MOLECULAR GENETICS OF INHERITED NEUROLOGIC AND PSYCHIATRIC DISORDERS

我们正在寻找与神经学和精神障碍有关的基因，特别是双相情感障碍和精神分裂症。在这些遗传性疾病中看到的临床异质性可能是由于环境影响以及基因突变(多因素)。分子技术被用来识别可能预测不同患者表现的突变，并理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障碍有关的基因，如神经递质生物合成酶人类酪氨酸羟基酶和色氨酸羟基酶。利用限制性内切酶片段多态和微卫星标记，我们正在对情感障碍高危家庭中的个体进行基因分型，并进行连锁分析，以确定包含双相情感障碍易感基因或保护基因的染色体区域(见项目#Z01 MH 02625-08 NS)。对于识别出的染色体区域，将分离和鉴定表达序列。含有三核苷酸重复序列的人类基因组DNA正在被分离和鉴定。我们在染色体17q上发现了一个三核苷酸重复序列，它解释了重复-扩展检测(RED)技术检测到的大多数扩展。目前正在进行细胞遗传学研究，包括荧光原位杂交(FISH)，对患有双相情感障碍、精神分裂症(尤其是儿童期发病，见项目#MH-02581-08CHP)、精神发育迟滞、自闭症和注意缺陷多动障碍的患者的细胞进行研究，以确定可能有助于识别疾病基因的染色体异常。我们已经在儿童精神分裂症患者中发现了染色体22q11.2间质缺失，并发现了X染色体十二聚体插入变异等位基因与精神发育迟滞的关联。这项研究的结果应该为这些疾病的诊断和新的治疗策略的开发提供分子基础。-神经学、精神障碍、DNA标记、基因分型、保护基因、双相情感障碍、ADHD、儿童期起病精神分裂症、MR

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. - neurologic, psychiatric disorders, DNA markers, genotyping, protective genes, bipolar affective disorder, ADHD, childhood onset schizophrenics, MR