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Thanatophoric dysplasia caused by double missense FGFR3 mutations

Stéphanie Pannier1, Jelena Martinovic, Solange Heuertz

  • 1INSERM U781, Université Paris Descartes, Hôpital Necker-Enfants Malades, Paris, France.

American Journal of Medical Genetics. Part A
|May 19, 2009
PubMed

Insights

Thanatophoric dysplasia, a lethal skeletal disorder, can be caused by a rare double mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. This unique genetic combination leads to a hyperactivated receptor, resulting in severe developmental abnormalities.

Area of Science:

  • Genetics
  • Molecular Biology
  • Skeletal Dysplasias

Background:

  • Thanatophoric dysplasia is a severe, lethal skeletal disorder characterized by extreme micromelia and a narrow thorax.
  • It is primarily caused by heterozygous missense mutations in the fibroblast growth factor receptor 3 (FGFR3) gene.
  • Known mutations affect various domains of the FGFR3 receptor, including those creating cysteine residues or eliminating the termination codon.

Observation:

  • This study reports a unique patient with thanatophoric dysplasia presenting a rare double de novo FGFR3 mutation on the same allele: c.[1620C>A;1454A>G] (p.[N540K;Q485R]).
  • The p.N540K mutation is commonly found in hypochondroplasia, while p.Q485R is a novel mutation within a conserved FGFR domain.
  • Structural analysis, including protein alignments and 3D modeling, provided evidence for the functional impact of these concurrent mutations.

Findings:

  • The identified double FGFR3 mutation significantly alters the receptor's structure.
  • This structural change results in the receptor being constitutively activated, remaining in a permanently "on" state.
  • This hyperactivation of FGFR3 is directly linked to the lethal phenotype of thanatophoric dysplasia observed in the patient.

Implications:

  • This case highlights the complex mutational landscape of FGFR3 in skeletal dysplasias.
  • Understanding the structural consequences of double mutations provides insights into receptor activation mechanisms.
  • Further research into genotype-phenotype correlations can improve diagnosis and potentially guide future therapeutic strategies for FGFR3-related disorders.

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