Annals of internal medicine · 2024
Impaired Wnt/Planar Cell Polarity Signaling in Yellow Nail Syndrome.
СтатьяНазвание и аннотация: Перевод в очереди
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Kurolap Alina, Chai Gadot Chofit, Eshach Adiv Orly, Hershkovitz Tova, Avitan-Hersh Emily, Martin Ludovic, Humeau Helene, Schatz Ulrich A, Westphal Dominik S, Lobmaier Silvia, Sofrin-Drucker Efrat, Stafler Patrick, Bugis Joshua, Chermesh Irit, Hardak Emilia, Geva Polina, Zohar Yaniv, Hershkovitz Dov, Mory Adi, Chatterji Sumit, Greenberger Shoshana, Shteinberg Michal, Baris Feldman Hagit
Аннотация
BACKGROUND: Yellow nail syndrome (YNS) is a rare disorder characterized by a triad of yellow dystrophic nails, lymphedema, and chronic lung disease. Most patients present in adulthood, with only a few congenital or familial cases described. The cause of YNS remains largely unknown, although defects in lymphatic vessel development are suggested to play a significant role.
OBJECTIVE: To elucidate the genetic mechanisms underlying YNS.
DESIGN: Analysis of genetic sequencing data and gene and protein expression studies.
SETTING: A tertiary care academic medical center.
PATIENTS: 6 patients with congenital YNS (cYNS) and 5 with sporadic YNS (sYNS).
MEASUREMENTS: Exome and genome sequencing were used to detect disease-causing variants, complemented by RNA analyses for intronic variants. Protein and gene expressions were studied by immunofluorescence staining and real-time reverse transcriptase quantitative polymerase chain reaction analyses.
RESULTS: Biallelic variants in CELSR1 (n = 5) or likely FZD6 (n = 1), both core molecules in the Wnt/planar cell polarity (PCP) pathway, were identified in all patients with cYNS; none of the patients with sYNS had candidate genetic variants. Immunofluorescence staining showed that CELSR1 colocalizes with lymphatic vessels in the skin but not in the lungs or the intestine. Moreover, levels of CELSR1 and FZD6 proteins were negligible to zero in patient tissues (n = 2) compared with control tissues. Gene expression of Wnt/PCP-related genes was reduced in patients with cYNS (n = 3), and patients with sYNS (n = 4) showed milder gene expression impairments.
LIMITATION: Small cohort size and limited sample availability.
CONCLUSION: Defects in PCP organization may play a major role in the pathogenesis of YNS. To the authors' knowledge, this is the first demonstration of a mechanism explaining YNS development, mainly in its congenital form but also in patients with sporadic disease.
PRIMARY FUNDING SOURCE: The Prof. Baum Research Fund of Israel Lung Association.
OBJECTIVE: To elucidate the genetic mechanisms underlying YNS.
DESIGN: Analysis of genetic sequencing data and gene and protein expression studies.
SETTING: A tertiary care academic medical center.
PATIENTS: 6 patients with congenital YNS (cYNS) and 5 with sporadic YNS (sYNS).
MEASUREMENTS: Exome and genome sequencing were used to detect disease-causing variants, complemented by RNA analyses for intronic variants. Protein and gene expressions were studied by immunofluorescence staining and real-time reverse transcriptase quantitative polymerase chain reaction analyses.
RESULTS: Biallelic variants in CELSR1 (n = 5) or likely FZD6 (n = 1), both core molecules in the Wnt/planar cell polarity (PCP) pathway, were identified in all patients with cYNS; none of the patients with sYNS had candidate genetic variants. Immunofluorescence staining showed that CELSR1 colocalizes with lymphatic vessels in the skin but not in the lungs or the intestine. Moreover, levels of CELSR1 and FZD6 proteins were negligible to zero in patient tissues (n = 2) compared with control tissues. Gene expression of Wnt/PCP-related genes was reduced in patients with cYNS (n = 3), and patients with sYNS (n = 4) showed milder gene expression impairments.
LIMITATION: Small cohort size and limited sample availability.
CONCLUSION: Defects in PCP organization may play a major role in the pathogenesis of YNS. To the authors' knowledge, this is the first demonstration of a mechanism explaining YNS development, mainly in its congenital form but also in patients with sporadic disease.
PRIMARY FUNDING SOURCE: The Prof. Baum Research Fund of Israel Lung Association.