MOLECULAR GENETICS OF INHERITED NEUROLOGIC AND PSYCHIATRIC DISORDERS

我们正在寻找导致遗传性神经疾病和 精神障碍，特别强调双相情感障碍 精神障碍和精神分裂症。内部的表型异质性 这些遗传性疾病很可能是由于环境的影响 以及多个基因(寡基因或多基因)的突变，其中每个 突变通过影响蛋白质的生物活性来影响蛋白质的生物活性 蛋白质的加工、分隔和/或稳定性。 在已经识别出蛋白质异常的遗传疾病中， 分子特征(如Southern分析和聚合酶 链扩增)用于识别发生在和可能 预测非神经病理性和神经病理性表型。这个 导致神经系统参与其中的分子机制 此外，还研究了精神障碍。这项研究的结果应该提供 诊断和研制新型治疗药物的分子基础 针对这些遗传性疾病的策略。可能涉及到的基因 神经精神障碍(如神经递质生物合成 人酪氨酸羟基酶和色氨酸羟基酶)是 与世隔绝的，有特点的。使用限制长度片段 多态(RFLP)和微卫星DNA标记我们正在对DNA进行基因分型 来自旧秩序阿米什血缘的个人，并表现出联系 分析以确定含有相关基因的染色体区域 双相情感障碍(见项目#ZO1，MH 02625-04 NS)。为 这些高兴趣的染色体区域，高分辨率的物理图谱 将开发和表达的序列将被分离和 特色化的。含有三核苷酸重复序列的人类基因组DNA是 也被分离和鉴定，包括侧翼序列 染色体的测定和定位。来自受影响个人的DNA 患有双相情感障碍、精神分裂症(尤其是童年 发病，见项目#MH 02581-06 CHP)或选定的其他精神病患者 疾病正在通过几种分子技术进行检查，包括 荧光原位杂交(FISH)，用于发生 染色体异常，包括缺失。

We are searching for mutations responsible for inherited neurological and psychiatric disorders, with a particular emphasis on bipolar affective disorder and schizophrenia. The phenotypic heterogeneity seen within these inherited disorders is likely due to environmental influences as well as mutations in multiple genes (oligogenic or polygenic) where each mutation affects the biological activity of the protein by influencing the processing, compartmentalization and/or stability of the protein. In genetic disorders where a protein abnormality has been identified, molecular characterizations (such as southern analysis and polymerase chain amplification) are used to identify mutations that occur in and may be predictive of non-neuronopathic and neuronopathic phenotypes. The molecular mechanisms leading to nervous system involvement in these disorders are also studied. The results of this research should provide a molecular basis for diagnosis and formulation of novel therapeutic strategies for these inherited disorders. Genes that may be involved in neuropsychiatric disorders (such as the neurotransmitter biosynthetic enzymes human tyrosine hydroxylase and tryptophan hydroxylase) are isolated and characterized. Using restriction length fragment polymorphisms (RFLP) and microsatellite DNA markers we are genotyping DNA from individuals in an Old Order Amish kindred and performing linkage analysis in order to identify chromosome regions harboring genes involved in bipolar affective disorder (see Project # ZO1 MH 02625-04 NS). For these high interest chromosome regions, high resolution physical maps will be developed and expressed sequences will be isolated and characterized. Human genomic DNA containing trinucleotide repeats is also being isolated and characterized, including flanking sequence determination and chromosome location. DNA from individuals affected with bipolar affective disorder, schizophrenia (particularly childhood onset, see Project # MH 02581-06 CHP), or selected other psychiatric disorders is being examined by several molecular techniques, including Fluorescent In Situ Hybridization (FISH), for the occurrence of chromosomal abnormalities, including deletions.