Impaired Wnt/Planar Cell Polarity Signaling in Yellow Nail Syndrome

Area of Science:

• Genetics
• Molecular Biology
• Rare Diseases

Background:

• Yellow nail syndrome (YNS) is a rare condition with yellow nails, lymphedema, and lung issues.
• Congenital and familial cases are rare, and the underlying cause of YNS is largely unknown.
• Lymphatic vessel development defects are suspected contributors to YNS.

Purpose of the Study:

• To investigate the genetic basis of yellow nail syndrome (YNS).
• To identify genetic variants and molecular pathways involved in YNS pathogenesis.

Main Methods:

• Exome and genome sequencing were performed on patients with congenital and sporadic YNS.
• RNA analyses, immunofluorescence staining, and quantitative PCR were used to study gene and protein expression.
• Analysis focused on variants in Wnt/planar cell polarity (PCP) pathway genes.

Main Results:

• Biallelic variants in CELSR1 or FZD6, key Wnt/PCP pathway molecules, were found in all congenital YNS patients.
• CELSR1 was observed in skin lymphatic vessels, but its protein levels were significantly reduced in patient tissues.
• Reduced gene expression of Wnt/PCP-related genes was noted in both congenital and sporadic YNS patients.

Conclusions:

• Defects in Wnt/planar cell polarity (PCP) organization are implicated in the pathogenesis of YNS.
• This study provides the first mechanistic explanation for YNS development, particularly in its congenital form.
• The findings suggest a role for Wnt/PCP pathway dysfunction in both congenital and sporadic YNS.