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A novel variant in the GJB6 gene in a large Chinese family with a unique phenotype of Clouston syndrome

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Abstract

Clouston syndrome (OMIM #129500), also known as hidrotic ectodermal dysplasia type 2, is a rare autosomal dominant skin disorder. To date, four mutations in the GJB6 gene, G11R, V37E, A88V, and D50N, have been confirmed to cause this condition. In previous studies, the focus has been mainly on gene sequencing, and there has been a lack of research on clinical manifestations and pathogenesis. To confirm the diagnosis of this pedigree at the molecular level and summarize and analyse the clinical phenotype of patients and to provide a basis for further study of the pathogenesis of the disease, we performed whole-exome and Sanger sequencing on a large Chinese Clouston syndrome pedigree. Detailed clinical examination included histopathology, hair microscopy, and scanning electron microscopy. We found a novel heterozygous missense variant (c.134G>C:p.G45A) for Clouston syndrome. We identified a new clinical phenotype involving all nail needling pain in all patients and found a special honeycomb hole structure in the patients’ hair under scanning electron microscopy. Our data reveal that a novel variant (c.134G>C:p.G45A) plays a likely pathogenic role in this pedigree and highlight that genetic testing is necessary for the diagnosis of Clouston syndrome.

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References

  1. Clouston HR. The major forms of hereditary ectodermal dysplasia: with an autopsy and biopsies on the anhydrotic type. Can Med Assoc J 1939; 40(1): 1–7

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Zhang XJ, Chen JJ, Yang S, Cui Y, Xiong XY, He PP, Dong PL, Xu SJ, Li YB, Zhou Q, Wang Y, Huang W. A mutation in the connexin 30 gene in Chinese Han patients with hidrotic ectodermal dysplasia. J Dermatol Sci 2003; 32(1): 11–17

    Article  PubMed  Google Scholar 

  3. Sugiura K, Teranishi M, Matsumoto Y, Akiyama M. Clouston syndrome with heterozygous GJB6 mutation p.Ala88Val and GJB2 variant p.Val27Ile revealing mild sensorineural hearing loss and photophobia. JAMA Dermatol 2013; 149(11): 1350–1351

    Article  PubMed  Google Scholar 

  4. Yildirim M, Yorgancilar E, Gun R, Topcu I. Ectodermal dysplasia: otolaryngologic evaluation of 23 cases. Ear Nose Throat J 2012; 91(2): E28–E33

    Article  PubMed  Google Scholar 

  5. Clouston HR. A hereditary ectodermal dystrophy. Can Med Assoc J 1929; 21(1): 18–31

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Taylor TD, Hayflick SJ, McKinnon W, Guttmacher AE, Hovnanian A, Litt M, Zonana J. Confirmation of linkage of Clouston syndrome (hidrotic ectodermal dysplasia) to 13q11–q12.1 with evidence for multiple independent mutations. J Invest Dermatol 1998; 111(1): 83–85

    Article  CAS  PubMed  Google Scholar 

  7. Lamartine J, Munhoz Essenfelder G, Kibar Z, Lanneluc I, Callouet E, Laoudj D, Lemaître G, Hand C, Hayflick SJ, Zonana J, Antonarakis S, Radhakrishna U, Kelsell DP, Christianson AL, Pitaval A, Der Kaloustian V, Fraser C, Blanchet-Bardon C, Rouleau GA, Waksman G. Mutations in GJB6 cause hidrotic ectodermal dysplasia. Nat Genet 2000; 26(2): 142–144

    Article  CAS  PubMed  Google Scholar 

  8. Smith FJ, Morley SM, McLean WH. A novel connexin 30 mutation in Clouston syndrome. J Invest Dermatol 2002; 118(3): 530–532

    Article  CAS  PubMed  Google Scholar 

  9. Baris HN, Zlotogorski A, Peretz-Amit G, Doviner V, Shohat M, Reznik-Wolf H, Pras E. A novel GJB6 missense mutation in hidrotic ectodermal dysplasia 2 (Clouston syndrome) broadens its genotypic basis. Br J Dermatol 2008; 159(6): 1373–1376

