CMT 1X: Two novel mutations of GJB1 gene associated with typical X linked CMT

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Zhonghua Yi Xue Za Zhi. 2009 Dec 22;89(47):3328-31.

Two novel mutations of GJB1 gene associated X-linked Charcot-Marie-Tooth

disease.

Qiao XH, Li YX, Chang XZ, Luan XH, Chen B, Bu DF, Yuan Y.

Department of Neurology, Peking University First Hospital, Beijing 100034,

China.

OBJECTIVE: To analyze the relationship between phenotype and genotype and the

role of immune cells in the pathogenesis of X-linked Charcot-Marie-Tooth disease

(CMT1X).

METHODS: The probands of the two families with X-linked dominant inherited

peripheral neuropathy were evaluated clinically, electrophysiologically,

pathologically and genetically. The available family members were genetic

analyzed and the novel mutations were compared with other known ones.

RESULTS: (1) In both families, affected members presented progressive weakness

and wasting of distal extremities and it seems that males suffered more severely

than affected females with onset in the first decade of their life. Proband of

family 1 showed moderately elevated CSF protein and marked increase of IgG-syn

in CSF.(2) Nerve conduction velocity (NCV) of the peripheral nerves was

intermediately slow in both motor and sensory nerves exhibiting the features of

demyelination. Brain-stem auditory evoked potentials (BAEPs) was abnormal in the

proband of family 1: delayed I-III interpeak intervals were recorded but with

nomal III-V interpeak intervals.

(3) Sural nerve biopsy in the probands of the two families showed a prominent

distinguished loss of myelinated fibers and a few clusters of regenerating axons

without conspicuous onion-bulb formations. Thinly myelinated fibers was

prominent in family 2 but not in family 1. Immunohistochemical staining showed

that there were positive CD68 cells in the endoneurial space and lamellar

sheath. (4) By genetic testing, we identified two novel missense mutations of

GJB1 gene, which resulted in Ile127Phe amino acid substitution in family

1(located in the intracellular loop of connexin 32) and Asp178Gly amino acid

substitution in family 2 (located in the 2(nd) extracellular loop of CX32),

respectively. Both mutations were highly conserved in low species and were

predicted to be possibly damaging through Polyphen prediction tool.

CONCLUSION: The two novel GJB1 gene mutations cause a spectrum of clinical

manifestations of CMT1X in both families. However, the mutations site of CX32

alone cannot predict these phenotypic variations in CMT1X fully. The immune

system may be involved in the pathogenesis of the disease.