Elsevier

Genomics

Volume 48, Issue 3, 15 March 1998, Pages 354-362
Genomics

Regular Article
HumanGFRA1: Cloning, Mapping, Genomic Structure, and Evaluation as a Candidate Gene for Hirschsprung Disease Susceptibility,☆☆

https://doi.org/10.1006/geno.1997.5191Get rights and content

Abstract

Congenital aganglionic megacolon, commonly known as Hirschsprung disease (HSCR), is the most frequent cause of congenital bowel obstruction. Germline mutations in theRETreceptor tyrosine kinase have been shown to cause HSCR. Knockout mice forRETand 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-α), its GPI-linked coreceptor, were demonstrated to be components of a functional ligand for RET. Moreover,GDNFhas been implicated in rare cases of HSCR. We have mappedGFRA1to 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 forGFRA1mutations 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 thatGFRA1'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.

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    Sequence data from this article have been deposited with the EMBL/GenBank Data Libraries under Accession Nos. AF038410–AF038421.

    ☆☆

    A. M. Holschneider

    1

    To whom correspondence should be addressed at Department of Genetics, BRB Room 721, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4955. Telephone: (216) 368-5847. Fax: (216) 368-5857. E-mail:[email protected].

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