Mutations of connexin32 in charcot-marie-tooth disease type X interfere with cell-to-cell communication but not cell proliferation and myelin-specific gene expression

Yoshimura, Teizo; Satake, Marie; Ohnishi, Akio; Tsutsumi, Yukiko; Fujikura, Yoshihisa

doi:10.1002/(sici)1097-4547(19980115)51:2<154::aid-jnr4>3.0.co;2-c

Cited by 52 publications

(16 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cx32 mutants identified in patients with CMTX include missense, frameshift, deletion, and nonsense mutations. Some of these mutations lead to complete loss of function with no expression of functional channels (68,79,124,425,429,480,671). Mutations within the noncoding region of the Cx32 gene have also been reported; some lead to a reduced level or lack of Cx32 mRNA (239, 403), while another affects mRNA translation (236).…”

Section: A Connexin Mutations Related To Human Peripheral Neuropathymentioning

confidence: 99%

Plasma Membrane Channels Formed by Connexins: Their Regulation and Functions

Sáez

Berthoud

Brañes

et al. 2003

Physiological Reviews

1,048

952

View full text Add to dashboard Cite

Members of the connexin gene family are integral membrane proteins that form hexamers called connexons. Most cells express two or more connexins. Open connexons found at the nonjunctional plasma membrane connect the cell interior with the extracellular milieu. They have been implicated in physiological functions including paracrine intercellular signaling and in induction of cell death under pathological conditions. Gap junction channels are formed by docking of two connexons and are found at cell-cell appositions. Gap junction channels are responsible for direct intercellular transfer of ions and small molecules including propagation of inositol trisphosphate-dependent calcium waves. They are involved in coordinating the electrical and metabolic responses of heterogeneous cells. New approaches have expanded our knowledge of channel structure and connexin biochemistry (e.g., protein trafficking/assembly, phosphorylation, and interactions with other connexins or other proteins). The physiological role of gap junctions in several tissues has been elucidated by the discovery of mutant connexins associated with genetic diseases and by the generation of mice with targeted ablation of specific connexin genes. The observed phenotypes range from specific tissue dysfunction to embryonic lethality.

show abstract

Section: A Connexin Mutations Related To Human Peripheral Neuropathymentioning

confidence: 99%

Plasma Membrane Channels Formed by Connexins: Their Regulation and Functions

Sáez

Berthoud

Brañes

et al. 2003

Physiological Reviews

1,048

952

View full text Add to dashboard Cite

show abstract

“…To date, it has not been possible to maintain either endogenous or exogenous Cx32 protein expression in cultured Schwann cells (Scherer et al, 1995;Yoshimura et al, 1998), necessitating the use of other systems for the in vitro study of CMTX-linked Cx32 mutants. When transfected into otherwise connexin-deficient PC12 cells, several Cx32 point mutants, including R142W, E186K, and E208K, showed no detectable staining on the plasma membrane but instead appeared to be defective in intracellular transport .…”

Section: Introductionmentioning

confidence: 99%

Intracellular Transport, Assembly, and Degradation of Wild-Type and Disease-linked Mutant Gap Junction Proteins

VanSlyke

Deschênes

Musil

2000

MBoC

194

126

View full text Add to dashboard Cite

More than 130 different mutations in the gap junction integral plasma membrane protein connexin32 (Cx32) have been linked to the human peripheral neuropathy X-linked Charcot–Marie–Tooth disease (CMTX). How these various mutants are processed by the cell and the mechanism(s) by which they cause CMTX are unknown. To address these issues, we have studied the intracellular transport, assembly, and degradation of three CMTX-linked Cx32 mutants stably expressed in PC12 cells. Each mutant had a distinct fate: E208K Cx32 appeared to be retained in the endoplasmic reticulum (ER), whereas both the E186K and R142W mutants were transported to perinuclear compartments from which they trafficked either to lysosomes (R142W Cx32) or back to the ER (E186K Cx32). Despite these differences, each mutant was soluble in nonionic detergent but unable to assemble into homomeric connexons. Degradation of both mutant and wild-type connexins was rapid (t1/2 < 3 h) and took place at least in part in the ER by a process sensitive to proteasome inhibitors. The mutants studied are therefore unlikely to cause disease by accumulating in degradation-resistant aggregates but instead are efficiently cleared from the cell by quality control processes that prevent abnormal connexin molecules from traversing the secretory pathway.

show abstract

“…Cx mutations may radically influence hemichannel assembly processes occurring during intracellular trafficking or gap-junction channel gating, and thus can provide a biochemical explanation of the pathophysiology underlying these diseases [7]. Defects in gap-junction channel operation resulting from Cx mutations have been studied by exogenous expression and electrophysiological techniques in Xenopus oocytes [12,13] and by intercellular transfer in cultured mammalian cells of the fluorescent dye Lucifer Yellow [14][15][16]. Several Cx32 mutations associated with CMT-X disease result in aberrant protein trafficking in mammalian cells [16][17][18].…”

Section: Introductionmentioning

confidence: 99%