Studies Of Hereditary Neurological Disease: Disease Gene Identification

该研究计划的目的是调查遗传性神经系统疾病的原因，目的是为这些疾病开发有效的治疗方法。遗传外展计划允许识别和描述遗传性神经系统疾病的患者和家庭。过去一年的具体研究成果包括：（1）描述了一名患有spoinal和bulbar肌萎缩症的患者的特征，以及比以前报道的更长的重复扩增突变，（2）与H3非洲联盟合作进行非洲遗传研究，（3）在杜氏肌营养不良症、MEGF 10相关肌病、FBXO 38相关远端脊髓性肌萎缩症、远端肌病、TRPV 4相关神经病、GRIN 2A相关癫痫性脑病、胶原VI相关肌病和GNE相关肌病。 脊髓延髓肌萎缩症（SBMA）是一种由雄激素受体基因三核苷酸（CAG）重复扩增引起的神经肌肉疾病。SBMA患者的延髓和四肢肌肉无力、萎缩和肌束震颤。CAG重复长度大于62的个体以前没有报道过。我们评估了一名患有68例冠状动脉造影的29岁SBMA患者，该患者发病异常早，并且在其他患有该疾病的患者中没有发现这些发现。雄激素受体基因的分析证实了68 CAG的重复长度在外周血和成纤维细胞。肌肉和感觉功能的评估显示SBMA的典型缺陷，此外，患者有自主神经功能障碍和性发育异常的表现。这些发现扩展了与SBMA相关的已知表型，并对突变的雄激素受体的影响提出了新的见解。 随着人类基因组计划的完成，我们对基因组生物学、基因组学和疾病的理解有了巨大的进步。技术进步加上基因组研究成本的显著降低，为世界上一些最棘手和最具破坏性的疾病（包括疟疾、艾滋病毒/艾滋病、结核病、癌症和糖尿病）的病因、诊断和治疗带来了新的见解。然而，尽管非洲面临传染病和最近的非传染性疾病的负担，非洲人对基因组学研究的参与却微乎其微。如果缺乏涉及非洲人的基因组学研究的情况持续下去，那么基因组科学产生的潜在健康和经济利益可能会使整个非洲大陆都无法获得。非洲缺乏大规模基因组学研究是许多深层次问题的结果，包括缺乏具有基因组研究专长的非洲科学家，缺乏生物医学研究基础设施，计算专长和资源有限，非洲政府对生物医学研究缺乏足够的支持，以及许多非洲科学家参与的合作研究仅限于样本收集水平。要克服这些局限性，部分取决于非洲科学家获得必要的专门知识和设施，以领导高质量的基因组学研究，了解与非洲人口有关的健康问题，并在基因组科学及其应用方面具有国际竞争力。

The purpose of this research program is to investigate the causes of hereditary neurological diseases, with the goal of developing effective treatments for these disorders. A genetic outreach program allows the identification and characterization of patients and families with hereditary neurological diseases. Specific research accomplishments in the past year include (1) characterization of a patient with spoinal and bulbar muscular atrophy and a longer repeat expansion mutation than previously reported, (2) collaboration in the H3Africa Consortium for genetic studies in Africa, (3) collaboration in gene identification and genotype-phenotype studies of Duchenne muscular dystrophy, MEGF10-associated myopathy, FBXO38-associated distal spinal muscular atrophy, distal myopathies, TRPV4-associated neuropathy, GRIN2A-associated epileptic encephalopathy, collagen VI-associated myopathy, and GNE-associated myopathy. Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a trinucleotide (CAG) repeat expansion in the androgen receptor gene. Patients with SBMA have weakness, atrophy, and fasciculations in the bulbar and extremity muscles. Individuals with CAG repeat lengths greater than 62 have not previously been reported. We evaluated a 29 year old SBMA patient with 68 CAGs who had unusually early onset and findings not seen in others with the disease. Analysis of the androgen receptor gene confirmed the repeat length of 68 CAGs in both peripheral blood and fibroblasts. Evaluation of muscle and sensory function showed deficits typical of SBMA, and in addition the patient had manifestations of autonomic dysfunction and abnormal sexual development. These findings extend the known phenotype associated with SBMA and shed new insight into the effects of the mutated androgen receptor. Our understanding of genome biology, genomics, and disease has advanced tremendously with the completion of the Human Genome Project. Technological advances coupled with significant cost reductions in genomic research have yielded novel insights into disease etiology, diagnosis, and therapy for some of the world's most intractable and devastating diseasesincluding malaria, HIV/AIDS, tuberculosis, cancer, and diabetes. Yet, despite the burden of infectious diseases and, more recently, noncommunicable diseases in Africa, Africans have only participated minimally in genomics research. If the dearth of genomics research involving Africans persists, the potential health and economic benefits emanating from genomic science may elude an entire continent. The lack of large-scale genomics studies in Africa is the result of many deep-seated issues, including a shortage of African scientists with genomic research expertise, lack of biomedical research infrastructure, limited computational expertise and resources, lack of adequate support for biomedical research by African governments, and the participation of many African scientists in collaborative research at no more than the level of sample collection. Overcoming these limitations will, in part, depend on African scientists acquiring the expertise and facilities necessary to lead high-quality genomics research aimed at understanding health problems relevant to African populations and to become internationally competitive in genomic science and its applications.