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

doi:10.1038/s41431-019-0350-4

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

Eur J Hum Genet. 2019 Jul;27(7):1113-1120. doi: 10.1038/s41431-019-0350-4. Epub 2019 Feb 20.

Authors

Affiliations

¹ Fondazione IRCCS Casa Sollievo della Sofferenza, Division of Medical Genetics, San Giovanni Rotondo, FG, Italy.
² Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Studi di Milano, Italy.
³ Fondazione IRCCS Casa Sollievo della Sofferenza, Unit of Bioinformatics, San Giovanni Rotondo, FG, Italy.
⁴ Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
⁵ Fondazione IRCCS Casa Sollievo della Sofferenza, Division of Pediatrics, San Giovanni Rotondo, FG, Italy.
⁶ Institute of Biosciences and Bioresources, National Research Council (CNR), Naples, Italy.
⁷ Fondazione IRCCS Casa Sollievo della Sofferenza, Division of Medical Genetics, San Giovanni Rotondo, FG, Italy. l.micale@operapadrepio.it.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Substitution
Cleft Lip* / genetics
Cleft Lip* / metabolism
Cleft Lip* / pathology
Cleft Palate* / genetics
Cleft Palate* / metabolism
Cleft Palate* / pathology
Female
Fingers / abnormalities*
Fingers / pathology
Genes, Dominant
Hand Deformities, Congenital* / genetics
Hand Deformities, Congenital* / metabolism
Hand Deformities, Congenital* / pathology
Holoprosencephaly* / genetics
Holoprosencephaly* / metabolism
Holoprosencephaly* / pathology
Humans
Intellectual Disability* / genetics
Intellectual Disability* / metabolism
Intellectual Disability* / pathology
MAP Kinase Signaling System*
Male
Mitogen-Activated Protein Kinase 1 / genetics
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / genetics
Mitogen-Activated Protein Kinase 3 / metabolism
Mutation, Missense*
Receptor, Fibroblast Growth Factor, Type 1* / genetics
Receptor, Fibroblast Growth Factor, Type 1* / metabolism
ras Proteins / genetics
ras Proteins / metabolism

Substances

FGFR1 protein, human
Receptor, Fibroblast Growth Factor, Type 1
MAPK1 protein, human
MAPK3 protein, human
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
ras Proteins

Supplementary concepts

Holoprosencephaly, Ectrodactyly, and Bilateral Cleft Lip-Palate