Functional Characterization of a GJA1 Frameshift Mutation Causing Oculodentodigital Dysplasia and Palmoplantar Keratoderma

Gong, Xiang-Qun; Shao, Qing; Lounsbury, Crystal S.; Bai, Donglin; Laird, Dale W.

doi:10.1016/s0021-9258(19)84095-4

Cited by 3 publications

(1 citation statement)

References 48 publications

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“…Oculodentodigital dysplasia is an autosomal-dominant disorder and its typical findings are microphthalmos, small nose, dental anomalies, microcephaly, developmental abnormalities of the hands and feet including syndactyly, brittle nails, and hypotrichosis. Recently, a further case of oculodentodigital dysplasia with an additional clinical feature of palmoplantar keratoderma, resulting from the heterozygous deletion mutation in connexin 43, 780-781del, has been described (Gong et al, 2006), along with a further report of oculodentodigital dysplasia with curly hair and hyperkeratosis caused by a missense mutation, p.L11P, on one allele (Kelly et al, 2006). This study by Gong et al (2006) also showed that the mutant connexin 43 resulted in abnormal gap junction function in keratinocytes, thus expanding the spectrum of connexin genodermatoses.…”

Section: Connexin 30mentioning

confidence: 99%

Genetic Diseases of Junctions

Lai-Cheong

Arita

McGrath

2007

Journal of Investigative Dermatology

136

104

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Tight junctions, gap junctions, adherens junctions, and desmosomes represent intricate structural intercellular channels and bridges that are present in several tissues, including epidermis. Clues to the important function of these units in epithelial cell biology have been gleaned from a variety of studies including naturally occurring and engineered mutations, animal models and other in vitro experiments. In this review, we focus on mutations that have been detected in human diseases. These observations provide intriguing insight into the biological complexities of cell-cell contact and intercellular communication as well as demonstrating the spectrum of inherited human diseases that are associated with mutations in genes encoding the component proteins. Over the last decade or so, human gene mutations have been reported in four tight junction proteins (claudin 1, 14, 16, and zona occludens 2), nine gap junction proteins (connexin 26, 30, 30.3, 31, 32, 40, 43, 46, and 50), one adherens junction protein (P-cadherin) and eight components of desmosomes (plakophilin (PKP) 1 and 2, desmoplakin, plakoglobin--which is also present in adherens junctions, desmoglein (DSG) 1, 2, 4, and corneodesmosin). These discoveries have often highlighted novel or unusual phenotypes, including abnormal skin barrier function, alterations in epidermal differentiation, and developmental anomalies of various ectodermal appendages, especially hair, as well as a range of extracutaneous pathologies. However, this review focuses mainly on inherited disorders of junctions that have an abnormal skin phenotype.

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Section: Connexin 30mentioning

confidence: 99%

Genetic Diseases of Junctions

Lai-Cheong

Arita

McGrath

2007

Journal of Investigative Dermatology

136

104

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Pannexin 1 and pannexin 3 are glycoproteins that exhibit many distinct characteristics from the connexin family of gap junction proteins

Peñuela

Bhalla

Gong

et al. 2007

Journal of Cell Science

372

607

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Pannexins are mammalian orthologs of the invertebrate gap junction proteins innexins and thus have been proposed to play a role in gap junctional intercellular communication. Localization of exogenously expressed pannexin 1 (Panx1) and pannexin 3 (Panx3), together with pharmacological studies, revealed a cell surface distribution profile and life cycle dynamics that were distinct from connexin 43 (Cx43, encoded by Gja1). Furthermore, N-glycosidase treatment showed that both Panx1 (~41-48 kD species) and Panx3 (~43 kD) were glycosylated, whereas N-linked glycosylation-defective mutants exhibited a decreased ability to be transported to the cell surface. Tissue surveys revealed the expression of Panx1 in several murine tissues -including in cartilage, skin, spleen and brain -whereas Panx3 expression was prevalent in skin and cartilage with a second higher-molecular-weight species present in a broad range of tissues. Tissue-specific localization patterns of Panx1 and Panx3 ranging from distinct cell surface clusters to intracellular profiles were revealed by immunostaining of skin and spleen sections. Finally, functional assays in cultured cells transiently expressing Panx1 and Panx3 were incapable of forming intercellular channels, but assembled into functional cell surface channels. Collectively, these studies show that Panx1 and Panx3 have many characteristics that are distinct from Cx43 and that these proteins probably play an important biological role as single membrane channels.

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Towards a Better Understanding of Genotype–Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction

Vermeer

Andrei

Marsili

et al. 2022

IJMS

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Genetic variants in gene-encoding proteins involved in cell–cell connecting structures, such as desmosomes and gap junctions, may cause a skin and/or cardiac phenotype, of which the combination is called cardiocutaneous syndrome. The cardiac phenotype is characterized by cardiomyopathy and/or arrhythmias, while the skin particularly displays phenotypes such as keratoderma, hair abnormalities and skin fragility. The reported variants associated with cardiocutaneous syndrome, in genes DSP, JUP, DSC2, KLHL24, GJA1, are classified by interpretation guidelines from the American College of Medical Genetics and Genomics. The genotype–phenotype correlation, however, remains poorly understood. By providing an overview of variants that are assessed for a functional protein pathology, we show that this number (n = 115) is low compared to the number of variants that are assessed by in silico algorithms (>5000). As expected, there is a mismatch between the prediction of variant pathogenicity and the prediction of the functional effect compared to the real functional evidence. Aiding to improve genotype–phenotype correlations, we separate variants into ‘protein reducing’ or ‘altered protein’ variants and provide general conclusions about the skin and heart phenotype involved. We conclude by stipulating that adequate prognoses can only be given, and targeted therapies can only be designed, upon full knowledge of the protein pathology through functional investigation.

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Functional Characterization of a GJA1 Frameshift Mutation Causing Oculodentodigital Dysplasia and Palmoplantar Keratoderma

Cited by 3 publications

References 48 publications

Genetic Diseases of Junctions

Genetic Diseases of Junctions

Pannexin 1 and pannexin 3 are glycoproteins that exhibit many distinct characteristics from the connexin family of gap junction proteins

Towards a Better Understanding of Genotype–Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction

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