2024-03-28T21:14:13Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/117962011-03-21T23:00:00Zcom_10261_11773com_10261_1col_10261_11774
A novel point variant in NTRK3, R645C, suggests a role of this gene in the pathogenesis of Hirschsprung disease
Fernández, Raquel M.
Sánchez-Mejías, Avencia
Mena, Marcela
Ruiz-Ferrer, Macarena
López-Alonso, Manuel
Antiñolo, Guillermo
Borrego, Salud
NTRK3
Hirschsprung disease (HSCR)
Mutational screening
Complex diseases
RET proto-oncogene
7 pages, 2 figures.-- PMID: 19040714 [PubMed].-- Available online Oct 22, 2008.
Hirschsprung disease (HSCR) is a developmental disorder characterized by the absence of ganglion cells in the myenteric and submucosal plexuses due to a defect in the migration process of neural crest neuroblasts. Manifestation of the disease has been linked to the dysfunction of two principal signalling pathways involved in the enteric nervous system (ENS) formation: the RET-GDNF and the EDN3-EDNRB receptor systems. However, the NTF3/NTRK3 signalling pathway plays an essential role in the development of the ENS suggesting a potential role for those genes in the pathogenesis of HSCR. We have sought to evaluate the candidature of the NTRK3 gene, which encodes the TrkC receptor, as a susceptibility gene for Hirschsprung disease. Using dHPLC technology we have screened the NTRK3 coding region in 143 Spanish HSCR patients. A total of four previously described polymorphisms and 12 novel sequence variants were detected. Of note, the novel R645C mutation was detected in 2 affected siblings of a HSCR family also carrying a RET splicing mutation. Using bioinformatics tools we observed that the presence of an additional cysteine residue might implicate structural alterations in the mutated protein. We propose haploinsufficiency as the most probable mechanism for the NTRK3 R645C mutation. NTRK3 and RET mutations in this family only appear together in the HSCR patients, suggesting that they per se are necessary but not sufficient to produce the phenotype. In addition, it is quite probable that the contribution of other still unidentified modifier genes, may be responsible for the different phenotypes (length of aganglionosis) in the two affected members.
We would like to thank all the patients who participated in the study as well as their families for their collaboration. This
study was funded by Fondo de Investigación Sanitaria, Spain (PI070080 and PI071325) and Consejeria de Innovación, Ciencia
y Empresa de la Junta de Andalucía (CTS2590). RMF and MRF are postdoctoral fellows of CIBERER, ISCIII, Spain. ASM is a
PhD student of the Fondo de Investigación Sanitaria.
Peer reviewed
2009-03-23T12:18:34Z
2009-03-23T12:18:34Z
2009-01
artículo
http://purl.org/coar/resource_type/c_6501
Annals of Human Genetics 73(1): 19-25 (2009)
0003-4800
http://hdl.handle.net/10261/11796
10.1111/j.1469-1809.2008.00479.x
en
http://dx.doi.org/10.1111/j.1469-1809.2008.00479.x
none
821264 bytes
application/pdf
Blackwell Publishing
University College London