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EnglishHartsfield syndrome (HS) is an ultrarare developmental disorder mainly featuring holoprosencephaly and ectrodactyly. It is caused by heterozygous or biallelic variants in FGFR1. Recently, a dominant-negative effect was suggested for FGFR1 variants associated with HS. Here, exome sequencing analysis in a 12-year-old boy with HS disclosed a novel de novo heterozygous variant c.1934C>T in FGFR1 predicted to cause the p.(Ala645Val) amino-acid substitution. In order to evaluate whether the variant, changing a highly conserved residue of the kinase domain, affects FGFR1 function, biochemical studies were employed. We measured the FGFR1 receptor activity in FGF2-treated cell lines exogenously expressing wild-type or Ala645Val FGFR1 by monitoring the activation status of FGF2/FGFR1 downstream pathways. Our analysis highlighted that RAS/ERK1/2 signaling was significantly perturbed in cells expressing mutated FGFR1, in comparison with control cells. We also provided preliminary evidence showing a modulation of the autophagic process in cells expressing mutated FGFR1. This study expands the FGFR1 mutational spectrum associated with HS, provides functional evidence further supporting a dominant-negative effect of this category of FGFR1 variants and offers initial insights on dysregulation of autophagy in HS.
A novel dominant-negative FGFR1 variant causes Hartsfield syndrome by deregulating RAS/ERK1/2 pathway / P. Palumbo, A. Petracca, R. Maggi, T. Biagini, G. Nardella, M. Carmine Sacco, E. Di Schiavi, M. Carella, L. Micale, M. Castori. - In: EUROPEAN JOURNAL OF HUMAN GENETICS. - ISSN 1018-4813. - 27:7(2019 Jul), pp. 1113-1120.
| Titolo: | A novel dominant-negative FGFR1 variant causes Hartsfield syndrome by deregulating RAS/ERK1/2 pathway |
| Autori: | |
| Parole Chiave: | FGFR1; mutation; Hartsfield syndrome; RAS; ERK |
| Settore Scientifico Disciplinare: | Settore BIO/09 - Fisiologia |
| Data di pubblicazione: | lug-2019 |
| Rivista: | |
| Tipologia: | Article (author) |
| Data ahead of print / Data di stampa: | 20-feb-2019 |
| Digital Object Identifier (DOI): | http://dx.doi.org/10.1038/s41431-019-0350-4 |
| Appare nelle tipologie: | 01 - Articolo su periodico |
File in questo prodotto:
| File | Descrizione | Tipologia | Licenza | |
|---|---|---|---|---|
| s41431-019-0350-4.pdf | Publisher's version/PDF | Administrator Richiedi una copia | ||
| 20 Preprint A novel dominant-negative FGFR1 variant.pdf | Articolo principale | Pre-print (manoscritto inviato all'editore) | Open Access Visualizza/Apri | |
| s41431-019-0350-4.pdf | Publisher's version/PDF | Administrator Richiedi una copia |
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