    Article  CAS  PubMed  Google Scholar 

  10. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17(5): 405–424

    Article  PubMed  PubMed Central  Google Scholar 

  11. Grifa A, Wagner CA, D’Ambrosio L, Melchionda S, Bernardi F, Lopez-Bigas N, Rabionet R, Arbones M, Monica MD, Estivill X, Zelante L, Lang F, Gasparini P. Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus. Nat Genet 1999; 23(1): 16–18

    Article  CAS  PubMed  Google Scholar 

  12. Fujimoto A, Kurban M, Nakamura M, Farooq M, Fujikawa H, Kibbi AG, Ito M, Dahdah M, Matta M, Diab H, Shimomura Y. GJB6, of which mutations underlie Clouston syndrome, is a potential direct target gene of p63. J Dermatol Sci 2013; 69(2): 159–166

    Article  CAS  PubMed  Google Scholar 

  13. Retamal MA, García IE, Pinto BI, Pupo A, Báez D, Stehberg J, Del Rio R, González C. Extracellular cysteine in connexins: role as redox sensors. Front Physiol 2016; 7: 1

    Article  PubMed  PubMed Central  Google Scholar 

  14. Salat-Canela C, Muñoz MJ, Sesé M, Ramón y Cajal S, Aasen T. Post-transcriptional regulation of connexins. Biochem Soc Trans 2015; 43(3): 465–470

    Article  CAS  PubMed  Google Scholar 

  15. Bosen F, Schütz M, Beinhauer A, Strenzke N, Franz T, Willecke K. The Clouston syndrome mutation connexin30 A88V leads to hyperproliferation of sebaceous glands and hearing impairments in mice. FEBS Lett 2014; 588(9): 1795–1801

    Article  CAS  PubMed  Google Scholar 

  16. Zhan Y, Luo S, Pi Z, Zhang G. A recurrent mutation of GJB6 in a big Chinese family with hidrotic ectodermal dysplasia. Hereditas 2020; 157(1): 34

    Article  PubMed  PubMed Central  Google Scholar 

  17. Yang R, Hu Z, Kong Q, Li W, Zhang L, Du X, Huang S, Xia X, Sang H. A known mutation in GJB6 in a large Chinese family with hidrotic ectodermal dysplasia. J Eur Acad Dermatol Venereol 2016; 30(8): 1362–1365

    Article  CAS  PubMed  Google Scholar 

  18. Chen N, Xu C, Han B, Wang ZY, Song YL, Li S, Zhang RL, Pan CM, Zhang L. G11R mutation in GJB6 gene causes hidrotic ectodermal dysplasia involving only hair and nails in a Chinese family. J Dermatol 2010; 37(6): 559–561

    Article  CAS  PubMed  Google Scholar 

  19. Kovacs JA, Baker KA, Altenberg GA, Abagyan R, Yeager M. Molecular modeling and mutagenesis of gap junction channels. Prog Biophys Mol Biol 2007; 94(1–2): 15–28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Essenfelder GM, Bruzzone R, Lamartine J, Charollais A, Blanchet-Bardon C, Barbe MT, Meda P, Waksman G. Connexin30 mutations responsible for hidrotic ectodermal dysplasia cause abnormal hemichannel activity. Hum Mol Genet 2004; 13(16): 1703–1714

    Article  CAS  PubMed  Google Scholar 

  21. Kantaputra P, Intachai W, Kawasaki K, Ohazama A, Carlson B, Quarto N, Pruksachatkun C, Chuamanochan M. Clouston syndrome with pili canaliculi, pili torti, overgrown hyponychium, onycholysis, taurodontism and absence of palmoplantar keratoderma. J Dermatol 2020; 47(6): e230–e232

  22. Kantaputra PN, Intachai W, Carlson BM, Pruksachatkunakorn C. Clouston syndrome with dental anomalies, micropores of hair shafts and absence of palmoplantar keratoderma. J Dermatol 2020; 47(3): e90–e91

    Article  PubMed  Google Scholar 

  23. Essenfelder GM, Larderet G, Waksman G, Lamartine J. Gene structure and promoter analysis of the human GJB6 gene encoding connexin 30. Gene 2005; 350(1): 33–40

