Short-rib polydactyly and the skeletal ciliopathies

 描述（由申请人提供）：基因组测序正在彻底改变我们对骨骼生物学的理解。通过确定骨骼发育不良的分子基础，揭示了对骨骼有深远影响的一组异质性遗传性疾病，对正常骨骼发育至关重要的意外分子和机制。虽然与大多数常见骨骼发育不良相关的基因已经确定，但短肋多指（SRP）是最常见的围产期致死性骨骼疾病， 其生物学基础和机制尚不完全清楚。SRP也是最常见的骨骼纤毛病，因此确定SRP疾病的分子基础和机制将定义骨骼发育中最重要的纤毛成分。通过我们的主要确认工具，国际骨骼发育不良登记处（ISDR），我们已经收集了一个大的SRP病例队列，这将支持基因组策略，从基因上解剖这种疾病。基因发现研究之后将在组织、培养细胞和小鼠中进行详细的机制研究，以确定每个突变如何发挥其表型效应，确定为什么SRP基因中的突变对骨骼具有不同的影响，并整合不同的分子参与到纤毛功能的途径中 在骨架上。这些发现将为骨骼的复杂生物学提供新的见解，并将在SRP人类表型的背景下这样做。拟议的实验是显着的，因为它们代表了潜在的有广泛的影响，我们的理解从机制和临床遗传学的角度纤毛骨骼生物学。一旦相关基因被确定，立即翻译的好处将通过提供具体和适当的遗传咨询，这些条件的家庭，以及遗传检测的机会。这些结果将揭示正常骨骼发育的新分子和机制，拟议的功能研究将验证分子发现并确定纤毛使骨骼发生的途径。

 DESCRIPTION (provided by applicant): Genome sequencing is revolutionizing our understanding of skeletal biology. By determining the molecular basis of the skeletal dysplasias, a heterogeneous group of inherited disorders that have a profound effect on the skeleton, unanticipated molecules and mechanisms essential for normal skeletal development are being revealed. While the genes associated with most of the common skeletal dysplasias have been determined, short-rib polydactyly (SRP) is the most frequent perinatal lethal skeletal disorder for which the biological basis and mechanism are incompletely understood. SRP is also the most common skeletal ciliopathy, so determining the molecular basis and mechanism(s) of disease in SRP will define the components of the cilia that are most important in skeletal development. Through our main ascertainment vehicle, the International Skeletal Dysplasia Registry (ISDR), we have assembled a large cohort of SRP cases that will support a genomic strategy for genetically dissecting this disorder. The gene discovery studies will be followed by detailed mechanistic studies in tissues, cultured cells and mice to determine how each mutation exerts its phenotypic effect, to determine why mutations in the SRP genes have a differential effect on the skeleton, and to integrate the different molecules involved into a pathway for ciliary function in the skeleton. The findings will provide new insights into the complex biology of the skeleton, and will do so in the context of the SRP human phenotype. The proposed experiments are significant in that they represent the potential to have an extensive impact on our understanding of ciliary skeletal biology from both the mechanistic and clinical genetics perspectives. Once the associated genes are identified, immediate translational benefit will result by providing specific and appropriate genetic counseling to families with these conditions as well as opportunities for genetic testing. The results will reveal new molecules and mechanisms of normal skeletal development, and the proposed functional studies will both validate the molecular findings and identify the pathways through which cilia enable skeletogenesis.