Date of Award

2004

Degree Name

Biomedical Sciences

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Dr. Elizabeth C. Bryda, Committee Chairperson

Second Advisor

Dr. Beverly C. Delidow

Third Advisor

Dr. Susan H. Jackman

Fourth Advisor

Dr. Donald A. Primerano

Fifth Advisor

Dr. Monica A. Valentovic

Abstract

Polycystic kidney disease (PKD) is one of the most common hereditary diseases and is characterized by progressive cyst formation, substantial renal enlargement, and frequently, progression to end-stage renal disease. One way to learn more about the etiology of this disease is to study mouse models that imitate the human situation. The juvenile congenital polycystic kidney disease (jcpk) gene on mouse Chromosome 10 has been found to cause a severe, early onset form of PKD when inherited in an autosomal recessive manner (Flaherty et al., 1995). Previous genetic studies mapped the jcpk locus to a 1 cM region on mouse Chromosome 10 between the markers D10Mit115 and D10Mit173 (Bryda et al., 1996). To positionally clone this gene, high resolution genetic and radiation hybrid maps were generated along with a detailed physical map of the critical region thought to contain the jcpk gene. Fine mapping studies allowed extensive reduction of this region to a section of mouse Chromosome 10 contained within three Bacterial Artificial Chromosomes (BACs). Nucleotide sequence analysis was performed to determine the presence of transcribed genes within this section of the chromosome. The only predicted gene was the mouse homologue of the Drosophila gene Bicaudal-C (Bicc1). Bicc1 was evaluated as a disease-susceptibility gene by examining the sequence of the Bicc1jcpk allele for mutations using a combination of RT-PCR and sequence analysis. A single base-pair change (G to A) was detected in the consensus splice acceptor site of exon 3. This frameshift mutation produces a premature stop codon predicted to result in a truncated protein. The function of the Bicc1 protein is unknown; however, several functional domains have been identified: three K Homology (KH) RNA binding domains and one sterile alpha motif (SAM). Ribonucleotide homopolymer analysis determined that Bicc1 binds RNA in vitro. In preliminary analyses of PKD-affected Bicc1jcpk/jcpk mice, left/right patterning defects including dextrocardia and lung isomerism were identified in one animal. The present work has enabled the identification of a gene, Bicc1, previously unknown to be involved in PKD pathogenesis and begins to explore the role of this gene and its corresponding protein in the kidney.

Subject(s)

RNA.

Gene mapping.

Polycystic kidney disease -- Etiology.

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