Molecular Characterization of Joubert Syndrome

描述（由申请人提供）：先天性共济失调在儿童早期表现为非进行性肌张力减退、粗大和精细运动延迟以及认知延迟。 这些疾病与进行性共济失调不同，因为存在先天性小脑畸形，而且是典型的遗传性共济失调。Joubert综合征和相关疾病（JSRD）构成了这些疾病的一个子集，包括小脑中线（蚓部）畸形、脑成像（MTI）上几乎特异性的臼齿征以及共存的眼神经失用症和阵发性呼吸节律障碍。JSRD被认为是单基因的，直到最近才有明确的证据表明表型和基因型异质性。人们对这些人类中脑/后脑畸形的遗传原因知之甚少，这阻碍了正确的诊断，预后，产前咨询和治疗。我们已经确定了家庭映射到9q34.3（MTI 1）与经典Joubert综合征，并已遗传映射的第二个基因座与一种形式的JS显示小脑，眼和肾参与（CORS）染色体11（MTI 2）。此外，我们已经确定了其他家庭不与任何一个位点，进一步证明了遗传异质性。我们计划识别和表征负责JSRD的基因和突变。将使用一般遗传连锁方法对与MTI 1或MTI 2不相关的疾病家族进行研究，以确定其他MTI基因座。我们将对与MTI位点连锁的候选基因进行突变分析。如果候选基因分析不成功，将采用各种定位克隆策略。JSRD基因的鉴定加上广泛的临床数据将使我们能够表征由单个基因突变引起的表型谱，并比较不同基因座突变患者的表型。特别令人感兴趣的是，是否存在特定基因和突变与自闭症的存在之间的相关性，发现存在于大部分JSRD患者中。JSRD的分子特征将导致一个新的遗传分类和更好地了解这些疾病。表征JBRD潜在的致病机制将有助于改善诊断，并将揭示人类小脑发育的遗传学以及更复杂的疾病，包括全身性共济失调和自闭症。

DESCRIPTION (provided by applicant): Congenital ataxia presents in early childhood with non-progressive hypotonia, gross and fine motor delay and cognitive delays. These disorders are distinct from the progressive ataxias because of the presence of congenital cerebellar malformations and because they are typically inherited recessively. Joubert Syndrome and Related Disorders (JSRD) constitutes a subset of these conditions, consisting of a cerebellar midline (vermis) malformation, a nearly pathognomonic Molar Tooth sign on brain Imaging (MTI) and co-existent oculomotor apraxia and episodic breathing dysrhythmias. JSRD was thought to be monogenic until recently when clear evidence of both phenotypic and genotypic heterogeneity was demonstrated. Very little is known about the genetic causes of these midbrain/hindbrain malformations in humans, which has hindered proper diagnosis, prognosis, prenatal counseling and treatment. We have identified families mapping to 9q34.3 (MTI 1) with classical Joubert syndrome, and have genetically mapped a second locus associated with a form of JS displaying cerebellar, ocular and renal involvement (CORS) to chromosome 11 (MTI2). Furthermore, we have identified other families not linked to either locus, demonstrating further genetic heterogeneity. We plan to identify and characterize the genes and mutations responsible for JSRD. Families in whom the disorder is not linked to MTI1 or MTI2 will be studied using a general genetic linkage approach to identify additional MTI loci. We will perform mutation analysis on candidate genes linked to the MTI loci. A variety of positional cloning strategies will be utilized if candidate gene analysis is unsuccessful. Identification of JSRD genes coupled with extensive clinical data will allow us to characterize the spectrum of phenotypes caused by mutations in single genes and to compare phenotypes of patients with mutations at different loci. Of particular interest will be whether there is a correlation between specific genes and mutations with presence of autism, found to be present in a large proportion of JSRD patients. Molecular characterization of the JSRDs will lead to a new genetic classification and a better understanding of these disorders. Characterization of the pathogenic mechanisms underlying the JBRDs will lead to improved diagnosis, and will shed light on the genetics of human cerebellar development as well as more complex disorders including generalized ataxia and autism.