Discovery and pathogenic characterization of novel monogenic causes of bladder dysfunction

PROJECT SUMMARY Title: Discovery and pathogenic characterization of novel monogenic causes of bladder dysfunction Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in childhood. Over 40 monogenic etiologies of CAKUT have been identified, and another 150 genes have been described to cause syndromes in which urinary tract malformations are an integral component. However, the majority of these genes coalesce into pathways that regulate upper urinary tract development, such as metanephric mesenchyme transition and ureteric bud formation. The pathogenesis and genetic regulation of lower urinary tract disease remain poorly understood. Recently, through the use of whole exome sequencing, I identified mutations in the α3-subunit of the nicotinic acetylcholine receptor, CHRNA3, as a novel cause of bladder dysfunction with secondary CAKUT. This is one of just eight known monogenic causes of congenital bladder dysfunction, and, uniquely, is a gene that regulates autonomic nervous system function. I hypothesize that additional monogenic causes of lower urinary tract disease can be identified through the use of whole exome sequencing, and additionally, that these genes will coalesce upon pathways that regulate urothelial signaling, detrusor contraction, and bladder innervation. The aims of the proposed research are twofold: (1) to apply both a candidate gene and unbiased analysis strategy to whole exome sequencing data in order to discover novel monogenic causes of bladder dysfunction and (2) to apply an integrated genomic approach using whole exome and whole transcriptome sequencing to an international cohort of children with CAKUT. Accomplishment of the proposed research above will provide additional insight into the pathomechanisms that govern bladder development and function, and, ultimately, could lead to novel therapeutic strategies for children with bladder dysfunction. In addition, validation of a method for urinary transcriptome sequencing can help to overcome current limitations in whole exome sequencing in the identification and interpretation of splice-altering genetic variants. This K08 application encompasses a comprehensive career development plan to not only ensure progress and success in carrying out the proposed research, but also to facilitate my transition to an independent investigator. It encompasses regular meetings with my mentor and advisory committee, research and career development seminars, courses in genomics and transcriptomics, and participation at national and international conferences. The research will be conducted in the rich academic environment at Boston Children's Hospital and Harvard Medical School, which provides an ideal environment for further training and career development.