FUNCTIONAL ANALYSIS OF CANDIDATE GENES FOR MLS SYNDROME

小眼球伴线状皮肤缺陷(MLS)是一种X连锁显性遗传 发育障碍的特征是头部的线状皮肤缺陷和 颈部、小眼球、视网膜病变、中枢神经系统 畸形，包括胼胝体发育不全、癫痫、精神障碍 发育迟缓和心脏缺陷。所有的MLS患者都有一个缺失的 Xp22，我们的实验室发现了两个候选基因 在Xp22.3上的450Kb临界间隔内。MLS共享表型特征 伴有三种X连锁非缺失综合征：Aicardi综合征、Goltz 综合征和组织细胞性心肌病，我们建议所有四个 疾病是由同一基因的破坏引起的(S)。一名已确定的 人全细胞色素C型合成酶(HCCS)基因编码 在线粒体呼吸链中起作用，是一个很好的候选者 为了美国职业棒球大联盟。在这里，我们提出了一个为期五年的职业发展研究项目。 对非缺失型HCCS基因进行突变分析 并通过产生小鼠建立MLS动物模型 缺乏HCCS基因，以及靶向缺失部分HCCS基因的小鼠 MLS区，利用胚胎干细胞中的同源重组。 申请人对分子生物学产生了浓厚的兴趣。 正常和不正常的人类发育以及先天畸形， 在她接受产前诊断和人类遗传学培训期间 在这一领域发展研究事业。佐格比博士的实验室在 贝勒医学院分子和人类遗传学系 致力于MLS综合征的研究，并提供了极好的 环境，以发展候选人的调查技能。这 研究将深入了解HCCS和HCS的相对贡献 从MLS区分离到的其他基因对表型特征的影响 MLS、Aicardi综合征、Goltz综合征和组织细胞性MP。表型 对各种突变小鼠的分析将提供对 MLS中受影响的器官系统的发展并提供信息 关于相关(神经)发育障碍的发病机制。

Microphthalmia with Linear Skin Defects (MLS) is an X-linked dominant developmental disorder characterized by linear skin defects on head and neck, microphthalmia, retinal lesions, central nervous system malformations including agenesis of the corpus callosum, seizures, mental retardation and cardiac defects. All MLS patients have a deletion of chromosome Xpter-Xp22, and our laboratory identified two candidate genes in the 450Kb critical interval on Xp22.3. MLS shares phenotypic features with three X-linked non-deletion syndromes: Aicardi syndrome, Goltz syndrome and histiocytic cardiomyopathy and we propose that all four disorders are caused by disruption of the same gene(s). One identified gene encodes for a human holocytochrome c-type synthetase (HCCS) which functions in the mitochondrial respiratory chain and is a good candidate for MLS. Here we propose a five year career development research project to perform mutation analysis of the HCCS gene in the non-deletion disorders and to create an animal model for MLS by generating mice lacking the HCCS gene, and mice with targeted deletions of portions of the MLS region, using homologous recombination in embryonic stem cells. The applicant has developed a strong interest in the molecular biology of normal and abnormal human development and of congenital malformations, during her training in prenatal diagnosis and human genetics and wants to develop a research career in this area. Dr. Zoghbi's laboratory in the Department of Molecular and Human Genetics at Baylor College of Medicine is committed to research on MLS syndrome and provides an excellent environment to develop the candidate's investigative skills. This research will provide insight into the relative contribution of HCCS and other genes, isolated from the MLS region, to the phenotypic features of MLS, Aicardi syndrome, Goltz syndrome and histiocytic CMP. The phenotypic analysis of the various mutant mice will provide insight into the development of the organ systems affected in MLS and provide information on the pathogenesis of related (neuro)developmental disorders.