CMT 1X: Phenotypic and cellular expression of two novel connexin32 mutations

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Neurology. 2006 Feb 14;66(3):396-402.

Phenotypic and cellular expression of two novel connexin32 mutations

causing CMT1X.

Kleopa KA, Zamba-Papanicolaou E, Alevra X, Nicolaou P, Georgiou DM,

Hadjisavvas A, Kyriakides T, Christodoulou K.

Department of Clinical Neurosciences, The Cyprus Institute of

Neurology and Genetics, Nicosia, Cyprus.

OBJECTIVE: To determine the phenotypic and cellular expression of two

novel connexin32 (Cx32) mutations causing X-linked Charcot-Marie-

Tooth disease (CMT1X).

METHODS: The authors evaluated several members of two families with

CMT1X clinically, electrophysiologically, pathologically, and by

genetic testing. The Cx32 mutations were expressed in vitro and

studied by immunocytochemistry.

RESULTS: In both families, men were more severely affected than women

with onset in the second decade of life. In the first family, the

phenotype was that of demyelinating polyneuropathy with variable

involvement of peripheral nerves. There was clinical evidence of CNS

involvement in at least three of the patients, with extensor plantar

responses and brisk reflexes. In the second family, the affected man

presented with symmetric polyneuropathy and intermediate slowing of

conduction velocities, whereas affected women had prominent

asymmetric atrophy of the leg muscles. The authors identified two

novel missense mutations resulting in L143P amino acid substitution

in the first family and in V140E substitution in the second family,

both located in the third transmembrane domain of Cx32. Expression of

these Cx32 mutations in communication-incompetent HeLa cells and

immunocytochemical analysis revealed that both mutants were retained

intracellularly and were localized in the Golgi apparatus. In

contrast to wild-type protein, they did not form gap junctions.

CONCLUSION: These novel connexin32 (Cx32) mutations cause a spectrum

of clinical manifestations characteristic of Charcot-Marie-Tooth

disease (CMT1X), including demyelinating or intermediate

polyneuropathy, which is often asymmetric, and CNS involvement in one

family. The position and cellular expression of Cx32 mutations alone

cannot fully predict these phenotypic variations in CMT1X.