A novel dominant-negative FGFR1 variant causes Hartsfield syndrome by deregulating RAS/ERK1/2 pathway

Pietro Palumbo, Antonio Petracca, Roberto Maggi, Tommaso Biagini, Grazia Nardella, Michele Carmine Sacco, Elia Di Schiavi, Massimo Carella, Lucia Micale, Marco Castori

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalEuropean Journal of Human Genetics
DOIs
Publication statusPublished - Jan 1 2019

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MAP Kinase Signaling System
Fibroblast Growth Factor 2
Holoprosencephaly
Exome
Autophagy
Amino Acid Substitution
Phosphotransferases
Holoprosencephaly, Ectrodactyly, and Bilateral Cleft Lip-Palate
Cell Line

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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A novel dominant-negative FGFR1 variant causes Hartsfield syndrome by deregulating RAS/ERK1/2 pathway. / Palumbo, Pietro; Petracca, Antonio; Maggi, Roberto; Biagini, Tommaso; Nardella, Grazia; Sacco, Michele Carmine; Di Schiavi, Elia; Carella, Massimo; Micale, Lucia; Castori, Marco.

In: European Journal of Human Genetics, 01.01.2019.

Research output: Contribution to journalArticle

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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.",
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AU - Palumbo, Pietro

AU - Petracca, Antonio

AU - Maggi, Roberto

AU - Biagini, Tommaso

AU - Nardella, Grazia

AU - Sacco, Michele Carmine

AU - Di Schiavi, Elia

AU - Carella, Massimo

AU - Micale, Lucia

AU - Castori, Marco

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