MOLECULAR GENETICS OF INHERITED NEUROLOGIC AND PSYCHIATRIC DISORDERS

遗传性神经和精神疾病的分子遗传学

• 批准号: 6111135
• 负责人: EDWARD I GINNS
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6111135
• 关键词: attention deficit disorder; autism; bipolar depression; congenital nervous system disorder; family genetics; fluorescent in situ hybridization; gene environment interaction; gene mutation; genetic disorder diagnosis; genetic markers; genotype; human genetic material tag; human tissue; linkage mapping; neurogenetics; nucleic acid repetitive sequence; phenotype; polymerase chain reaction; restriction fragment length polymorphism; schizophrenia; tryptophan 5 monooxygenase; tyrosine 3 monooxygenase

We are searching for genes involved in neurologic and psychiatric disorders, with a particular emphasis on bipolar affective disorder and schizophrenia. The clinical heterogeneity seen within these inherited disorders is likely due to environmental influences as well as mutations in genes (multifactorial). Molecular techniques are used to identify mutations that may be predictive of different phenotypes and to understand the molecular mechanisms leading to nervous system abnormalities. We have isolated and characterized genes, such as the neurotransmitter biosynthetic enzymes human tyrosine hydroxylase and tryptophan hydroxylase, that may be involved in neuropsychiatric disorders. Using restriction length fragment polymorphisms (RFLP) and microsatellite DNA markers, we are genotyping DNA from individuals in large families where there is a high risk for affective disorder and we are performing linkage analysis in order to identify chromosome regions harboring susceptibility or protective genes involved in bipolar affective disorder (see Project #Z01 MH 02625-07 NS). For the chromosome regions that are identified expressed sequences will be isolated and characterized. Human genomic DNA containing trinucleotide repeats is being isolated and characterized. We have found a trinucleotide repeat on chromosome 17q that accounts for most expansions detected by the Repeat-Expansion Detection (RED) technique. Cytogenetic studies, including fluorescent in-situ hybridization (FISH), on cells from individuals affected with bipolar affective disorder, schizophrenia (particularly childhood onset, see Project #MH-02581-07 CHP), mental retardation, autism, and attention deficit hyperactivity disorder (ADHD), are being performed to identify chromosomal abnormalities that may aid in the identification of disease genes. We have identified chromosome 22q11.2 interstitial deletions among childhood onset schizophrenics, and also the association of an X-chromosome dodecamer insertional variant allele with mental retardation. The results of this research should provide a molecular basis for diagnosis and for the development of novel therapeutic strategies for these disorders.

我们正在寻找与神经系统相关的基因， 和精神疾病，特别是双相情感障碍 情感障碍和精神分裂症。临床异质性 在这些遗传性疾病中，可能是由于环境 影响以及基因突变（多因素）。分子 技术用于鉴定可能预测 不同的表型，并了解分子机制 导致神经系统异常我们已经分离出 特征基因，如神经递质生物合成 酶人酪氨酸羟化酶和色氨酸羟化酶， 可能与神经精神疾病有关使用 限制性长度片段多态性（RFLP）， 微卫星DNA标记，我们正在对来自 在大家庭中，有高风险的情感 我们正在进行连锁分析，以确定 携带易感基因或保护基因的染色体区域 参与双相情感障碍（见项目#Z01 MH 02625-07 NS）。对于被识别的染色体区域 表达的序列将被分离和表征。人类 含有三核苷酸重复序列的基因组DNA正在被分离， 表征了我们发现了一个三核苷酸重复序列， 染色体17 q，占大多数扩增检测到的 重复扩增检测（RED）技术。细胞遗传学研究， 包括荧光原位杂交（FISH）， 患有双相情感障碍、精神分裂症 （尤其是儿童期发作，见项目#MH-02581-07 CHP）， 智力迟钝、自闭症和注意力缺陷多动 多动症（ADHD），正在进行，以确定染色体 可能有助于识别疾病基因的异常。我们 已经确定了染色体22q11.2间质缺失， 儿童期精神分裂症患者，以及 X染色体十二聚体插入变异等位基因 迟钝这项研究的结果应该提供一个分子 诊断和开发新型治疗药物的基础 这些疾病的治疗策略。