1. A novel dominant-negative FGFR1 variant causes Hartsfield syndrome by deregulating RAS/ERK1/2 pathway
- Author
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Michele Sacco, Pietro Palumbo, Massimo Carella, Roberto Maggi, Antonio Petracca, Lucia Micale, Elia Di Schiavi, Marco Castori, Tommaso Biagini, and Grazia Nardella
- Subjects
Male ,autophagy ,MAP Kinase Signaling System ,Cleft Lip ,growth ,Mutation, Missense ,Biology ,medicine.disease_cause ,Article ,Fingers ,Kallmann-syndrome ,mutation ,Intellectual Disability ,Hartsfield syndrome ,Holoprosencephaly ,Genetics ,medicine ,Missense mutation ,Humans ,Receptor, Fibroblast Growth Factor, Type 1 ,Receptor ,Gene ,Genetics (clinical) ,Exome sequencing ,Genes, Dominant ,Mitogen-Activated Protein Kinase 1 ,Mutation ,Mitogen-Activated Protein Kinase 3 ,Fibroblast growth factor receptor 1 ,Cleft Palate ,stomatognathic diseases ,FGFR1 ,Protein kinase domain ,Amino Acid Substitution ,Cell culture ,ras Proteins ,Female ,Hand Deformities, Congenital - Abstract
Hartsfield 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.
- Published
- 2019