Human GFRA1: cloning, mapping, genomic structure, and evaluation as a candidate gene for Hirschsprung disease susceptibility

Genomics. 1998 Mar 15;48(3):354-62. doi: 10.1006/geno.1997.5191.


Congenital aganglionic megacolon, commonly known as Hirschsprung disease (HSCR), is the most frequent cause of congenital bowel obstruction. Germline mutations in the RET receptor tyrosine kinase have been shown to cause HSCR. Knockout mice for RET and for its ligand, glial cell line-derived neurotrophic factor (GDNF), exhibit both complete intestinal aganglionosis and renal defects. Recently, GDNF and GFRA1 (GDNF family receptor, also known as GDNFR-alpha), its GPI-linked coreceptor, were demonstrated to be components of a functional ligand for RET. Moreover, GDNF has been implicated in rare cases of HSCR. We have mapped GFRA1 to human chromosome 10q25, isolated human and mouse genomic clones, determined the gene's intron-exon boundaries, isolated a highly polymorphic microsatellite marker adjacent to exon 7, and scanned for GFRA1 mutations in a large panel of HSCR patients. No evidence of linkage was detected in HSCR kindreds, and no sequence variants were found to be in significant excess in patients. These data suggest that GFRA1'S role in enteric neurogenesis in humans remains to be elucidated and that RET signaling in the gut may take place via alternate pathways, such as the recently described GDNF-related molecule neurturin and its GFRA1-like coreceptor, GFRA2.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Chromosome Mapping
  • Chromosomes, Human, Pair 10
  • Cloning, Molecular
  • DNA, Complementary / isolation & purification
  • Drosophila Proteins*
  • Exons
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Hirschsprung Disease / genetics*
  • Hirschsprung Disease / metabolism
  • Humans
  • Introns
  • Ligands
  • Microsatellite Repeats
  • Molecular Sequence Data
  • Mutation
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Sequence Alignment
  • Sequence Analysis, DNA


  • DNA, Complementary
  • Drosophila Proteins
  • GFRA1 protein, human
  • GFRA2 protein, human
  • Genetic Markers
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Ligands
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila

Associated data

  • GENBANK/AF038410
  • GENBANK/AF038411
  • GENBANK/AF038412
  • GENBANK/AF038413
  • GENBANK/AF038414
  • GENBANK/AF038415
  • GENBANK/AF038416
  • GENBANK/AF038417
  • GENBANK/AF038418
  • GENBANK/AF038419
  • GENBANK/AF038420
  • GENBANK/AF038421