Does epidermal thickening explain GJB2 high carrier frequency and heterozygote advantage?

D’Adamo, Pio; Guerci, Veronica Ileana; Fabretto, Antonella; Faletra, Flavio; Grasso, Domenico Leonardo; Ronfani, Luca; Montico, Marcella; Morgutti, Marcello; Guastalla, Pierpaolo; Gasparini, Paolo

doi:10.1038/ejhg.2008.225

Cited by 30 publications

(22 citation statements)

References 13 publications

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“…So, we expect a large number of normal-hearing 35delG carriers in the general population based on two reasons: first, Romanians are settling in Southeast Europe; second, the Caucasian origin of Romanian people. The 35delG carriers keep the mutation in the population because of the heterozygous advantage (D'Adamo et al, 2009). We detected 11 carriers among 350 analyzed samples, the carrier rate being calculated as 1 in 35 or *3.14%.…”

Section: Discussionmentioning

confidence: 99%

Prenatal Screening for the35delG GJB2, Del (GJB6-D13S1830), and Del (GJB6-D13S1854) Mutations in the Romanian Population

Dragomir¹,

Stan²,

Stefanescu³

et al. 2011

Genetic Testing and Molecular Biomarkers

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Section: Discussionmentioning

confidence: 99%

Prenatal Screening for the35delG GJB2, Del (GJB6-D13S1830), and Del (GJB6-D13S1854) Mutations in the Romanian Population

Dragomir¹,

Stan²,

Stefanescu³

et al. 2011

Genetic Testing and Molecular Biomarkers

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“…However, another possibility that has been proposed is that these mutations could confer some selective advantage [13]. 35delG and R75W carriers have been reported to have a thicker epidermis [30, 31], with the latter heterozygotes also showing higher sweat salinity. These phenotypes may confer a higher resistance to injury or microbial infection.…”

Section: Connexin Phenotypes Affecting the Ear And Epidermismentioning

confidence: 99%

The role of connexins in ear and skin physiology — Functional insights from disease-associated mutations

Nicholson

2013

Biochimica et Biophysica Acta (BBA) - Biomembranes

115

123

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Defects in several different connexins have been associated with several different diseases. The most common of these is deafness, where a few mutations in connexin (Cx) 26 have been found to contribute to over 50% of the incidence of non-syndromic deafness in different human populations. Other mutations in Cx26 or Cx30 have also been associated with various skin phenotypes linked to deafness (PPK, BPS, VS, KID, etc.). The large array of disease mutants offer unique opportunities to gain insights into the underlying function of gap junction proteins and their channels in the normal and pathogenic physiology of the cochlea and epidermis. This review focuses on those mutants where the impact on channel function has been assessed, and correlated with the disease phenotype, or organ function in knock-out mouse models. These approaches have provided evidence supporting a role of gap junctions and hemichannels in K+ removal and recycling in the ear, as well as possible roles for nutrient passage, in the cochlea. In contrast, increases in hemichannel opening leading to increased cell death, was associated with several KID skin disease/hearing mutants. In addition to providing clues for therapeutic strategies, these findings allow us to better understand the specific functions of connexin channels that are important for normal tissue function.

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“…For example, the V84L mutation found in recessive non-syndromic deafness forms channels with similar gross unitary channel conductance to wild-type Cx26 gap junctions but with deficient permeability to inositol 1,4,5-trisphosphate [58, 59]. Thus, total or partial loss-of-function mutations are responsible for non-syndromic deafness and these patients do not suffer from defective cutaneous wound healing or skin abnormalities [60, 61], other than anecdotal reports of increased epidermal thickness [62, 63]. …”

Section: Connexin26 In Epidermal Pathologymentioning

confidence: 99%

Pathological hemichannels associated with human Cx26 mutations causing Keratitis–Ichthyosis–Deafness syndrome

Levit

Meşe

Basaly

et al. 2012

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Connexin (Cx) proteins form intercellular gap junction channels by first assembling into single membrane hemichannels that then dock to connect the cytoplasm of two adjacent cells. Gap junctions are highly specialized structures that allow the direct passage of small molecules between cells to maintain tissue homeostasis. Functional activity of nonjunctional hemichannels has now been shown in several experimental systems. Hemichannels may constitute an important diffusional exchange pathway with the extracellular space, but the extent of their normal physiological role is currently unknown. Aberrant hemichannel activity has been linked to mutations of connexin proteins involved in genetic diseases. Here, we review a proposed role for hemichannels in the pathogenesis of Keratitis-Ichthyosis-Deafness (KID) syndrome associated with connexin26 (Cx26) mutations. Continued functional evaluation of mutated hemichannels linked to human hereditary disorders may provide additional insights into the mechanisms governing their regulation in normal physiology and dysregulation in disease.

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Does epidermal thickening explain GJB2 high carrier frequency and heterozygote advantage?

Abstract: Normal controls CarriersMean Min Max SD± Mean Min Max SD±

Cited by 30 publications

References 13 publications

Prenatal Screening for the35delG GJB2, Del (GJB6-D13S1830), and Del (GJB6-D13S1854) Mutations in the Romanian Population

Prenatal Screening for the35delG GJB2, Del (GJB6-D13S1830), and Del (GJB6-D13S1854) Mutations in the Romanian Population

The role of connexins in ear and skin physiology — Functional insights from disease-associated mutations

Pathological hemichannels associated with human Cx26 mutations causing Keratitis–Ichthyosis–Deafness syndrome

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