Novel mutations at RET ligand genes preventing receptor activation are associated to Hirschsprung's disease |
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Authors: | Ruiz-Ferrer Macarena Torroglosa Ana Luzón-Toro Berta Fernández Raquel M Antiñolo Guillermo Mulligan Lois M Borrego Salud |
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Institution: | (1) Unidad de Gesti?n Cl?nica de Gen?tica, Reproducci?n y Medicina Fetal, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Roc?o/CSIC/Universidad de Sevilla, Avda. Manuel Siurot s/n, 41013 Seville, Spain;(2) Centro de Investigaci?n Biom?dica en Red de Enfermedades Raras (CIBERER), Seville, Spain;(3) Department of Pathology and Molecular Medicine, Division of Cancer Biology and Genetics, Cancer Research Institute, Queen’s University, Kingston, ON, Canada; |
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Abstract: | Hirschsprung disease (HSCR) is a developmental disorder characterized by the absence of ganglion cells along variable lengths
of the distal gastrointestinal tract. The major susceptibility gene for the disease is the RET proto-oncogene, which encodes a receptor tyrosine kinase activated by the glial cell-derived neurotrophic factor (GDNF) family
ligands. We analyzed the coding sequence of GDNF, NTRN, and, for the first time, ARTN and PSPN in HSCR patients and detected several novel variants potentially involved in the pathogenesis of HSCR. In vitro functional
analysis revealed that the variant R91C in PSPN would avoid the correct expression and secretion of the mature protein. Moreover, this study also highlighted the role of
both this variant and F127L in NRTN in altering RET activation by a significant reduction in phosphorylation. To support the role of PSPN R91C in HSCR phenotype, enteric nervous system (ENS) progenitors were isolated from human postnatal gut tissues and expression
of GFRα4, the main co-receptor for PSPN, was demonstrated. This suggests that not only GDNF and NRTN but also PSPN might promote
survival of precursor cells during ENS development. In summary, we report for the first time the association of PSPN gene with HSCR and confirm the involvement of NRTN in the disease, with the identification of novel variants in those genes. Our results suggest that the biological consequence
of the mutations NTRN F127L and PSPN R91C would be a reduction in the activation of RET-dependent signaling pathways, leading to a defect in the proliferation,
migration, and/or differentiation process of neural crest cells within the developing gut and thus to the typical aganglionosis
of the HSCR phenotype. |
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