Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling

Area of Science:

• Skeletal biology
• Human genetics
• Developmental biology

Background:

• Fibroblast Growth Factor Receptor 2 (FGFR2) is essential for embryonic bone formation, regulating osteoprogenitor cell proliferation and differentiation.
• Dysregulation of FGFR2 signaling is implicated in various skeletal disorders.

Purpose of the Study:

• To investigate the genetic basis of a rare, lethal skeletal dysplasia.
• To characterize the molecular mechanisms underlying this newly identified condition.

Main Methods:

• Identification of de novo FGFR2 mutations in affected individuals.
• Histological analysis of long bones from affected individuals.
• Functional studies using patient-derived chondrocytes and cell-based assays to assess FGFR2 signaling.

Main Results:

• Identified heterozygous missense mutations in FGFR2 in four unrelated individuals with a severe skeletal dysplasia.
• Clinical features include poor calvarial mineralization, craniosynostosis, dysmorphic features, and osteopenia.
• Mutations selectively reduced cell-surface FGFR2 levels and impaired FGF responsiveness, impacting chondrocyte and periosteal development.

Conclusions:

• These findings describe a novel skeletal dysplasia caused by specific FGFR2 mutations.
• The identified mutations represent a distinct pathogenic mechanism separate from previously known FGFR2-related disorders.
• This study expands our understanding of FGFR2's role in skeletal development and human disease.