Novel GJA1 mutations in patients with oculo-dento-digital dysplasia (ODDD)

Debeer, Ph.; Esch, Hilde Van; Huysmans, Christel; Pijkels, E; Smet, Luc De; Ven, Willem Van de; Devriendt, Koen; Fryns, Jean‐Pierre

doi:10.1016/j.ejmg.2005.05.003

Cited by 39 publications

(20 citation statements)

References 33 publications

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“…The most common are gait difficulties, [153, 157-169] due to either spasticity or ataxia, and urinary incontinence; [166-169] these typically present by the second decade. A wider range of neurologic symptoms have been reported, [153] including cognitive deficiencies, [157, 170] deafness, [171, 172] disorders of extraocular motility, [161, 168, 171] generalized muscle weakness, and seizures. [152] MRI abnormalities include hypointensity of the deep grey matter, which may reflect iron deposition, and changes in the occipital and periventricular white matter [153, 164, 165].…”

Section: Disease Manifestations Of Gja1 Mutationsmentioning

confidence: 99%

Gap junctions in inherited human disorders of the central nervous system

Abrams

Scherer

2012

Biochimica et Biophysica Acta (BBA) - Biomembranes

102

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CNS glia and neurons express connexins, the proteins that form gap junctions in vertebrates. We review the connexins expressed by oligodendrocytes and astrocytes, and discuss their proposed physiologic roles. Of the 21 members of the human connexin family, mutations in three are associated with significant central nervous system manifestations. For each, we review the phenotype and discuss possible mechanisms of disease. Mutations in GJB1, the gene for connexin 32 (Cx32) cause the second most common form of Charcot-Marie-Tooth disease (CMT1X). Though the only consistent phenotype in CMT1X patients is a peripheral demyelinating neuropathy, CNS signs and symptoms have been found in some patients with CMT1X. Recessive mutations in GJC2, the gene for Cx47, are one cause of Pelizaeus-Merzbacher-like disease (PMLD), which is characterized by nystagmus within the first 6 months of life, cerebellar ataxia by 4 years, and spasticity by 6 years of age. MRI imaging shows abnormal myelination. A different recessive GJC2 mutation causes a form of hereditary spastic paraparesis, which is a milder phenotype than PMLD. Dominant mutations in GJA1, the gene for Cx43, cause oculodentodigital dysplasia (ODDD), a pleitropic disorder characterized by oculo-facial abnormalities including micropthalmia, microcornia and hypoplastic nares, syndactyly of the fourth to fifth fingers and dental abnormalities. Neurologic manifestations, including spasticity and gait difficulties, are often but not universally seen. Recessive GJA1 mutations cause Hallermann-Streiff syndrome, a disorder showing substantial overlap with ODDD.

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Section: Disease Manifestations Of Gja1 Mutationsmentioning

confidence: 99%

Gap junctions in inherited human disorders of the central nervous system

Abrams

Scherer

2012

Biochimica et Biophysica Acta (BBA) - Biomembranes

102

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“…eye disorders (Debeer et al, 2005) including glaucoma (Vasconcellos et al, 2005) [see also Table 3 of Loddenkemper et al (Loddenkemper et al, 2002)]. A mouse model of ODDD with a G60S mutation in Cx43 also shows eye abnormalities (Flenniken et al, 2005).…”

Section: Oddd Patients With Different Cx43 Mutations Show Variablementioning

confidence: 99%

Connexin43 is required for production of the aqueous humor in the murine eye

Calera

Topley

Liao

et al. 2006

Journal of Cell Science

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Connexin43 is a major component of the gap junctions between pigmented and non-pigmented cells of the double-layered epithelium in the ciliary body of the eye. We directly tested the hypothesis that gap junctions play a crucial role in the production of the aqueous humor by inactivating the GJA1 (connexin43) gene in the pigmented epithelium with cre-loxP technology. To accomplish this, we crossed a line expressing cre recombinase driven by the nestin promoter and a line with floxed connexin43 alleles. Resultant lines exhibited loss of connexin43 from the pigmented epithelium, iris, retinal pigment epithelium and the lens. We observed plasma proteins in the aqueous humor and pathological changes consistent with a loss of intraocular pressure. As the ciliary body is responsible for aqueous humor production, these data support the hypothesis that the gap junctions between pigmented and non-pigmented epithelium are necessary for production of the aqueous humor that is in turn required for the generation of normal intraocular pressure and nourishment of the postnatal lens. The loss of connexin43 expression in the iris correlated with a separation of the posterior pigmented epithelium from the anterior myoepithelium and with meiosis, possibly resulting from a loss of function of the dilator pupillae.

