Hirschsprung associated GDNF mutations do not prevent RET activation

Borghini, Silvia; Bocciardi, Renata; Bonardi, Giulia; Matera, Ivana; Santamaria, Giuseppe; Ravazzolo, Roberto; Ceccherini, Isabella

doi:10.1038/sj.ejhg.5200785

Cited by 9 publications

(2 citation statements)

References 35 publications

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“…Subsequent to the discovery of RET in HSCR pathogenesis, mutation screening was performed on interacting partners and other key members of RET signaling pathway with reference to known biological processes and animal models. Damaging rare variants in all four ligands of RET have been detected in patients with HSCR, yet RET still contributes to the vast majority of rare variants reported in genes in this core HSCR pathway ( 13 – 15 , 17 , 28 , 51 , 58 – 62 ). Mutations in these GDNF family ligands typically co-occurred with variants in other major HSCR genes, particularly in RET , except in a few instances ( 59 , 61 ).…”

Section: Pre-gwas Era: Identification Of Core Hscr Pathways Through Linkage Mapping and Candidate Gene Studies On Syndromic And Familial mentioning

confidence: 99%

The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications

2021

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Hirschsprung disease (HSCR) is the leading cause of neonatal functional intestinal obstruction. It is a rare congenital disease with an incidence of one in 3,500–5,000 live births. HSCR is characterized by the absence of enteric ganglia in the distal colon, plausibly due to genetic defects perturbing the normal migration, proliferation, differentiation, and/or survival of the enteric neural crest cells as well as impaired interaction with the enteric progenitor cell niche. Early linkage analyses in Mendelian and syndromic forms of HSCR uncovered variants with large effects in major HSCR genes including RET, EDNRB, and their interacting partners in the same biological pathways. With the advances in genome-wide genotyping and next-generation sequencing technologies, there has been a remarkable progress in understanding of the genetic basis of HSCR in the past few years, with common and rare variants with small to moderate effects being uncovered. The discovery of new HSCR genes such as neuregulin and BACE2 as well as the deeper understanding of the roles and mechanisms of known HSCR genes provided solid evidence that many HSCR cases are in the form of complex polygenic/oligogenic disorder where rare variants act in the sensitized background of HSCR-associated common variants. This review summarizes the roadmap of genetic discoveries of HSCR from the earlier family-based linkage analyses to the recent population-based genome-wide analyses coupled with functional genomics, and how these discoveries facilitated our understanding of the genetic architecture of this complex disease and provide the foundation of clinical translation for precision and stratified medicine.

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Section: Pre-gwas Era: Identification Of Core Hscr Pathways Through Linkage Mapping and Candidate Gene Studies On Syndromic And Familial mentioning

confidence: 99%

The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications

2021

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“…Although a GFRA1 mutation has not been found in Hirschsprung’s patients, Hirschsprung’s disease has been observed in heterozygous GDNF+/− mice [ 43 ]. However, mutated GDNF does not reduce the activation of RET [ 44 ]. Interestingly, mutated NRTN has also been shown to be involved in this disease.…”

Section: Physiological Roles Of Gfra1 In Diseasementioning

confidence: 99%

GFRA1: A Novel Molecular Target for the Prevention of Osteosarcoma Chemoresistance

Kim

2018

IJMS

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The glycosylphosphatidylinositol-linked GDNF (glial cell derived neurotrophic factor) receptor alpha (GFRA), a coreceptor that recognizes the GDNF family of ligands, has a crucial role in the development and maintenance of the nervous system. Of the four identified GFRA isoforms, GFRA1 specifically recognizes GDNF and is involved in the regulation of proliferation, differentiation, and migration of neuronal cells. GFRA1 has also been implicated in cancer cell progression and metastasis. Recent findings show that GFRA1 can contribute to the development of chemoresistance in osteosarcoma. GFRA1 expression was induced following treatment of osteosarcoma cells with the popular anticancer drug, cisplatin and induction of GFRA1 expression significantly suppressed apoptosis mediated by cisplatin in osteosarcoma cells. GFRA1 expression promotes autophagy by activating the SRC-AMPK signaling axis following cisplatin treatment, resulting in enhanced osteosarcoma cell survival. GFRA1-induced autophagy promoted tumor growth in mouse xenograft models, suggesting a novel function of GFRA1 in osteosarcoma chemoresistance.

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