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

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.

Keywords

Clouston syndrome / whole exome sequencing / GJB6 gene / novel variant / unique phenotype

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

[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

[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

[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

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

[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

[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

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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[25] MousumiTXiong ZLuLLiuSXiaK HuZ. 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)

[26] QiaoWXLiu 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)

[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

[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

[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

[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

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

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).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-022-0933-2 and is accessible for authorized users.

Compliance with ethics guidelines

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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