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

Hum Genet. 1998 Apr;102(4):474-8. doi: 10.1007/s004390050724.


Glial cell line-derived neurotrophic factor (GDNF) mediates signaling across the cell membrane by interaction with the RET-GDNFR alpha 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-GDNFR alpha signaling complex in this family. RET and GDNF were excluded as the causative VUR gene by haplotype and sequence analysis. The GDNFR alpha 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 GDNFR alpha 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 GDNFR alpha maps to 10q25-26 and that its RNA transcript is alternatively processed. Mutation abnormalities in the GDNF/RET-GDNFR alpha signaling system do not cause VUR in this family.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Animals
  • Carcinoma, Medullary / genetics
  • Child
  • DNA Mutational Analysis
  • Drosophila Proteins*
  • Female
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Humans
  • Mice
  • Middle Aged
  • Molecular Sequence Data
  • Nerve Growth Factors / genetics*
  • Nerve Tissue Proteins / genetics*
  • Pedigree
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-ret
  • Proto-Oncogenes
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Signal Transduction / genetics*
  • Thyroid Neoplasms / genetics
  • Vesico-Ureteral Reflux / genetics*


  • Drosophila Proteins
  • GDNF protein, human
  • Gdnf protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • MAS1 protein, human
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila
  • Ret protein, mouse

Associated data

  • GENBANK/AF042080