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“…Using a combination of fluorescent voltage-reporter dyes to characterize spatial V mem distributions and functional studies using targeted misexpression of well-characterized ion transporters to specifically modify those gradients in vivo, instructive signaling roles of transmembrane voltage gradients have been identified in embryogenesis and regeneration, adding to the list of such roles identified in classical work that utilized functional physiology [248,249]. A number of recent molecular studies using unbiased approaches in human syndromes and non-human model systems have identified a range of ion channels, gap junctions, and ion pumps in developmental and regenerative morphogenesis of the face, brain, heart, appendages, growth of the cerebellum [250][251][252][253][254][255][256][257][258] and many other structures [259][260][261][262][263][264][265][266][267][268][269][270][271]. These physiological states are ideal inputs for the computational analysis delineated in the next section.…”

Section: Spatio-temporal Gradients Of V Mem Are Instructive Cues Mainmentioning

confidence: 99%

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

Moore

Walker

Levin

2017

Converg. Sci. Phys. Oncol.

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TOPICAL REVIEWCancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem IntroductionCancer is well-recognized not only as an extremely pernicious medical problem, but also as a group of phenomena deeply connected to the fundamental questions of evolution, multicellularity, pattern (disregulation, and the interplay between the genome and the environment [1,2]. Two fundamental paradigms currently divide the field. One is that cancer results from disorders of genetics: cancer cells are fundamentally broken due to genomic mutation or instability, and their clonal progeny form tumors and metastases. This view is sometimes called the SMT, somatic mutation theory [3][4][5]. A competing perspective is that of cancer as a circuit disease-a disorder of the complex biophysical, transcriptional, and epigenetic dynamics that regulate cellular state and the ability of cells to cooperate in vivo [6][7][8]. Under this view (sometimes called the tissue organization field theory or TOFT, [9,10]), cancer is akin to a traffic jam [11]-the problem is not a permanent discrete alteration within a founder cell and all of its clonal descendants, but an undesirable stable attractor in the complex network of controls that normally guides anatomical homeostasis [12].The relative merits of the two models have been discussed extensively [10,[13][14][15][16][17] AbstractThe current paradigm views cancer as arising clonally from a degradation of genetic information in single cells. A complementary perspective, originating at the dawn of modern developmental biology, is that cancer is the result of a system disorder of algorithms that normally orchestrate individual cell activities toward specific anatomical structures and away from tumorigenesis. A view of cancer as a disease of geometry focuses on the pathways that allow cells to cooperate to build and maintain large-scale anatomical patterning. Cancer may result when cells stop maintaining higher-order structures and reduce the boundary of their computational selves to a single-cell level, reverting to a unicellular lifestyle in which the rest of the organism is merely part of the environment at the expense of which all living things survive. While this view has been widely discussed, little progress has been made in providing a quantitative, mechanistic framework within which this perspective's specific and unique implications for treatment strategies can be tested and biomedically exploited. Here, we highlight two recent areas of progress which may facilitate much-needed progress on the cancer problem. First, we review the roles that endogenous bioelectrical networks, operating across many tissues in vivo, play as a medium of information processing in tumor suppression, progression, and reprogramming. Second, we provide a primer to the development of computational theory and tools for quantifying the information and causal control structures in cancer and other complex biological systems. Rigorous mathematical formalisms now exist to...

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Novel GJA1 mutations in patients with oculo-dento-digital dysplasia (ODDD)

Cited by 39 publications

References 33 publications

Gap junctions in inherited human disorders of the central nervous system

Gap junctions in inherited human disorders of the central nervous system

Connexin43 is required for production of the aqueous humor in the murine eye

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

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