A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia

Area of Science:

• Genetics and Molecular Biology
• Skeletal Dysplasias
• Human Disease Genetics

Background:

• Grebe, Hunter-Thompson, and du Pan dysplasias are autosomal recessive skeletal disorders.
• Characterized by short stature and severe limb shortening with a normal axial skeleton.
• Most cases involve GDF5 mutations; some involve BMPR1B mutations, a GDF5 receptor.

Observation:

• A consanguineous family presented with acromesomelic chondrodysplasia.
• Genetic sequencing identified a novel BMPR1B mutation (c.91C>T, p.(Arg31Cys)) in a patient with du Pan dysplasia.
• Functional studies revealed this mutation causes a significant but partial loss of BMPR1B function.

Findings:

• The p.(Arg31Cys) BMPR1B mutation results in du Pan dysplasia, a milder phenotype than Grebe dysplasia caused by p.Cys53Arg.
• This extends the genotype-phenotype correlation for BMPR1B mutations in acromesomelic chondrodysplasias.
• The degree of BMPR1B functional loss directly correlates with disease severity.

Implications:

• The phenotypic spectrum of these related skeletal dysplasias is influenced by the extent of GDF5-BMPR1B ligand-receptor functional impairment.
• Understanding these genotype-phenotype correlations aids in diagnosing and managing skeletal dysplasia patients.
• Further research into the GDF5-BMPR1B pathway could reveal therapeutic targets.