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New Study Identifies Genetic Defects in Planar Cell Polarity Pathway as a Key Factor
A groundbreaking study published on December 23 in the Annals of Internal Medicine has provided crucial insights into the genetic basis of Yellow Nail Syndrome (YNS), a rare and poorly understood disorder. The research, conducted by scientists at the Genetics Institute and Genomics Center, Tel Aviv Sourasky Medical Center, has identified disruptions in the planar cell polarity (PCP) pathway as a key contributor to the development of YNS, especially in its congenital form.
What is Yellow Nail Syndrome?
Yellow Nail Syndrome is characterized by three main symptoms: yellow, thickened nails, lymphedema (swelling due to lymphatic fluid buildup), and chronic lung disease. While the exact cause of YNS has long been a mystery, previous studies have hinted at issues with lymphatic vessel development as a potential factor. However, the specific genetic causes of YNS, particularly whether it is congenital or acquired later in life, remained unclear—until now.
Groundbreaking Genetic Analysis
In an effort to uncover the genetic roots of YNS, the researchers studied the genetic data of six patients with congenital YNS (cYNS) and five with sporadic YNS (sYNS). Among the patients with cYNS, symptoms typically appeared prenatally or shortly after birth. For those with sYNS, the median age of symptom onset was around 12 years. For the majority of patients, yellow nails and lung disease were the first signs of the condition.
By employing advanced next-generation sequencing techniques, the researchers identified genetic variants associated with YNS. The gene CELSR1 was singled out as the primary disease-causing gene, with an autosomal recessive inheritance pattern. Notably, all but one patient with cYNS had biallelic variants in CELSR1, while the remaining patient carried a heterozygous loss-of-function variant in FZD6. Both CELSR1 and FZD6 play crucial roles in the Wnt/PCP pathway, a signaling pathway involved in the development of tissues and organs.
Disruption of the Wnt/PCP Pathway
In addition to the genetic sequencing, the research team examined the expression of the Wnt/PCP pathway in YNS patients by extracting RNA samples. Their findings revealed that the pathway is disrupted in patients with cYNS who carry genetic variants in CELSR1 and FZD6. While this disruption was also observed in patients with sYNS, the effect was less pronounced in those without genetic variants in these genes.
These findings strongly suggest that defects in the Wnt/PCP signaling pathway are central to the development of YNS, providing new avenues for understanding the disease’s pathogenesis and potential therapeutic targets.
A New Understanding of YNS
This study marks a significant advancement in the understanding of Yellow Nail Syndrome. By identifying the genetic and molecular mechanisms underlying the disease, it opens the door to more targeted research and potentially new treatments. The discovery that both congenital and sporadic forms of YNS are linked to disruptions in the Wnt/PCP pathway could lead to novel diagnostic tools and therapies for those suffering from this rare and often debilitating condition.
For further details, refer to the full study published in the Annals of Internal Medicine: “Impaired Wnt/planar cell polarity signaling in yellow nail syndrome” (DOI: 10.7326/ANNALS-24-01101).
This research is expected to lead to a better understanding of the genetic causes of Yellow Nail Syndrome and may pave the way for new, more effective treatments for those affected by the condition.
