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Clinical And Experimental Studies Of A Novel P525r Fus Mutation In Amyotrophic Lateral Sclerosis, Lisha Kuang, Marisa Kamelgarn, Alexandra Arenas, Jozsef Gal, Deborah Taylor, Weiming Gong, Martin Brown, Daret St. Clair, Edward J. Kasarskis, Haining Zhu

Molecular and Cellular Biochemistry Faculty Publications

Objective: To describe the clinical features of a novel fused in sarcoma (FUS) mutation in a young adult female amyotrophic lateral sclerosis (ALS) patient with rapid progression of weakness and to experimentally validate the consequences of the P525R mutation in cellular neuronal models.

Methods: We conducted sequencing of genomic DNA from the index patient and her family members. Immunocytochemistry was performed in various cellular models to determine whether the newly identified P525R mutant FUS protein accumulated in cytoplasmic inclusions. Clinical features of the index patient were compared with 19 other patients with ALS carrying the P525L mutation in the same …

Impact Of Home Visit Capacity On Genetic Association Studies Of Late-Onset Alzheimer's Disease., David W Fardo, Laura E Gibbons, Shubhabrata Mukherjee, M Maria Glymour, Wayne Mccormick, Susan M Mccurry, James D Bowen, Eric B Larson, Paul K Crane

Articles, Abstracts, and Reports

INTRODUCTION: Findings for genetic correlates of late-onset Alzheimer's disease (LOAD) in studies that rely solely on clinic visits may differ from those with capacity to follow participants unable to attend clinic visits.

METHODS: We evaluated previously identified LOAD-risk single nucleotide variants in the prospective Adult Changes in Thought study, comparing hazard ratios (HRs) estimated using the full data set of both in-home and clinic visits (n = 1697) to HRs estimated using only data that were obtained from clinic visits (n = 1308). Models were adjusted for age, sex, principal components to account for ancestry, and additional health indicators.

RESULTS: …

The Clinical Impact Of Copy Number Variants In Inherited Bone Marrow Failure Syndromes, Nicolas Waespe, Santhosh Dhanraj, Manju Wahala, Elena Tsangaris, Tom Enbar, Bozana Zlateska, Hongbing Li, Robert J Klaassen, Conrad V Fernandez, Geoff D E Cuvelier, John K Wu, Yves D Pastore, Mariana Silva, Jeffrey H Lipton, Joseé Brossard, Bruno Michon, Sharon Abish, Macgregor Steele, Roona Sinha, Mark J Belletrutti, Vicky R Breakey, Lawrence Jardine, Lisa Goodyear, Liat Kofler, Michaela Cada, Lillian Sung, Mary Shago, Stephen W Scherer, Yigal Dror

Paediatrics Publications

Inherited bone marrow failure syndromes (IBMFSs) comprise a genetically heterogeneous group of diseases with hematopoietic failure and a wide array of physical malformations. Copy number variants (CNVs) were reported in some IBMFSs. It is unclear what impact CNVs play in patients evaluated for a suspected diagnosis of IBMFS. Clinical and genetic data of 323 patients from the Canadian Inherited Marrow Failure Registry from 2001 to 2014, who had a documented genetic work-up, were analyzed. Cases with pathogenic CNVs (at least 1 kilobasepairs) were compared to cases with other mutations. Genotype-phenotype correlations were performed to assess the impact of CNVs. Pathogenic …

Identification Of A Functional Genetic Variant Driving Racially Dimorphic Platelet Gene Expression Of The Thrombin Receptor Regulator, Pctp., Xianguo Kong, Lukas M. Simon, Michael Holinstat, Chad A. Shaw, Paul F. Bray, Leonard C. Edelstein

Cardeza Foundation for Hematologic Research

Platelet activation in response to stimulation of the Protease Activated Receptor 4 (PAR4) receptor differs by race. One factor that contributes to this difference is the expression level of Phosphatidylcholine Transfer Protein (PCTP), a regulator of platelet PAR4 function. We have conducted an expression Quantitative Trait Locus (eQTL) analysis that identifies single nucleotide polymorphisms (SNPs) linked to the expression level of platelet genes. This analysis revealed 26 SNPs associated with the expression level of PCTP at genome-wide significance (p < 5×10(-8)). Using annotation from ENCODE and other public data we prioritised one of these SNPs, rs2912553, for functional testing. The allelic frequency of rs2912553 is racially-dimorphic, in concordance with the racially differential expression of PCTP. Reporter gene assays confirmed that the single nucleotide change caused by rs2912553 altered the transcriptional potency of the surrounding genomic locus. Electromobility shift assays, luciferase assays, and overexpression studies indicated a role for the megakaryocytic transcription factor GATA1. In summary, we have integrated multi-omic data to identify and functionalise an eQTL. This, along with the previously described relationship between PCTP and PAR4 function, allows us to characterise a genotype-phenotype relationship through the mechanism of gene expression.

Neuropathological And Genetic Correlates Of Survival And Dementia Onset In Synucleinopathies: A Retrospective Analysis, David J. Irwin, Murray Grossman, Daniel Weintraub, Howard I. Hurtig, John E. Duda, Sharon X. Xie, Edward B. Lee, Vivianna M. Van Deerlin, Oscar L. Lopez, Julia K. Kofler, Peter T. Nelson, Gregory A. Jicha, Randy Woltjer, Joseph F. Quinn, Jeffery Kaye, James B. Leverenz, Debby Tsuang, Katelan Longfellow, Dora Yearout, Walter Kukull, C. Dirk Keene, Thomas J. Montine, Cyrus P. Zabetian, John Q. Trojanowski

Sanders-Brown Center on Aging Faculty Publications

Background

Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies.

Methods

In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of …

Epidemiological, Clinical And Genetic Aspects Of Adult Onset Isolated Focal Dystonia In Ireland, L. Williams, E. Mcgovern, O. Kimmich, A. Molloy, I. Beiser, John Butler, F. Molloy, P. Logan, D.G. Healy, T. Lynch, R. Walsh, L. Cassidy, P. Moriarty, H. Moore, T. Mcswiney, C. Walsh, S. O'Riordan, M. Hutchinson

Articles

Background: Adult onset idiopathic isolated focal dystonia presents with a number of phenotypes. Reported prevalence rates vary considerably; well-characterized cohorts are important to our understanding of this disorder.

Aim: To perform a nationwide epidemiological study of adult onset idiopathic isolated focal dystonia in the Republic of Ireland.

Methods: Patients with adult onset idiopathic isolated focal dystonia were recruited from multiple sources. Diagnosis was based on assessment by a neurologist with an expertise in movement disorders. When consent was obtained, a number of clinical features including family history were assessed.

Results: On the prevalence date there were 592 individuals in Ireland …