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, Hagit Baris Feldman
{"title":"黄指甲综合征中Wnt/平面细胞极性信号通路受损。","authors":"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, Hagit Baris Feldman","doi":"10.7326/ANNALS-24-01101","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>To elucidate the genetic mechanisms underlying YNS.</p><p><strong>Design: </strong>Analysis of genetic sequencing data and gene and protein expression studies.</p><p><strong>Setting: </strong>A tertiary care academic medical center.</p><p><strong>Patients: </strong>6 patients with congenital YNS (cYNS) and 5 with sporadic YNS (sYNS).</p><p><strong>Measurements: </strong>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.</p><p><strong>Results: </strong>Biallelic variants in <i>CELSR1</i> (<i>n</i> = 5) or likely <i>FZD6</i> (<i>n</i> = 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 (<i>n</i> = 2) compared with control tissues. Gene expression of Wnt/PCP-related genes was reduced in patients with cYNS (<i>n</i> = 3), and patients with sYNS (<i>n</i> = 4) showed milder gene expression impairments.</p><p><strong>Limitation: </strong>Small cohort size and limited sample availability.</p><p><strong>Conclusion: </strong>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.</p><p><strong>Primary funding source: </strong>The Prof. Baum Research Fund of Israel Lung Association.</p>","PeriodicalId":7932,"journal":{"name":"Annals of Internal Medicine","volume":" ","pages":"39-49"},"PeriodicalIF":19.6000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Impaired Wnt/Planar Cell Polarity Signaling in Yellow Nail Syndrome.\",\"authors\":\"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, Hagit Baris Feldman\",\"doi\":\"10.7326/ANNALS-24-01101\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>To elucidate the genetic mechanisms underlying YNS.</p><p><strong>Design: </strong>Analysis of genetic sequencing data and gene and protein expression studies.</p><p><strong>Setting: </strong>A tertiary care academic medical center.</p><p><strong>Patients: </strong>6 patients with congenital YNS (cYNS) and 5 with sporadic YNS (sYNS).</p><p><strong>Measurements: </strong>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.</p><p><strong>Results: </strong>Biallelic variants in <i>CELSR1</i> (<i>n</i> = 5) or likely <i>FZD6</i> (<i>n</i> = 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 (<i>n</i> = 2) compared with control tissues. Gene expression of Wnt/PCP-related genes was reduced in patients with cYNS (<i>n</i> = 3), and patients with sYNS (<i>n</i> = 4) showed milder gene expression impairments.</p><p><strong>Limitation: </strong>Small cohort size and limited sample availability.</p><p><strong>Conclusion: </strong>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.</p><p><strong>Primary funding source: </strong>The Prof. Baum Research Fund of Israel Lung Association.</p>\",\"PeriodicalId\":7932,\"journal\":{\"name\":\"Annals of Internal Medicine\",\"volume\":\" \",\"pages\":\"39-49\"},\"PeriodicalIF\":19.6000,\"publicationDate\":\"2025-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of Internal Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.7326/ANNALS-24-01101\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/12/24 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, GENERAL & INTERNAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Internal Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7326/ANNALS-24-01101","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/12/24 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICINE, GENERAL & INTERNAL","Score":null,"Total":0}
Impaired Wnt/Planar Cell Polarity Signaling in Yellow Nail Syndrome.
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.
期刊介绍：
Established in 1927 by the American College of Physicians (ACP), Annals of Internal Medicine is the premier internal medicine journal. Annals of Internal Medicine’s mission is to promote excellence in medicine, enable physicians and other health care professionals to be well informed members of the medical community and society, advance standards in the conduct and reporting of medical research, and contribute to improving the health of people worldwide. To achieve this mission, the journal publishes a wide variety of original research, review articles, practice guidelines, and commentary relevant to clinical practice, health care delivery, public health, health care policy, medical education, ethics, and research methodology. In addition, the journal publishes personal narratives that convey the feeling and the art of medicine.
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