Recent genetic studies have demonstrated the importance of epidermal gap junctions with mutations in four β-connexins associated with autosomal dominant epidermal disease. One of these disorders, ...erythrokeratoderma variabilis, is associated with germline mutations in the genes encoding connexins (Cx) Cx31 and Cx30.3. Towards understanding the functional mechanism of Cx31 mutations in epidermal disease, we have developed and characterized a polyclonal antibody raised against human Cx31. Using this antibody to immunostain normal epidermis, Cx31 protein was found to be expressed predominately in the stratum granulosum with a punctate pattern of staining at the plasma membrane. In addition, we used reverse transcriptase polymerase chain reaction and, where reagents were available, immunocytochemistry to investigate which other connexins are expressed in the epidermis. Surprisingly, this analysis revealed that there are at least 10 connexins expressed with an overlapping distribution and localization to distinct keratinocyte subpopulations. These data provide additional evidence for multiple gap junction channel types in the human epidermis. Elucidation of this complexity of channel types with respect to specific permeabilities and function of each wildtype and mutant channel type in epidermal biology will require further investigations.
Summary
Background
Arrhythmogenic cardiomyopathy (AC) is an inherited, frequently underdiagnosed disorder, which can predispose individuals to sudden cardiac death. Rare, recessive forms of AC can be ...associated with woolly hair and palmoplantar keratoderma, but most autosomal dominant AC forms have been reported to be cardiac specific. Causative mutations frequently occur in desmosomal genes including desmoplakin (DSP).
Objectives
In this study, we systematically investigated the presence of a skin and hair phenotype in heterozygous DSP mutation carriers with AC.
Methods
Six AC pedigrees with 38 carriers of a dominant loss‐of‐function (nonsense or frameshift) mutation in DSP were evaluated by detailed clinical examination (cardiac, hair and skin) and molecular phenotyping.
Results
All carriers with mutations affecting both major DSP isoforms (DSPI and II) were observed to have curly or wavy hair in the pedigrees examined, except for members of Family 6, where the position of the mutation only affected the cardiac‐specific isoform DSPI. A mild palmoplantar keratoderma was also present in many carriers. Sanger sequencing of cDNA from nonlesional carrier skin suggested degradation of the mutant allele. Immunohistochemistry of patient skin demonstrated mislocalization of DSP and other junctional proteins (plakoglobin, connexin 43) in the basal epidermis. However, in Family 6, DSP localization was comparable with control skin.
Conclusions
This study identifies a highly recognizable cutaneous phenotype associated with dominant loss‐of‐function DSPI/II mutations underlying AC. Increased awareness of this phenotype among healthcare workers could facilitate a timely diagnosis of AC in the absence of overt cardiac features.
What's already known about this topic?
The diagnosis of the early phases of arrhythmogenic cardiomyopathy (AC) remains challenging.
AC is linked to mutations in desmosomal genes including desmoplakin (DSP).
Desmosomes have key functions in the heart, skin and hair, highlighted by rare predominantly recessively inherited DSP mutations linked to ‘woolly’ hair, keratoderma and severe cardiomyopathy in childhood.
What does this study add?
The presence of curly hair and keratoderma is likely to be a useful additional clinical identifier of autosomal dominant patients with AC associated with DSPI/II mutations.
Haploinsufficiency is the underlying genetic mechanism.
Immunohistochemistry of patient skin demonstrated mislocalization of DSP and other junctional proteins (plakoglobin, connexin 43) in the basal epidermis.
What is the translational message?
Here, we show that dominant AC‐associated loss‐of‐function DSP mutations can also be linked to curly hair and mild palmoplantar keratoderma.
These cutaneous features could therefore provide clinical clues enabling early diagnosis and directed family screening, especially in the subtle early phases of AC.
Linked Comment: Ramot. Br J Dermatol 2019; 180:983–984.
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The study of a desmoglein 2 murine model of arrhythmogenic cardiomyopathy revealed cardiac inflammation as a key early event leading to fibrosis. Arrhythmogenic cardiomyopathy (AC) is an inherited ...heart muscle disorder leading to ventricular arrhythmias and heart failure due to abnormalities in the cardiac desmosome. We examined how loss of desmoglein 2 (
Dsg2
) in the young murine heart leads to development of AC. Apoptosis was an early cellular phenotype, and RNA sequencing analysis revealed early activation of inflammatory-associated pathways in
Dsg2
-null (
Dsg2
−/−
) hearts at postnatal day 14 (2 weeks) that were absent in the fibrotic heart of adult mice (10 weeks). This included upregulation of iRhom2/ADAM17 and its associated pro-inflammatory cytokines and receptors such as TNFα, IL6R and IL-6. Furthermore, genes linked to specific macrophage populations were also upregulated. This suggests cardiomyocyte stress triggers an early immune response to clear apoptotic cells allowing tissue remodelling later on in the fibrotic heart. Our analysis at the early disease stage suggests cardiac inflammation is an important response and may be one of the mechanisms responsible for AC disease progression.
