X linked dominant research from Taiwan

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Abstract from Neurobiol Dis. 2004 Mar;15(2):361-70.

Functional analysis of connexin-32 mutants associated with X-linked

dominant Charcot-Marie-Tooth disease.

Wang HL, Chang WT, Yeh TH, Wu T, Chen MS, Wu CY.

Department of Physiology, Chang Gung University School of Medicine,

Tao-Yuan, Taiwan, ROC.

To investigate the pathogenic role of connexin-32 (Cx32) mutation in

X-linked dominant Charcot-Marie-Tooth disease (CMTX), dual whole-cell

voltage-clamp recordings and tracer coupling were performed to

investigate functional properties of wild-type and 22 CMTX mutant Cx32

proteins expressed in N2A cells. Ten mutant Cx32 proteins either formed

defective junctional channels (Y65C, V95M, R107W, L156R, R164W and

G199R) or failed to form gap junctions (G12S, S182T, E208K and

Y211stop). Except (G12S) and (E208K) mutants, other mutant Cx32 proteins

were localized in the cell membrane despite their impaired ability to

form functional gap junctions. Twelve CMTX mutations (V13L, R15Q, R22Q,

I30N, V35M, V63I, R75Q, Q80R, W133R, P158A, P172S and N205S) did not

affect the ability of Cx32 to form homotypic gap junctions in N2A cells.

Our results indicate that 10 of 22 CMTX Cx32 mutations studied in the

present investigation could lead to the assembly of defective Cx32 gap

junctions, which in turn may result in peripheral neuropathy. However,

further studies are required to elucidate the exact mechanism by which

CMTX mutant Cx32 proteins, which retain the ability to form homotypic

junctional channels, damage Schwann cells and cause demyelinating

neuropathy.