Pathogenesis of Rett Syndrome: Molecular Genetics and Animal Models

Rett综合征（RS）是一种影响运动和智力发育的破坏性进行性遗传疾病，几乎只发生在女性身上。它的特点是在生命的前6-12个月发育正常，随后发育倒退，失去习得的有目的的手功能，失去获得的语言和交流能力，有时会导致自闭症的错误诊断。它可能是女孩进行性智力迟钝的最常见原因，据估计，在澳大利亚，每10,000名12岁以下女性中就有1人患有此病。一种名为MECP2的基因突变似乎是导致多达80%的受影响女孩和妇女RS的原因。既然已经发现了导致许多RS病例的基因，就有了许多新的问题。是否所有患有RS的女孩都有MECP2基因突变？了解MECP2基因的确切突变是否有助于预测该疾病在个体患者中的严重程度？为什么大脑似乎主要受到影响？哪些其他基因可能在RS症状中起作用？有可能开发出针对RS的特异性治疗方法吗？这项研究将解决一些重要问题。首先，我们对RS受试者的基因研究将导致早期诊断，这通常延迟到孩子满5岁之后。其次，我们正在开发人类疾病的小鼠模型，这将使我们在开始了解RS的生物学基础方面处于更好的位置。早期诊断可以在短期内启动早期治疗策略，长期目标是开发可能治愈这种疾病的特异性治疗方法。最后，它将为直系亲属和大家庭成员提供准确的遗传咨询。

Rett syndrome (RS) is a devastating progressive genetic disorder affecting motor and intellectual development, and occurs almost exclusively in females. It is characterised by normal development for the first 6-12 months of life, followed by developmental regression with the loss of learned purposeful hand function, loss of acquired speech and communicative abilities, sometimes leading to the incorrect diagnosis of autism. It may be the most common cause of progressive mental retardation in girls, with an estimated prevalence in Australia of 1 per 10,000 females under the age of twelve years. Mutations in a gene called MECP2 appears to be the cause of RS in up to 80% of affected girls and women. Now that the gene responsible for many cases of RS has been found, there are many new questions. Do all girls with RS have mutations in the MECP2 gene? Will knowing the exact mutation in the MECP2 gene be of help in predicting how severe the disorder will be in individual patients? Why is it that the brain appears to be primarily affected? Which other genes might play a role in the symptoms seen in RS? Could it be possible to develop specific treatments for RS? This research will address a number of important issues. Firstly, our genetic studies of RS subjects will result in early diagnosis, which is often delayed until after a child turns 5 years of age. Secondly, we are developing mouse models of the human disease, which will put us in a much better position in beginning to understand the biological basis of RS. Early diagnosis may enable the initiation of early treatment strategies in the short term, with the long-term goal of developing specific therapies that may potentially cure the disorder. Finally it will enable accurate genetic counselling for both the immediate and extended family members.