Abnormal WNT5A Signaling Causes Mandibular Hypoplasia in Robinow Syndrome

Area of Science:

• Genetics
• Developmental Biology
• Molecular Biology

Background:

• Rare genetic diseases offer insights into human gene function.
• Robinow syndrome (RS) is a genetic disorder affecting the WNT5A signaling pathway.
• Dominant RS stems from WNT5A missense mutations or DVL1/DVL3 nonsense mutations; recessive RS involves ROR2 loss-of-function.

Purpose of the Study:

• To investigate the functional impact of WNT5A missense mutations in dominant Robinow syndrome.
• To analyze the morphologic, cellular, and molecular effects of wild-type and mutant WNT5A in chicken embryo mandibles.
• To elucidate the mechanism by which WNT5A mutations lead to RS phenotypes.

Main Methods:

• Expression of wild-type and mutant human WNT5A (WNT5A^C83S, WNT5A^C182R) in chicken embryo mandibles using viral vectors.
• Morphological analysis of mandible development.
• Cellular analysis of chondrocyte polarity, shape, and migration.
• Molecular analysis of target gene expression and JNK signaling pathway activity.

Main Results:

• Expression of both wild-type and mutant WNT5A led to mandible shortening.
• Mutant WNT5A specifically disrupted chondrocyte polarity and shape, inhibited cell migration, altered gene expression, and abolished JNK signaling.
• Mutant WNT5A inhibited cell migration in paracrine experiments, suggesting receptor binding is not blocked.
• The study ruled out simple gain or loss of function for these WNT5A missense mutations.

Conclusions:

• WNT5A missense mutations in Robinow syndrome do not cause straightforward gain or loss of function.
• These mutations likely redirect WNT signaling from JNK-PCP to other noncanonical pathways.
• WNT5A missense mutations in RS exhibit dominant neomorphic effects, interfering with wild-type protein function.