Familial form of Hirschsprung disease: Nucleotide sequence studies reveal point mutations in the ret proto-oncogene in two of six families but not in other candidate genes

Ester Margarit, M. Dolors Coll, Rafael Oliva, David Gómez, Anna Soler, Francisca Ballesta

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    Abstract

    Hirschsprung disease (HSCR; McKusick 142623) or aganglionic megacolon is a frequent (1 in 5,000 live births) heritable disorder of the enteric nervous system. By haplo-typing with a variety of microsatellite markers, by amplifying all 20 exons of the RET proto-oncogene and by applying a direct DNA sequencing protocol, we have analyzed the DNA from HSCR patients in 6 different families. In one family with a joint occurrence of HSCR and FMTC (follicular medullary thyroid carcinoma), we have identified a mutation in codon 609 in one out of 6 cysteine residues encoded in exon 10 of the RET gene. This C609R point mutation has not previously been reported to cause HSCR. In 2 of the HSCR patients described here from different families, we have found a mutation in exon 2 (R77C) and a silent mutation in exon 3 (Y204Y), respectively, in the extracellular part of the RET proto-oncogeneo. In introns 2 and 17 of the RET proto-oncogene in 2 families, we have detected single nucleotide exchanges that are probably polymorphisms with unknown, if any, relations to HSCR. The DNA sequences of 5 further genes (GDNF, GDNFRα, EDN3, EDNRB, and NTN), that may contribute to the development of HSCR, have not shown mutations in the patients analyzed so far. In 2 of the reported families with several affected children and one grandchild, sequence analyses revealed no mutations in the coding regions of any of the candidate genes analyzed. (C) 2000 Wiley-Liss, Inc.
    Original languageEnglish
    Pages (from-to)19-27
    JournalAmerican Journal of Medical Genetics
    Volume94
    Issue number1
    Publication statusPublished - 4 Sep 2000

    Keywords

    • EDN3
    • EDNRB
    • Follicular medullary thyroid carcinoma
    • GDNF
    • GDNFRα
    • Intestinal aganglionosis
    • Long segmented form of HSCR
    • Multigene disorder
    • NTN genes
    • RET

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