    Article  CAS  PubMed  Google Scholar 

  24. van Steensel MA, Jonkman MF, van Geel M, Steijlen PM, McLean WH, Smith FJ. Clouston syndrome can mimic pachyonychia congenita. J Invest Dermatol 2003; 121(5): 1035–1038

    Article  CAS  PubMed  Google Scholar 

  25. Mousumi T, Xiong Z, Lu L, Liu S, Xia K, Hu Z. Identification of a known GJB6 mutation in an autosomal dominant inherited Chinese family with hidrotic ectodermal dysplasia. J Central South Univ (Med Sci) (Zhong Nan Da Xue Xue Bao Yi Xue Ban) 2013; 38(8): 761–765 (in Chinese)

    Google Scholar 

  26. Qiao WX, Liu L. A gene study of a family with hidrotic ectodermal dysplasia. Chin J Contemp Pediatr (Zhongguo Dang Dai Er Ke Za Zhi) 2016; 18(11): 1141–1144 (in Chinese)

    Google Scholar 

  27. Odell ID, Lilly E, Reeve K, Bosenberg MW, Milstone LM. Well-differentiated syringofibrocarcinoma in a patient with Clouston syndrome. JAMA Dermatol 2016; 152(4): 484–486

    Article  PubMed  Google Scholar 

  28. Agarwal N, Singh PK, Gupta K, Gupta N, Kabra M. Identification of GJB6 gene mutation in an Indian man with Clouston syndrome. Indian J Dermatol Venereol Leprol 2016; 82(6): 697–700

    Article  PubMed  Google Scholar 

  29. Hu YH, Lin YC, Hwu WL, Lee YM. Pincer nail deformity as the main manifestation of Clouston syndrome. Br J Dermatol 2015; 173(2): 581–583

    Article  PubMed  Google Scholar 

  30. Cammarata-Scalisi F, Rinelli M, Pisaneschi E, Diociaiuti A, Willoughby CE, Avendaño A, Digilio MC, Novelli A, Callea M. Novel clinical features associated with Clouston syndrome. Int J Dermatol 2019; 58(8): e143–e146

    Article  PubMed  Google Scholar 

  31. Marakhonov A, Skoblov M, Galkina V, Zinchenko R. Clouston syndrome: first case in Russia. Balkan J Med Genet 2012; 15(1): 51–54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the individuals who participated in this project, and the patients in this study who provided written informed consent for the publication of their case details. This study was funded by Anhui Provincial Quality Engineering Project of Higher Education Institutions (No. 2020jyxm0922), Natural Science Research Project of Higher Education Department of Anhui Province (No. KJ2021A0284), Fund of Anhui Provincial Institute of Translational Medicine (No.2021zhyx-C31), and Research Foundation of Anhui Medical University (No. 2020xkj154).

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Dermatology and Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, 230000, China

    Hequn Huang, Mengyun Chen & Bo Liang

  2. Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, 230000, China

    Hequn Huang, Mengyun Chen & Bo Liang

  3. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230000, China

    Hequn Huang, Mengyun Chen & Bo Liang

  4. Huai’an District Skin Disease Prevention and Treatment Hospital, Huai’an, 223000, China

    Xia Liu

  5. Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China

    Xixi Xiong, Lanbo Zhou, Zhonglan Su & Yan Lu

  6. Department of Clinical Laboratory, The First Affiliated Hospital, Anhui Medical University, Hefei, 230000, China

    Bo Liang

Authors
  1. Hequn Huang
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  2. Mengyun Chen
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  3. Xia Liu
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  7. Yan Lu
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Corresponding authors

Correspondence to Yan Lu or Bo Liang.

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Hequn Huang, Mengyun Chen, Xia Liu, Xixi Xiong, Lanbo Zhou, Zhonglan Su, Yan Lu, and Bo Liang declare that they have no conflicts of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for inclusion in the study.

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Huang, H., Chen, M., Liu, X. et al. A novel variant in the GJB6 gene in a large Chinese family with a unique phenotype of Clouston syndrome. Front. Med. 17, 330–338 (2023). https://doi.org/10.1007/s11684-022-0933-2

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  • DOI: https://doi.org/10.1007/s11684-022-0933-2

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