View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector COMMENTARY See related article on pg 1540 translocated into the plasma membrane. Once expressed on the cell surface, the hemichannel docks with a connexon of an adjacent cell to form a channel that Erythrokeratodermia Variabilis et is termed gap junction. Connexons can form either homotypic (docking of two Progressiva Allelic to Oculo-Dento- identical connexons), heterotypic (docking of two dissimilar homomeric Digital Dysplasia connexons), or heteromeric (docking of two heteromeric connexons) channels Sabine Duchatelet1,2 and Alain Hovnanian1,2,3 (Mese et al., 2007). These diverse Erythrokeratodermia variabilis et progressiva (EKVP) is a genodermatosis with combinations of connexins create clinical and genetic heterogeneity, most often transmitted in an autosomal different types of channels, each having dominant manner, caused by mutations in GJB3 and GJB4 genes encoding unique properties (ionic conductance, connexins (Cx)31 and 30.3, respectively. In this issue, Boyden et al. (2015) report permeability, sensitivity to voltage, or for the first time de novo dominant mutations in GJA1 encoding the ubiquitous pH). Of note, several connexins may also Cx43 in patients with EKVP. These results expand the genetic heterogeneity of form functional nonjunctional hemi- EKVP and the human disease phenotypes associated with GJA1 mutations. They channels, although their physiological disclose that EKVP is allelic to oculo-dento-digital dysplasia, a rare syndrome relevance remains uncertain (Pfenniger previously known to be caused by dominant GJA1 mutations. et al., 2010). Mutations in 11 connexin genes cause a variety of genetic dis- Journal of Investigative Dermatology (2015) 135, 1475–1478. doi:10.1038/jid.2014.535 orders, implicating a key role in tissue homeostasis (Lai-Cheong et al., 2007). Mutations in connexins have been Clinical features of EKVP clinical heterogeneity of the disease. associated with deafness, neuropathy, EKVP (MIM 133200) is characterized by EKVP is usually inherited as an auto- and various skin phenotypes. Several the co-existence of localized or general- somal dominant trait, but rare auto- genodermatosis have been shown to be ized hyperkeratotic plaques back- somal recessive transmission has also caused by mutations in genes encoding ground and transient stationary or been reported (Gottfried et al., 2002; connexin (Cx)26, 30, 30.3, 31, and more migratory erythematous plaques Fuchs-Telem et al., 2011). rarely Cx43 (Mese et al., 2007). Speci- (Macfarlane et al., 1991). The hallmark fically, mutations in GJB2 encoding of EKVP is the continual occurrence of Connexins and genetic skin diseases Cx26 can lead to the Vohwinkel transient, sharply outlined, figurate red Gap junctions are transmembrane com- syndrome (mutilating PPK associated patches of variable intensity that fade plexes that permit the rapid exchange of with honeycomb-like keratoderma and within a few hours or days. Approxi- ions, secondary messengers, and small starfish-like keratoses and deafness, MIM matively 50% of EKVP patients have metabolites between neighboring cells 124500), the keratitis-ichtyosis-deafness palmoplantar keratoderma (PPK). (Mese et al., 2007). They are formed by (KID) syndrome (MIM 148210), the Initially, two separate clinical entities connexins, a multigen family of at least hystrix-like ichthyosis with deafness syn- were distinguished according to the 21 members. Connexin proteins are drome (MIM 602540), PPK associated presence of migratory or stationary named after their molecular mass, and with deafness (MIM 148350), and the erythematous patches, defining erythro- their genes have been classified by Bart-Pumphrey (knuckle pads, leukony- keratodermia variabilis (Mendes da sequence similarities, defining three chia and sensorineural deafness) syn- Costa, 1925) and progressive sym- main groups––gap junction α (GJA), β γ drome (MIM 149200). Mutations in GJB6 metric erythrokeratodermia (Gottron, (GJB), and (GJC). Connexins consist of encoding Cx30 cause the Clouston 1922), respectively. The observation of four transmembrane domains with syndrome (Hidrotic ectodermal dyspla- both phenotypes in two sisters disclosed intracellular N- and C-termini. sia, MIM 129500), and mutations in that these two conditions represented, Connexin monomers oligomerize to GJB3 and GJB4, encoding Cx31 and in fact, variable expression of a single hexameric homomeric or heteromeric 30.3, respectively, have been identified inherited clinical entity (Macfarlane hemichannels (also called connexons) in EKVP (Common et al., 2005). et al., 1991). Thus, the designation in the endoplasmic reticulum (ER) and EKVP was proposed to account for the the Golgi