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Research Article| Volume 33, ISSUE 1, P99-102, January 1998

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GDNF deficit in Hirschsprung's disease

  • G Martucciello
    Correspondence
    Address reprint request to Giuseppe Martucciello, MD, Department of Pediatric Surgery, Istituto Giannina Gaslini, Largo G. Gaslini, 5-16148 Genoa, Italy.
    Affiliations
    Department of Chair of Pediatric Surgery, the Laboratory of Molecular Genetics, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.

    the Department of Pathology, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.
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  • H Thompson
    Affiliations
    Department of Chair of Pediatric Surgery, the Laboratory of Molecular Genetics, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.

    the Department of Pathology, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.
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  • C Mazzola
    Affiliations
    Department of Chair of Pediatric Surgery, the Laboratory of Molecular Genetics, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.

    the Department of Pathology, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.
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  • A Morando
    Affiliations
    Department of Chair of Pediatric Surgery, the Laboratory of Molecular Genetics, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.

    the Department of Pathology, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.
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  • M Bertagnon
    Affiliations
    Department of Chair of Pediatric Surgery, the Laboratory of Molecular Genetics, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.

    the Department of Pathology, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.
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  • F Negri
    Affiliations
    Department of Chair of Pediatric Surgery, the Laboratory of Molecular Genetics, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.

    the Department of Pathology, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.
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  • A Brizzolara
    Affiliations
    Department of Chair of Pediatric Surgery, the Laboratory of Molecular Genetics, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.

    the Department of Pathology, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.
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  • L Rocchetti
    Affiliations
    Department of Chair of Pediatric Surgery, the Laboratory of Molecular Genetics, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.

    the Department of Pathology, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.
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  • C Gambini
    Affiliations
    Department of Chair of Pediatric Surgery, the Laboratory of Molecular Genetics, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.

    the Department of Pathology, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.
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  • V Jasonni
    Affiliations
    Department of Chair of Pediatric Surgery, the Laboratory of Molecular Genetics, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.

    the Department of Pathology, Giannina Gaslini Children's Hospital, University of Genoa, Genoa, Italy.
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DOI:https://doi.org/10.1016/S0022-3468(98)90371-2
GDNF deficit in Hirschsprung's disease
Previous ArticleDelayed maturation of the interstitial cells of Cajal: A new diagnosis for transient neonatal pseudoobstruction. Report of two cases
Next ArticleTurnover of radioactive mucin precursors in the colon of patients with Hirschsprung's disease correlates with the development of enterocolitis
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      Abstract

      Background/Purpose: In 1996, the glial cell line-derived neurotrophic factor (GDNF) was identified as one of the ligands of the RET transmembrane receptor. In the same year, GDNF mutations were found in association with RET protooncogene mutations in Hirschsprung patients. Mutations in GDNF per se are thought neither necessary nor sufficient to cause Hirschsprung's disease (HD). To data, our study group has identified GDNF mutations only in 2 of 98 cases of intestinal dysganglionosis. The aim of our study was to investigate a possible expression deficit of GDNF in the enteric nervous system of Hirschsprung patients not mutated for the GDNF gene.
      Methods: We used rabbit polyclonal antibodies raised against a peptide corresponding to amino acids 186–205 mapping within the carboxy-terminal domain of human GDNF. GDNF expression was studied immunohistochemically in surgical specimens from 30 HD cases (27 classic forms and 3 ultralong forms) and from 10 age-matched controls. Serial sections from the same full-thickness specimens were investigated with the following histochemical and immunohistochemical techniques: acetylcholinesterase, lactate dehydrogenase, succinic dehydrogenase, α-naphthylesterase, glial fibrillary acid protein, S-100 protein, and neuron-specific enolase.
      Results: A high level of GDNF expression was found in normal intestine and in Hirschsprung ganglionic segment. Satellite elements of myenteric ganglia presented a strong immunoreactivity to GDNF. Conversely, the aganglionic segment showed cholinergic hyperinnervation and hypertrophic trunks of nerve fibers in the muscular interstitium with complete absence of GDNF expression. The small ganglia of the hypoganglionic segment showed a reduced GDNF immunoreactivity.
      Conclusions: GDNF, a distantly related member of the transforming growth factor-beta superfamily, is a potent neurotrophic and survival factor for neurons and enteric ganglion cells. Mutations of the GDNF gene or GDNF expression deficit interrupt the faithful GDNF signaling via Ret, contributing to HD pathogenesis.

      Keywords

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      References

        • Molenaar JC
        Pathogenetic aspects of Hirschsprung's disease.
        Br J Surg. 1995; 82: 145-147
        • Martucciello G
        Hirschsprung's disease as a neurochristopathy.
        Pediatr Surg Int. 1997; 12: 2-10
        • Kusafuka T
        • Puri P
        The RET proto-oncogene: A challenge to understanding of disease pathogenesis.
        Pediatr Surg Int. 1997; 12: 11-18
        • Trupp M
        • Arenas E
        • Fainzilber M
        • et al.
        Functional receptor for GDNF encoded by the c-ret proto-oncogene.
        Nature. 1996; 381: 785-789
        • Lin LH
        • Doherty DH
        • Lile JD
        • et al.
        GDNF: A glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons.
        Science. 1993; 260: 1130-1132
        • Treanor JJS
        • Goodman L
        • de Sauvage F
        • et al.
        Characterization of a multicomponent receptor for GDNF.
        Nature. 1996; 382: 80-83
        • Robertson K
        • Mason I
        The GDNF-RET signalling partnership.
        Trends in Genetics. 1997; 13: 1-3
        • Angrist M
        • Bolk S
        • Halushka M
        • et al.
        Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient.
        Nature Genet. 1996; 14: 341-344
        • Salomon R
        • Attié T
        • Pelet A
        • et al.
        Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease.
        Nature Genet. 1996; 14: 345-347
        • Ivanchuk SM
        • Myers SM
        • Eng C
        • et al.
        De novo mutation of GDNF, ligand for the Math Eq receptor complex, in Hirschsprung disease.
        Human Mol Genet. 1996; 5: 2023-2026
        • Meier-Ruge W
        Morphological diagnosis.
        in: Holschneider AM Hirschsprung's Disease. 1982: 62-71 (Germany, Stuttgart)
        • Dodero P
        • Martucciello G
        Hirschsprung's disease: α-naphthylesterase activity for enzyme-histochemical evaluation of the extent of the aganglionic segment during surgery.
        Pediatr Surg Int. 1988; 4: 269-274
        • Ullrich A
        • Schlessinger J
        Signal transduction by receptors with tyrosine kinase activity.
        Cell. 1990; 61: 203-212
        • Martucciello G
        • Favre A
        • Takahashi M
        • et al.
        Immunohistochemical localization of Ret protein in Hirschsprung's disease.
        J Pediatr Surg. 1995; 30: 433-436
        • Sanchez MP
        • Silos-Santiago I
        • Frisen J
        • et al.
        Renal agenesis and absence of enteric neurons in mice lacking GDNF.
        Nature. 1996; 382: 70-73

      Article info

      Footnotes

      ☆Presented at the 44th Annual International Congress of the British Association of Paediatric Surgeons, Istanbul, Turkey, July 22–25, 1997.

      Identification

      DOI: https://doi.org/10.1016/S0022-3468(98)90371-2

      Copyright

      © 1998 Published by Elsevier Inc.

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