Prune Belly Syndrome

 描述（由申请人提供）：本项目的总体目标是扩大对梅肚综合征（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。我们将采取个性化的医学方法来确定这种罕见但严重的疾病的分子原因。PBS的标志性特征包括以下三联征：1）发育不良或缺乏腹壁骨骼肌组织，2）膀胱平滑肌发育不良导致尿路扩张伴巨膀胱和膀胱炎，以及3）双侧隐睾。尽管其罕见性和产前检测，PBS往往是毁灭性的，20%的死胎，43%的早产儿，30%死于肾衰竭或尿脓毒症的年龄2岁。PBS的男性优势和家族性病例支持性限制常染色体隐性遗传或X连锁遗传。最近，有几个基因与PBS有关，但绝大多数PBS患者在这些基因中不携带基因组变异。因此，其他导致PBS的基因仍然未知。我们的研究将利用我们招募的大量PBS先证者和多重PBS激酶。我们将使用下一代测序来鉴定引起PBS的新基因，我们将研究这些基因中临床突变的功能影响。我们的具体目标是：1） 鉴定PBS的新致病基因组变体，2）表征PBS影响器官的分子特征，和3）表征我们最近鉴定的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.