Next Generation gene discovery in neurogenetics

神经遗传学中的下一代基因发现

基本信息

批准号：
9263767
负责人：
WENDY H RASKIND
金额：
$ 50.51万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9263767
关键词：
Adenylate Cyclase Ataxia Biological Biological Models Biology Birds Candidate Disease Gene Cardiac Cells Cellular biology Chorea Chromosome Mapping Clinical Code Collaborations Collection Copy Number Polymorphism Data Development Diagnosis Diagnostic Disease Dyskinetic syndrome Dysmyelopoietic Syndromes Dystonia Emerging Technologies Ensure Etiology Facial Myokymias Family Family member Generations Genes Genome Genomic Segment Genotype Goals Hereditary Choreas Human Human Biology Human Genetics Inherited Investigation Knowledge Lead Learning Light Link Maintenance Massive Parallel Sequencing Mendelian disorder Methods Molecular Molecular Biology Molecular Genetics Molecular and Cellular Biology Mutation Myeloid Leukemia Nature Nervous system structure Neurologic Neurons Pancytopenia Parkinsonian Disorders Pathogenesis Pathogenicity Pathologic Patients Peptide Sequence Determination Phase Phenotype Physicians Process Rare Diseases Research Research Personnel Resources Sampling Scientist Spastic Speed Stem cells Study models System Technology Validation Variant base biological systems clinical phenotype disease-causing mutation disorder prevention exome exome sequencing gene discovery gene function genetic linkage analysis genetic variant human disease improved mutation screening nervous system disorder neurogenetics new technology next generation novel novel strategies prognostic programs protein complex protein protein interaction public health relevance sample collection spasticity therapy design

项目摘要

DESCRIPTION (provided by applicant): Our goals are to identify genes that cause Mendelian neurologic disorders, determine the effect of mutations on the functions of the genes, delineate the effect of mutations on the spectrum of clinical manifestations and generate models for studies of disease pathogenesis. Each new gene discovery for an inherited neurologic disorder, no matter how rare that disorder, provides an opportunity to learn about the function of the human nervous system and the processes that lead to its malfunction and degeneration. We take advantage of a rich sample set of patients with neurogenetic diseases of unknown etiology, amassed through decades of ascertainment and clinical characterization. In addition to gene discovery, these families are invaluable resources for investigation of genotype effects on the phenotype. Our studies not only shed light on the biological effects of mutations, but also provide clinically useful diagnostic and prognostic information for these patients and their physicians, and have the potential to influence therapy. The speed of disease-gene discovery has increased tremendously in recent years mainly because of advances in sequencing technology that allow broad investigation of the genome with or without linkage information. Using these methods, during the current cycle, we discovered causative genes for multiple neurogenetic disorders, and demonstrated effects of mutations on the function of the genes and their contribution to disease pathogenesis. In some cases our findings have implications beyond the nervous system. One of these disorders is the first human disease definitively tied to an adenylate cyclase gene and has potential cardiac implications. Another disorder with hematologic manifestations as well as ataxia has implications for myeloid leukemias and myelodysplasia. We will continue to apply gene localization methods and exome sequencing to identify additional genes for neurogenetic disorders in our large, well-characterized collection of families. We will use a variety of cell-based systems to verify the pathologic effect of mutations on gene function and initiate studies on other genes as we discover them. We incorporate new approaches, such as molecular inversion probe panels to aid in categorizing families for further study, GIGI-Pick to select the optimal family members to sequence, and induced pluripotential stem cell generation to obtain patient- derived neuronal cells. This new proposal builds on the strength of established collaborations among all four Investigators with expertise in diagnosis and characterization of neurologic disorders, human and molecular genetics, and cell biology, and with ongoing and new collaborations with scientists at the forefronts of their fields we strengthen our ability to apply new and emerging technologies to our research.

描述（由适用提供）：我们的目标是确定引起孟德尔神经系统疾病的基因，确定突变对基因功能的影响，描述突变对临床表现光谱的影响，并为疾病病原体研究产生模型。对于遗传神经系统疾病的每个新基因发现，无论这种疾病多么罕见，都为了解人类神经系统功能以及导致其故障和变性的过程提供了机会。通过数十年的确定性和临床表征，我们利用丰富的患有未知病因的神经遗传疾病的患者样本。除了基因发现外，这些家族是投资基因型对表型的影响的宝贵资源。我们的研究不仅阐明了突变的生物学作用，而且还为这些患者及其医生提供了临床上有用的诊断和预后信息，并有可能影响治疗。近年来，疾病 - 基因发现的速度大大提高，主要是因为测序技术的进步可以通过有或没有连锁信息对基因组进行广泛投资。使用这些方法，在当前周期中，我们发现了多种神经遗传疾病的严重基因，并证明了突变对基因功能及其对疾病发病机理的贡献的影响。在某些情况下，我们的发现超出了神经系统的影响。这些疾病之一是与腺苷酸环化酶基因相关的第一种人类疾病，并具有潜在的心脏影响。血液学表现以及共济失调的另一种疾病对髓样白血病和骨髓增生性具有影响。我们将继续采用基因定位方法和外显子组测序，以确定我们大型，充分表征的神经遗传疾病的其他基因家庭。我们将使用各种基于细胞的系统来验证突变对基因功能的病理影响，并在发现其他基因时启动对其他基因的研究。我们结合了新方法，例如分子反转探针面板，以帮助对家族进行进一步研究，Gigi-Pick选择最佳家族成员进行序列，并诱导多能干细胞的产生以获得患者衍生的神经元细胞。这项新提案以在神经系统疾病，人和分子遗传学以及细胞生物学的诊断和表征方面的专业知识以及与科学家在其领域前沿的科学家进行持续的和新的合作方面的专业知识中建立合作的力量建立在其领域的诊断和表征方面的专业知识。