Prune Belly Syndrome

 描述(由申请者提供)：本项目的总体目标是扩大对梅花肚皮综合征(PBS)的遗传基础和分子机制的了解，PBS是一种严重的多系统先天性人类泌尿系统异常。我们将采用个性化医学方法来确定这种罕见但严重疾病的分子原因。PBS的特点包括：1)腹壁骨骼肌发育不良或缺失；2)膀胱平滑肌发育不良导致尿路扩张伴巨囊肿和反流；3)双侧隐睾症。尽管PBS罕见且产前检测，但它往往是毁灭性的，20%的死产，43%的早产，30%的人在2岁前死于肾功能衰竭或尿毒症。男性为主的PBS家族性病例支持性别受限的常染色体隐性遗传或X连锁遗传。最近，几个基因被认为与PBS有关，但绝大多数PBS患者都没有携带这些基因的基因组变异。因此，其他导致PBS的基因仍然未知。我们的研究将利用大量的PBS先证者和我们招募的多个PBS家族。我们将使用下一代测序来识别导致PBS的新基因，并研究这些基因的临床突变对功能的影响。我们的具体目标是：1) 确定PBS的新的致病基因组变异，2)表征受PBS影响的器官的分子特征，以及3)表征我们最近发现的PBS候选基因的作用。

 DESCRIPTION (provided by applicant): The overall goal of this project is to expand the knowledge on the genetic basis and molecular mechanisms of Prune Belly Syndrome (PBS), a severe multi-system congenital human urologic anomaly. We will take a personalized medicine approach to identifying the molecular cause of this rare but severe disorder. The hallmark features of PBS include the triad of: 1) hypoplastic or absent abdominal wall skeletal musculature, 2) bladder smooth muscle dysplasia leading to urinary tract dilation with megacystis and refluxing, and 3) bilateral undescended testes. Despite its rarity and prenatal detection, PBS is often devastating, with 20% stillborn, 43% born premature, and 30% dying of renal failure or urosepsis by age 2 years. Male predominance and familial cases of PBS support a sex-limited autosomal recessive or X-linked inheritance. Recently, several genes have been implicated in PBS, but the overwhelming majority of PBS patients do not carry genomic variants in these genes. Thus, additional PBS-causing genes remain unknown. Our study will take advantage of a large cohort of PBS probands and the multiplex PBS kindreds we have recruited. We will use next generation sequencing to identify novel genes causing PBS, and we will study the functional impact of clinical mutations in these genes. Our specific aims are to: 1) identify novel causal genomic variants for PBS, 2) characterize the molecular signature of PBS affected organs, and 3) characterize the role of our recently identified PBS candidate gene.