apparatus, which are then Clinical and genetic heterogeneity of EKVP 1INSERM UMR 1163, Laboratory of Genetic Skin Diseases, Imagine Institute for Genetic Diseases, Paris, EKVP shows considerable intra- and 2 3 France; University Paris Descartes, Sorbonne Paris Cité, Paris, France and Department of Genetics, Necker interfamilial clinical heterogeneity Enfants Malades Hospital, Paris, France (Common et al., 2005). The clinical Correspondence: Alain Hovnanian, INSERM UMR 1163, Department of Genetics, Laboratory of Genetic Skin Diseases, Imagine Institute for Genetic Diseases, 2nd Floor, 24 bld du Montparnasse, 75015 Paris, variability observed, even in patients France. E-mail: [email protected] from the same family, suggests the www.jidonline.org 1475 COMMENTARY Clinical Implications rarely, GJA1 mutations have been reported in craniometaphyseal dysplasia ● Erythrokeratodermia variabilis et progressiva (EKVP) has been known to and sudden infant death (Laird, 2014). be caused by mutations in GJB3 and GJB4 genes encoding connexin (Cx) Most ODDD mutations are dominant 31 and 30.3, respectively. Boyden et al. (2015) provide evidence that EKVP missense mutations spread through the can also be caused by mutations in GJA1 encoding the ubiquitous first two-thirds of the protein, and more expressed Cx43. rarely in the C-terminal domain (see ● Aside from enlarged porcelain-white lunulae found in the three patients Figure 4 by Boyden et al. 2015) (Laird, with GJA1 mutations, no obvious genotype–phenotype correlation can be 2014). Rare nonsense or small found in EKVP. In particular, EKVP shares no clinical features with oculo- frameshift or inframe indels have also dento-digital dysplasia and shows limited overlap with the keratoderma- been reported. In particular, ODDD hypotrichosis-leukonychia totalis syndrome, both conditions which are mutations associated with palmoplantar also caused by GJA1 mutations. hyperkeratosis were initially identified as ● The co-existence of hyperkeratotic plaques with transient erythematous truncating mutations in the C-terminal fi part of the protein. Subsequent reports plaques and no extra-cutaneous ndings remains the main clinical fi features of EKVP, which allows one to distinguish it from these two allelic described missense mutations in the rst conditions. cytoplasmic loop and the N-terminal part of the molecule. Thus, there is no correlation between the localization or nature of the mutation and the effects of modifier genes, epigenetics, channel with Cx37, 40, and 43 (White development of keratoderma. and/or environmental factors. and Bruzzone, 1996; He et al., 1999; More generally, no specific geno- Heterozygous mutations in GJB3 and Abrams et al., 2006). This expands the type–phenotype correlation has been GJB4 were reported in EKVP patients possibility of distinct functional conse- evidenced in ODDD as individuals (Richard et al., 1998; Macari et al., quences resulting in different hetero- carrying mutations in the same Cx43 2000). They are mainly missense muta- typic or heteromeric gap junctions. domain can exhibit significant differ- tions. Recessive mutations in GJB3 have In this issue, Boyden et al. (2015) ences in clinical features, although rare also been identified in EKVP patients reported the identification, by exome reported recessive mutations lead to (Gottfried et al., 2002; Fuchs-Telem sequencing, dominant de novo muta- more severe phenotypes. et al., 2011). However, some patients tions in GJA1 encoding Cx43 in three Very recently, a GJA1 mutation was do not carry mutations in either gene patients with EKVP. These patients identified in two familial cases and (Richard et al., 2003; Common et al., were not phenotypically different from one sporadic case affected with the 2005). Of note, mutations in GJB3, patients with GJB3 or GJB4 mutations, keratoderma-hypotrichosis-leukonychia expressed in the skin, cochlea, and the although enlarged porcelain-white totalis syndrome (KHLS), a rare disorder peripheral nervous system, also cause lunulae has not been previously characterized by severe skin hyperker- hearing loss or neuropathy associated observed in EKVP. This result expands atosis, congenital alopecia, and leuko- with deafness (Rabionet et al., 2000). EKVP genetic heterogeneity and the nychia totalis, with no additional extra- There is no clear correlation between disease phenotypes associated with cutaneous features (Wang et al., 2014). phenotype and the nature and/or locali- GJA1 mutations, which have been Thus, mutations in GJA1 underlie zation of GJB3 mutations as missense previously identified in oculo-dento- severe skin phenotypes such as KHLS mutations responsible for EKVP or deaf- digital dysplasia (ODDD; see below). and EKVP, as well as, in a less