Connexin channels in congenital skin disorders

Lilly, Evelyn; Sellitto, Caterina; Milstone, Leonard M.; White, Thomas W.

doi:10.1016/j.semcdb.2015.11.018

Cited by 68 publications

(93 citation statements)

References 104 publications

(121 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…; Sanchez and Verselis ; Levit and White ; Lilly et al. ). Our data now provide an alternative or additional potential hypothesis – that the loss of CO 2 ‐dependent modulation of hemichannel gating could contribute to pathology, at least for some mutations of Cx26.…”

Section: Discussionmentioning

confidence: 99%

Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro

et al. 2016

View full text Add to dashboard Cite

Connexin26 (Cx26) mutations underlie human pathologies ranging from hearing loss to keratitis ichthyosis deafness (KID) syndrome. Cx26 hemichannels are directly gated by CO 2 and contribute to the chemosensory regulation of breathing. The KID syndrome mutation A88V is insensitive to CO 2, and has a dominant negative action on the CO 2 sensitivity of Cx26WT hemichannels, and reduces respiratory drive in humans. We have now examined the effect of further human mutations of Cx26 on its sensitivity to CO 2 . Mutated Cx26 subunits, carrying one of A88S, N14K, N14Y, M34T, or V84L, were transiently expressed in HeLa cells. The CO 2‐dependence of hemichannel activity, and their ability to exert dominant negative actions on cells stably expressing Cx26WT, was quantified by a dye‐loading assay. The KID syndrome mutation, N14K, abolished the sensitivity of Cx26 to CO 2. Both N14Y and N14K exerted a powerful dominant negative action on the CO 2 sensitivity of Cx26WT. None of the other mutations (all recessive) had a dominant negative action. A88S shifted the affinity of Cx26 to slightly higher levels without reducing its ability to fully open to CO 2. M34T did not change the affinity of Cx26 for CO 2 but reduced its ability to open in response to CO 2. V84L had no effect on the CO 2‐sensitivity of Cx26. Some pathological mutations of Cx26 can therefore alter the CO 2 sensitivity of Cx26 hemichannels. The loss of CO 2 sensitivity could contribute to pathology and consequent reduced respiratory drive could be an unrecognized comorbidity of these pathologies.

show abstract

Section: Discussionmentioning

confidence: 99%

Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In 2015, Wang et al . identified a heterozygous mutation in the gap junction protein alpha 1 ( GJA1 ) gene, encoding connexin 43 (Cx43), in two unrelated patients suffering from KHLS. Cx43 is important in gap junction channel formation and allows intercellular passage of small molecules and ions.…”

Section: Complex Palmoplantar Keratodermasmentioning

confidence: 99%

Hereditary palmoplantar keratodermas. Part I. Non‐syndromic palmoplantar keratodermas: classification, clinical and genetic features

Guerra

Castori

Didona

et al. 2018

Acad Dermatol Venereol

View full text Add to dashboard Cite

The term palmoplantar keratoderma (PPK) indicates any form of persistent thickening of the epidermis of palms and soles and includes genetic as well as acquired conditions. We review the nosology of hereditary PPKs that comprise an increasing number of entities with different prognoses, and a multitude of associated cutaneous and extracutaneous features. On the basis of the phenotypic consequences of the underlying genetic defect, hereditary PPKs may be divided into the following: (i) non-syndromic, isolated PPKs, which are characterized by a unique or predominant palmoplantar involvement; (ii) non-syndromic PPKs with additional distinctive cutaneous and adnexal manifestations, here named complex PPKs; (iii) syndromic PPKs, in which PPK is associated with specific extracutaneous manifestations. To date, the diagnosis of the different hereditary PPKs is based mainly on clinical history and features combined with histopathological findings. In recent years, the exponentially increasing use of next-generation sequencing technologies has led to the identification of several novel disease genes, and thus substantially contributed to elucidate the molecular basis of such a heterogeneous group of disorders. Here, we focus on hereditary non-syndromic isolated and complex PPKs. Syndromic PPKs are reviewed in the second part of this 2-part article, where other well-defined genetic diseases, which may present PPK among their phenotypic manifestations, are also listed and diagnostic and therapeutic approaches for PPKs are summarized.

show abstract

“…PPKs associated with deafness are mostly due to mutations in GJB2 , encoding the gap junction protein connexin‐26 (Cx26) (Table ), which is widely expressed in several body tissues and, in particular, in the epithelia of skin, cochlea and cornea. Cx26 has an important role in gap junction formation and function.…”

Section: Syndromic Palmoplantar Keratodermasmentioning

confidence: 99%

Hereditary palmoplantar keratodermas. Part II: syndromic palmoplantar keratodermas – Diagnostic algorithm and principles of therapy

Guerra

Castori²,

Didona

et al. 2018

Acad Dermatol Venereol

View full text Add to dashboard Cite

Hereditary palmoplantar keratodermas (PPKs) comprise a large and heterogeneous group of disorders characterized by persistent thickening of the epidermis at palmar and plantar surfaces. Clinical and genetic features of isolated and complex PPKs have been reviewed in part I of this 2-part review. Here we focus on clinical and molecular classification of syndromic PPKs which are recognized by additional extracutaneous manifestations, in particular deafness, specific mucosal lesions, cardiomyopathy, inborn errors of metabolism, involvement of internal organs or disorders of sexual development. Other genetic diseases, which may show palmoplantar involvement, such as selected subtypes of hereditary epidermolysis bullosa, various hereditary ichthyoses and other keratinization disorders, several ectodermal dysplasias and some multisystem genetic disorders, are also briefly summarized. PPK diagnosis is based on inheritance pattern, age at onset, morphology, distribution and severity of hyperkeratosis, pattern of additional dermatological and systemic manifestations and laboratory findings. Molecular analysis is at present the gold standard to confirm the diagnosis in PPK forms due to mutations in known causative genes. No specific and curative therapy is currently available for PPKs which highly impair patients' quality of life. Topical treatments are symptomatic and offer only temporary relief. Among systemic treatments, retinoids improve disease symptoms in the majority of patients.

show abstract

Connexin channels in congenital skin disorders

Cited by 68 publications

References 104 publications

Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro

Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro

Hereditary palmoplantar keratodermas. Part I. Non‐syndromic palmoplantar keratodermas: classification, clinical and genetic features

Hereditary palmoplantar keratodermas. Part II: syndromic palmoplantar keratodermas – Diagnostic algorithm and principles of therapy

Contact Info

Product

Resources

About

Connexin channels in congenital skin disorders

Cited by 68 publications

References 104 publications

Altered CO2 sensitivity of connexin26 mutant hemichannels in vitro

Altered CO2 sensitivity of connexin26 mutant hemichannels in vitro

Hereditary palmoplantar keratodermas. Part I. Non‐syndromic palmoplantar keratodermas: classification, clinical and genetic features

Hereditary palmoplantar keratodermas. Part II: syndromic palmoplantar keratodermas – Diagnostic algorithm and principles of therapy

Contact Info

Product

Resources

About

Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro

Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro