Gap 26

Closing the gap on autosomal dominant connexin-26 and connexin-43 mutants linked to human disease

Cells within the vast majority of human tissues communicate directly through clustered arrays of intercellular channels called gap junctions. Gene ablation studies in mouse models have revealed that these intercellular channels are necessary for a variety of organ functions and that some of these genes are essential for survival. Molecular genetics has uncovered that germ line mutations in nearly half of the genes that encode the 21-member connexin family of gap junction proteins are linked to one or more human diseases. Frequently, these mutations are autosomal recessive, whereas in other cases, autosomal dominant mutations manifest as disease. Given the broad and overlapping distribution of connexins in a wide arrangement of tissues, it is hard to predict where connexin-linked diseases will clinically manifest. For instance, the most prevalent connexin in the human body is connexin-43 (Cx43), yet autosomal dominant mutations in the GJA1 gene, which encodes Cx43, exhibit modest developmental disorders resulting in a disease termed oculodentodigital dysplasia. Autosomal recessive mutations in the gene encoding Cx26 result in moderate to severe sensorineural hearing loss, whereas autosomal dominant mutations produce hearing loss and a wide range of skin diseases, including palmoplantar keratoderma. Here, we will focus on autosomal dominant mutations of the genes encoding Cx26 and Cx43 in relation to models that link genotypes to phenotypic outcomes with particular reference to how these approaches provide insight into human disease.

Actin-independent trafficking of cochlear connexin 26 to non-lipid raft gap junction plaques

Hereditary hearing loss affects about 1 per 1000 children. Mutations in GJB2, which encodes the connexin 26 protein (Cx26) involved in cochlear homeostasis, are found in about 50% of patients with autosomal recessive non-syndromic hearing loss. Deciphering the trafficking pathway of cochlear Cx26 in situ should represent an advance in understanding the pathogenic significance of many of these mutations. Connexins trafficking and delivery to lipid raft-associated gap junction plaques usually requires successively microtubule and actin networks. Here we show that cochlear Cx26 exhibits an unusual trafficking pathway. We observed that Cx26 assembly occurs in non-lipid raft membrane domains and that junctional plaques are devoid of actin and associated zonula occludens proteins. Using cytoskeleton-disrupting drugs in organotypic culture, we found that cochlear Cx26 gap junction assembly requires microtubules but not actin filaments. Altogether, our data provide an unexpected insight into Cx26 trafficking pathway and gap junction assembly in the cochlea.

The role of parenthood in shaping the gender wage gap - A comparative analysis of 26 European countries

We use cross-national data on 26 EU countries to estimate how parenthood contributes to the gender wage gap, and assess how institutional elements affect this relationship. We find that irrespective of cultural norms and policies, fathers receive a wage premium, which increases the gender gap. Motherhood gaps vary across countries. The highest gaps are seen in Eastern European countries, where policies and norms lead to long absences from work. Moderate to small penalties are found in Continental Europe, Anglo-Saxon and Nordic countries, alongside higher maternal employment. No motherhood penalties are found for Southern EU countries, where mothers return to work quickly or exit the labor market indefinitely.

(Na0.74 Ag1.26 )BaSnS4 : A New AgGaS2 -Type Nonlinear Optical Sulfide with a Wide Band Gap and High Laser Induced Damage Threshold

The development of high-power solid-state lasers is in urgent need of infrared (IR) nonlinear optical (NLO) materials with wide band gaps and high laser-induced damage thresholds (LIDTs). Herein, a new compressed chalcopyrite-like IR NLO crystal (Na_0.74 Ag_1.26 )BaSnS₄ was successfully synthesized using a facile high-temperature solid-state method. Its structure can be considered as a variant of chalcopyrite AgGaS₂ (AGS)-type ones. It features a three-dimensional framework constructed by corner-sharing {[(Na/Ag)S₄ ]^7- }_∞ layers and isolated SnS₄ tetrahedra with negative cavities occupied by counter ion Ba²⁺ . (Na_0.74 Ag_1.26 )BaSnS₄ exhibits phase-matchable moderate SHG response (0.31 × AGS), wide band gap (3.70 eV), and high LIDT (6.44 × AGS). Theoretical calculations reveal that the NLO response of (Na_0.74 Ag_1.26 )BaSnS₄ is mainly originated from the synergetic effects of AgS₄ and SnS₄ tetrahedra, and the inclusion of alkaline and alkaline earth metals is responsible for the wide band gap and high LIDT. Moreover, the discovery of this chalcopyrite-like compound will provide a feasible design strategy for the exploration of new promising IR NLO materials.

Gap junctions and connexins in the inner ear: their roles in homeostasis and deafness

Purpose of review: Mutations in GJB2 and GJB6, the genes encoding the gap-junction proteins connexin 26 and connexin 30, are the most common cause of autosomal recessive nonsyndromic deafness in many populations across the world. In this review, we discuss current ideas about the roles of gap junctions in the inner ear and the implications of connexin mutations on auditory function.
Recent findings: In recent years, a complex picture of the roles of gap junctions in cochlear physiology emerged. Rather than being mere conduits for the circulation of potassium ions in the inner ear, gap junctions have been implicated in intercellular signaling among nonsensory cells and may be involved in the maintenance of the endothelial barrier in the stria vascularis. Studies of mutant channels and mouse models for connexin-related deafness have provided valuable insights into some of the mechanisms by which connexin dysfunction causes cochlear degeneration. They have also identified potential therapeutic interventions for specific connexin mutations, such as the restoration of normal connexin 26 protein levels in GJB6-associated deafness.
Summary: Despite recent advances, a better understanding of the complexity of gap-junctional communication in the inner ear and the structure-function relationships of connexin proteins is required for the development of mechanism-based treatments of connexin-associated hearing loss.