Summary
A whole array of cutaneous syndromes is associated with distinct dominant mutations in GJB2 encoding the gap junction protein connexin 26 (Cx26), including Vohwinkel's syndrome and ...keratitis–ichthyosis–deafness syndrome. In contrast, recessive GJB2 mutations occur in a large proportion of individuals with hearing loss but no obvious dermatological phenotype. Recently, a large deletion of ∼342 kb, encompassing the coding region of GJB6 encoding Cx30, but not affecting GJB2, was shown to be associated with hearing loss. From analysis of patient skin, we provide immunohistochemical and bioinformatic data to show that the expression of Cx26 is affected by del(GJB6‐D13S1830) in a cell‐type‐specific manner within the sweat gland. This putative regulatory element of Cx26 expression may be a key factor related to the severe or profound deafness associated with del(GJB6‐D13S1830).
Summary
Background Hereditary subtotal leuconychia is a rare nail disease. The gene(s) underlying this phenotype is (are) not known. Immunohistochemical and ultrastructural studies of nails are ...performed infrequently.
Objectives To perform genetic linkage analysis and to assess ultrastructure and soft/hard keratin expression in hereditary white nails.
Methods We have analysed microscopically and ultrastructurally the white nails of a patient from a family in which the trait is inherited in an autosomal dominant manner as an isolated symptom. No skin lesions or hair abnormalities could be detected. Genetic linkage studies were performed on DNA samples obtained from several members of the affected family. A longitudinal surgical biopsy of the nail from a great toe was split in two parts. One part was fixed in formalin and processed for histopathology. Another part was further subdivided and embedded either in Epon, following fixation in 2% glutaraldehyde, or in Lowicryl K4M, after fixation in 3% paraformaldehyde. Dewaxed nail sections and Lowicryl ultrathin sections were also stained with various antikeratin antibodies.
Results Genetic linkage studies of the family pointed to the disease gene mapping to the chromosomal 12q13 region. Genes mapping within this chromosomal region include the genes coding for type II (basic) cytokeratins and hard keratins. The nail matrix presented an abnormal hypergranulosis. The upper part of the nail plate, originating from the proximal nail matrix, had a nonhomogeneous lamellar appearance, with numerous intracellular ‘lipidic’ vacuoles and ‘empty’ spaces separating keratin filament bundles. These cells were progressively shed at the nail surface. The cell loss was compensated by hyperproliferation of the distal matrix and of the nail bed keratinocytes, with persistent marked parakeratosis and loose arrangement of keratin bundles. The distal matrix and the nail bed contributed equally to formation of the lower plate. This presented the characteristics of a tissue composed of soft keratins. Accordingly, there was virtually no labelling with the Hb1 antibody to a basic hard keratin in the white nail, whereas the labelling with AE3 antibody to all type II keratins and with KL1 recognizing suprabasal soft keratins was normal or even enhanced.
Conclusions Genetic linkage indicates that the gene defect underlying the leuconychia in the family studied resides on chromosome 12q13. As the type II keratins map within this chromosomal interval, it is possible that a mutation in one of these keratin genes may be a cause of the hereditary leuconychia. The white appearance of nails in this disease seems to be due to an abnormal keratinization of cells originating from the proximal nail matrix, leading to the presence of abundant intracellular vacuoles and to a lesser compactness of keratins.
Dominant transmission of multiple uterine and cutaneous smooth-muscle tumors is seen in the disorder multiple leiomyomatosis (ML). We undertook a genomewide screen of 11 families segregating ML and ...found evidence for linkage to chromosome 1q42.3-q43 (maximum multipoint LOD score 5.40). Haplotype construction and analysis of recombinations permitted the minimal interval containing the locus, which we have designated “
MCUL1,” to be refined to an ∼14-cM region flanked by markers D1S517 and D1S2842. Allelic-loss studies of tumors indicated that
MCUL1 may act as a tumor suppressor. Identification of
MCUL1 should have wide interest, since this gene may harbor low-penetrance variants predisposing to the common form of uterine fibroids and/or may undergo somatic mutation in sporadic leiomyomata.
ABSTRACT
Mutations in the gene GJB2, encoding the gap junction protein Connexin26 (Cx26), are the most prevalent cause of inherited hearing loss, and Cx26M34T was one of the first mutations linked to ...deafness (Kelsell et al., 1997; Nature 387, 80–83). We report the first characterization of the gating properties of M34T, which had previously been reported to be nonfunctional. Although homotypic mutant channels did not produce detectable currents, heterotypic pairings with wtCx26 confirmed that M34T formed intercellular channels, although the gating properties were altered. Cx26M34T displayed an inverted response to transjunctional voltage (Vj), mediating currents that activate in a time‐ and Vj‐dependent manner. These characteristics suggest that the channel population is only partially open at rest, consistent with previous reports that dye transfer in M34T‐expressing cells is reduced or abolished (e.g., Thonnissen et al., Human Genet. 111, 190–197). To investigate the controversial recessive/dominant behavior of this mutant, we coexpressed M34T with wtCx26 RNA at equimolar levels, mimicking the situation in heterozygotic individuals. Under these conditions, M34T did not significantly reduce Cx26/Cx26 coupling, or alter the electrophysiological properties of the wt channels, consistent with the recessive nature of the allele. Overexpression of the mutant did have some inhibitory effects on conductance, possibly explaining some of the previous reports in exogenous expression systems and some patients. Consistent with its electrophysiological behavior, we also show that M34T localizes to cell junctions in both transfected HeLa cells and patient‐derived tissue.
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