experiments to define the genetic lesion underlying this disorder and to identify a cognate disease in humans with mutation at the same locus. Through linkage and sequence analysis we show here that this disorder is caused by a homozygous in-frame 18-bp deletion in Itpr1 (Itpr1Δ18/Δ18), encoding inositol 1,4,5-triphosphate receptor 1. A previously reported spontaneous Itpr1 mutation in mice causes a phenotype identical to that observed here. In both models in-frame deletion within Itpr1 leads to a decrease in the normally high level of Itpr1 expression in cerebellar Purkinje cells. Spinocerebellar ataxia 15 (SCA15), a human autosomal dominant disorder, maps to the genomic region containing ITPR1; however, to date no causal mutations had been identified. Because ataxia is a prominent feature in Itpr1 mutant mice, we performed a series of experiments to test the hypothesis that mutation at ITPR1 may be the cause of SCA15. We show here that heterozygous deletion of the 5′ part of the ITPR1 gene, encompassing exons 1–10, 1–40, and 1–44 in three studied families, underlies SCA15 in humans

Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research

Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

AbstractObjectiveWe sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk.MethodsWe evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.ResultsWe observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p &lt; 4.4 × 10−4 in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p &gt; 0.1).ConclusionsGenetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.</jats:sec

Prevalence of Parkinson's disease in populations of African ancestry: A review

This article is free to read on the publishers website There have been a number of studies looking at the prevalence of Parkinson's disease (PD) in different racial and geographical populations. Some of the earliest studies suggested a difference in the prevalence of PD in African Americans as compared with Caucasians. As such a difference would have important implications for healthcare and research into the etiology of PD, we undertook a review of published studies to determine whether evidence suggested that such a difference exists. We reviewed 20 studies that looked at incidence, prevalence, and percentages of neurology patients with PD and Parkinsonism in Africa and in African-American populations. Two of these were door-to-door studies that relied on questionnaires for initial ascertainment, another was performed by review of outpatient records of a large health maintenance organization, while the remainder were based on hospital admissions, diagnosis in the community, or death certificate reports. In the aggregate, these studies suggest PD may be less frequent among Africans and African Americans than among Caucasians, although the most well-designed study showed only a statistically insignificant reduction in the prevalence of PD among African Americans. Although an apparently lower disease frequency among people of African origin may have a basis in the pathobiology of the disease, nearly all of these studies were vulnerable to a variety of ascertainment biases, and many lacked stringent application of diagnostic criteria applied by specialists trained in movement disorders. We conclude that a difference in the prevalence of PD and Parkinsonism between black and other populations is unproven and will require additional well-designed studies to determine if previously reported ethnic differences in disease prevalence are real

Exercise-induced dystonia as a preceding symptom of familial Parkinson's disease

peer reviewedParoxysmal exercise-induced dystonia can occur with Parkinson's disease (PD), and in rare cases, this can also be the presenting symptom. We report on 2 second cousins (no known consanguinity) who presented with paroxysmal exercise-induced dystonia who later developed clinical features of PD. Although autosomal recessive inheritance was suggested, and the dystonic features further suggest parkin as a possible cause, ssequencing for parkin mutations was negative and this family may represent a genetic variant of PD. Further genotype-phenotype studies in this and similar families may give clues to pre-symptomatic symptoms in PD and may reflect a particular phenotype of interest for genetics studies in the future

Analysis of SCA-2 and SCA-3 repeats in parkinsonism: Evidence of SCA-2 expansion in a family with autosomal dominant Parkinson's disease

The spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders linked to more than 20 genetic loci. Most often, these diseases are caused by expansion of triplet repeats encoding polyglutamine (polyQ) tracts. The phenotype is variable and can cause a disease that overlaps clinically with Parkinson's disease (PD). L-Dopa-responsive parkinsonism with minimal cerebellar deficits has been described in SCA2 and SCA3. In order to define if mutation at these loci is a common cause of clinically defined parkinsonism we typed the SCA-2 and SCA-3 repeats for expansion in a series of 280 patients diagnosed with PD or parkinsonism. We identified one pathogenic expansion in SCA-2 in a North American family with autosomal dominant parkinsonism

Genome-wide analysis of the parkinsonism-dementia complex of Guam

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Comprehensive Screening of a North American Parkinson's Disease Cohort for LRRK2 Mutation

Background Recently, mutations in LRRK2 encoding the protein dardarin have been linked to an autosomal dominant form of parkinsonism. Objective To identify mutations causing Parkinson’s disease (PD) in a cohort of North Americans with familial PD. Methods We sequenced exons 1–51 of LRRK2 in 79 unrelated North American PD patients reporting a family history of the disease. Results One patient had a missense mutation (Thr2356Ile) while two others had the common Gly2019Ser mutation. In addition, 1 patient had a 4-bp deletion in close proximity to the exon 19 splice donor (IVS20+4delGTAA) that in vitro abrogates normal splicing. Conclusions Our observations in the 79 North American patients indicate that mutations in LRRK2 are associated with approximately 5% of PD cases with a positive family history. The results also show that G2019S represents approximately half of the LRRK2 mutations in United States PD cases with a family history of the disease. We have identified two novel mutations in LRRK2

Analysis of the PINK1 Gene in a Large Cohort of Cases With Parkinson Disease

Background Mutations in the PTEN-induced kinase (PINK1) gene located within the PARK6 locus on chromosome 1p35-p36 have recently been identified in patients with recessive early-onset Parkinson disease. Objective To assess the prevalence of PINK1 mutations within a series of early- and late-onset Parkinson disease patients living in North America. Design All coding exons of the PINK1 gene were sequenced in a series of 289 Parkinson disease patients and 80 neurologically normal control subjects; the mutation frequencies were evaluated in additional controls (100 white and 50 Filipino subjects). Results We identified 27 variants, including the first reported compound heterozygous mutation (Glu240Lys and Leu489Pro) and a homozygous Leu347Pro mutation in 2 unrelated young-onset Parkinson disease patients. Conclusion Autosomal recessive mutations in PINK1 are a rare cause of young-onset Parkinson disease

Amyotrophic lateral sclerosis: an emerging era of collaborative gene discovery.

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND). It is currently incurable and treatment is largely limited to supportive care. Family history is associated with an increased risk of ALS, and many Mendelian causes have been discovered. However, most forms of the disease are not obviously familial. Recent advances in human genetics have enabled genome-wide analyses of single nucleotide polymorphisms (SNPs) that make it possible to study complex genetic contributions to human disease. Genome-wide SNP analyses require a large sample size and thus depend upon collaborative efforts to collect and manage the biological samples and corresponding data. Public availability of biological samples (such as DNA), phenotypic and genotypic data further enhances research endeavors. Here we discuss a large collaboration among academic investigators, government, and non-government organizations which has created a public repository of human DNA, immortalized cell lines, and clinical data to further gene discovery in ALS. This resource currently maintains samples and associated phenotypic data from 2332 MND subjects and 4692 controls. This resource should facilitate genetic discoveries which we anticipate will ultimately provide a better understanding of the biological mechanisms of neurodegeneration in ALS