Mutational analysis of the GDNF/RET-GDNFRα signaling complex in a kindred with vesicoureteral reflux

Glial cell line-derived neurotrophic factor (GDNF) mediates signaling across the cell membrane by interaction with the RET-GDNFRα receptor complex. We identified a family in which one member had medullary thyroid carcinoma (MTC) and four members had vesicoureteral reflux (VUR). Knowledge that mutations in the RET proto-oncogene cause MTC and studies documenting genitourinary abnormalities in RET or GDNF knockout mice led us to examine the GDNF/RET-GDNFRα signaling complex in this family. RET and GDNF were excluded as the causative VUR gene by haplotype and sequence analysis. The GDNFRα gene was mapped to chromosome 10q25-26 by radiation hybrid techniques and was eliminated as the causative gene by haplotype analysis and sequencing of cDNA from an obligate carrier. Sequencing identified a 15-nucleotide deletion in GDNFRα mRNA, which was found to code for a single exon; analysis of several cell types revealed an identical mRNA form, indicating that this variant is a product of alternative RNA processing. We conclude that GDNFRα maps to 10q25-26 and that its RNA transcript is alternatively processed. Mutation abnormalities in the GDNF/RET-GDNFRα signaling system do not cause VUR in this family.