GJB6 – Clouston syndrome

Clouston syndrome, also known as hidrotic ectodermal dysplasia, is an autosomal dominant disorder characterized by a triad of nail dystrophy, hypotrichosis (alopecia), and palmoplantar hyperkeratosis. The GJB6 gene (encoding connexin 30, Cx30) has been unequivocally implicated in Clouston syndrome, with heterozygous missense mutations leading to disruption of gap-junction communication in ectodermal structures. GJB6 mutations segregate with disease in multiple unrelated pedigrees across diverse ethnicities, and no convincing loss-of-function variants have been found in unaffected controls. Functional studies demonstrate that disease-associated Cx30 mutants impair trafficking and exhibit abnormal hemichannel activity, consistent with a dominant disease mechanism. This summary integrates genetic and experimental evidence to support diagnostic testing and underscores the clinical utility of GJB6 analysis in patients presenting with ectodermal dysplasia features.

1. Clinical validity (ClinGen Definitive)

The association between GJB6 and Clouston syndrome meets Definitive strength: multiple independent reports over >20 years, involving at least six large pedigrees and singleton cases with consistent phenotype, segregation, and functional concordance. Over 98 affected relatives have been documented with segregating heterozygous GJB6 variants across diverse populations (28 patients [PMID:12788524], 1 patient [PMID:11874494], 8 patients [PMID:23981984], 25 patients [PMID:27137747], 24 patients [PMID:32843087], 12 patients [PMID:36926140]). No pathogenic recessive alleles or alternative loci have been convincingly proposed, and all variants occur at highly conserved residues in transmembrane or extracellular domains.

2. Genetic evidence (ClinGen Strong)

Inheritance is autosomal dominant. Segregation analysis across six pedigrees revealed co-segregation of heterozygous GJB6 missense variants in 98 affected relatives with no unaffected carriers. Case reports and series include 28 probands with p.Gly11Arg in a Chinese Han family (c.31G>A (p.Gly11Arg)) [PMID:12788524], 8 probands with p.Gly11Arg in a Chinese familial study (c.31G>C (p.Gly11Arg)) [PMID:23981984], 25 probands with p.Ala88Val in a large Chinese family (c.263C>T (p.Ala88Val)) [PMID:27137747], 24 probands with p.Ala88Val in another Chinese pedigree (c.263C>T (p.Ala88Val)) [PMID:32843087], 12 probands with p.Gly11Arg in a Chinese Han pedigree including functional assays (c.31G>A (p.Gly11Arg)) [PMID:36926140], and a spontaneous V37E case (c.110T>A (p.Val37Glu)) [PMID:11874494]. Four recurrent codons (Gly11, Val37, Asp50, Ala88) define the pathogenic spectrum, with no apparent genotype-phenotype correlation beyond domain localization.

3. Functional evidence (ClinGen Moderate)

In vitro studies in keratinocytes and HeLa cells show that Cx30 missense mutants (p.Gly11Arg, p.Ala88Val) are retained intracellularly, impairing plasma membrane targeting and gap-junction formation [PMID:12419304]. Electrophysiological assays reveal that these mutants form leaky hemichannels with increased ATP release and altered permeability, indicating a gain-of-function mechanism that likely perturbs epidermal differentiation [PMID:15213106]. Expression of mutant Cx30 in mouse models recapitulates key skin and hearing phenotypes, confirming pathogenicity and supporting haploinsufficiency versus dominant-negative effects depending on the variant.

4. Conflicting evidence

No studies have convincingly refuted the GJB6–Clouston syndrome association. The uniform autosomal dominant presentation and absence of pathogenic alleles in controls argue against a benign variant classification.

5. Conclusion and clinical utility

The definitive gene‐disease relationship, robust segregation data, and concordant functional assays establish GJB6 as a critical diagnostic target in patients with nail dystrophy, hypotrichosis, and palmoplantar hyperkeratosis. Clinical genetic testing for GJB6 missense variants, particularly at codons 11, 37, 50, and 88, is recommended for accurate diagnosis, genetic counseling, and prenatal assessment. Key take-home: heterozygous GJB6 missense mutations cause Clouston syndrome via dominant pathogenic mechanisms, and early molecular diagnosis enables targeted management of ectodermal dysplasia.

References

• The Journal of investigative dermatology • 2002 • A novel connexin 30 mutation in Clouston syndrome PMID:11874494
• Journal of dermatological science • 2003 • A mutation in the connexin 30 gene in Chinese Han patients with hidrotic ectodermal dysplasia PMID:12788524
• Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences • 2013 • Identification of a known GJB6 mutation in an autosomal dominant inherited Chinese family with hidrotic ectodermal dysplasia PMID:23981984
• Journal of the European Academy of Dermatology and Venereology : JEADV • 2016 • A known mutation in GJB6 in a large Chinese family with hidrotic ectodermal dysplasia PMID:27137747
• Hereditas • 2020 • A recurrent mutation of GJB6 in a big Chinese family with Hidrotic ectodermal dysplasia PMID:32843087
• World journal of clinical cases • 2023 • Hidrotic ectodermal dysplasia in a Chinese pedigree: A case report PMID:36926140
• Biochemical and biophysical research communications • 2002 • Functional studies of human skin disease- and deafness-associated connexin 30 mutations PMID:12419304
• Human molecular genetics • 2004 • Connexin30 mutations responsible for hidrotic ectodermal dysplasia cause abnormal hemichannel activity PMID:15213106

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