A new study identifies the planar cell polarity pathway as a significant factor in Yellow Nail Syndrome, offering the first genetic explanation for the disease’s development.
A new study published today (December 23) in the Annals of Internal Medicine has identified defects in the planar cell polarity (PCP) pathway as a key factor in the development of yellow nail syndrome (YNS).
This analysis, based on genetic sequencing and gene and protein expression data from YNS patients, provides the first evidence linking PCP pathway disruptions to the disease, particularly in its congenital form.
Characteristics and Mysteries of YNS
Yellow nail syndrome is a rare condition marked by three main symptoms: yellow, thickened nails; lymphedema; and chronic lung disease. While its exact cause has long been a mystery, previous research has suggested that defects in lymphatic vessel development may contribute to the disorder. However, the specific genetic basis of YNS — whether congenital or acquired later in life — has remained unclear until now.
Detailed Genetic Analysis in YNS Patients
Researchers from the Genetics Institute and Genomics Center, Tel Aviv Sourasky Medical Center and colleagues studied genetic data from six patients with congenital YNS (cYNS) and five with sporadic YNS (sYNS) to determine the genetic mechanisms underlying the disease. Among the patients with cYNS, their first symptoms appeared prenatally or shortly after birth. The median age for onset of symptoms for those with sYNS was 12 years. Yellow nails and lung disease were the presenting symptoms in most patients with YNS.
Implications of Genetic Findings on YNS Pathogenesis
The researchers examined next generation sequencing data for all patients with YNS to identify and analyze genetic variants. CELSR1 was highlighted as the principal candidate disease-causing gene with autosomal recessive inheritance. The researchers found that all but one patient with cYNS had biallelic variants in CELSR1. The remaining patient had a heterozygous loss-of-function variant in FZD6. Both CELSR1 and FZD6 are core molecules in the Wnt/PCP pathway. None of the patients with sYNS had candidate variants in either CELSR1 or FZD6.
The researchers then extracted RNA from all patients to assess the Wnt/PCP pathway expression, and found that the pathway is disrupted both in cYNS patients with genetic variants and, to a lesser degree, in sYNS patients without genetic defects.
These results suggest a strong case for the involvement of Wnt/PCP signaling and PCP defects in the pathogenesis of YNS.
Reference: “Impaired Wnt/Planar Cell Polarity Signaling in Yellow Nail Syndrome” by Alina Kurolap, Chofit Chai Gadot, Orly Eshach Adiv, Tova Hershkovitz, Emily Avitan-Hersh, Ludovic Martin, Helene Humeau, Ulrich A. Schatz, Dominik S. Westphal, Silvia Lobmaier, Efrat Sofrin-Drucker, Patrick Stafler, Joshua Bugis, Irit Chermesh, Emilia Hardak, Polina Geva, Yaniv Zohar, Dov Hershkovitz, Adi Mory, Sumit Chatterji, Shoshana Greenberger, Michal Shteinberg and Hagit Baris Feldman, 23 December 2024, Annals of Internal Medicine.
DOI: 10.7326/ANNALS-24-01101
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