MOLECULAR GENETICS OF INHERITED NEUROLOGIC AND PSYCHIATRIC DISORDERS

我们正在寻找与神经和精神疾病有关的基因，特别强调双相情感障碍和精神分裂症。这些遗传疾病的临床异质性可能是由于环境影响以及基因突变（多因素）。分子技术用于识别可能预测不同患者表现的突变，并了解导致神经系统异常的分子机制。我们已经分离并鉴定了可能与神经精神疾病有关的基因，如神经递质生物合成酶人类酪氨酸羟化酶和色氨酸羟化酶。使用限制性长度片段多态性（RFLP）和微卫星DNA标记，我们对情感障碍高风险的大家族个体的DNA进行基因分型，我们正在进行连锁分析，以确定包含双相情感障碍易感性或保护性基因的染色体区域（见项目#Z01 MH 02625-08 NS）。对于已鉴定的染色体区域，将分离和表征表达序列。含有三核苷酸重复序列的人类基因组DNA正在被分离和表征。我们在染色体17q上发现了一个三核苷酸重复序列，该重复序列解释了重复扩增检测（RED）技术检测到的大多数扩增。细胞遗传学研究，包括荧光原位杂交（FISH），对患有双相情感障碍、精神分裂症（特别是儿童期发病，见项目#MH-02581-08 CHP）、智力迟钝、自闭症和注意缺陷多动障碍（ADHD）的个体进行细胞研究，以确定可能有助于识别疾病基因的染色体异常。我们已经在儿童期精神分裂症患者中发现了22q11.2染色体间质缺失，以及x染色体十二体插入变异等位基因与智力迟钝的关联。这项研究的结果将为这些疾病的诊断和新的治疗策略的发展提供分子基础。

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 patient presentations 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 02625-08 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-02581-08 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.