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[Two novel mutations of GJB1 gene associated with typical X-linked Charcot-Marie-Tooth disease].
Zhonghua Yi Xue Za Zhi. 2009 Dec 22; 89(47):3328-31.ZY

Abstract

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 normal 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.

Authors+Show Affiliations

Department of Neurology, Peking University First Hospital, Beijing 100034, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

English Abstract
Journal Article
Research Support, Non-U.S. Gov't

Language

chi

PubMed ID

20193560

Citation

Qiao, Xiao-hui, et al. "[Two Novel Mutations of GJB1 Gene Associated With Typical X-linked Charcot-Marie-Tooth Disease]." Zhonghua Yi Xue Za Zhi, vol. 89, no. 47, 2009, pp. 3328-31.
Qiao XH, Li YX, Chang XZ, et al. [Two novel mutations of GJB1 gene associated with typical X-linked Charcot-Marie-Tooth disease]. Zhonghua Yi Xue Za Zhi. 2009;89(47):3328-31.
Qiao, X. H., Li, Y. X., Chang, X. Z., Luan, X. H., Chen, B., Bu, D. F., & Yuan, Y. (2009). [Two novel mutations of GJB1 gene associated with typical X-linked Charcot-Marie-Tooth disease]. Zhonghua Yi Xue Za Zhi, 89(47), 3328-31.
Qiao XH, et al. [Two Novel Mutations of GJB1 Gene Associated With Typical X-linked Charcot-Marie-Tooth Disease]. Zhonghua Yi Xue Za Zhi. 2009 Dec 22;89(47):3328-31. PubMed PMID: 20193560.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - [Two novel mutations of GJB1 gene associated with typical X-linked Charcot-Marie-Tooth disease]. AU - Qiao,Xiao-hui, AU - Li,Yue-xing, AU - Chang,Xing-zhi, AU - Luan,Xing-hua, AU - Chen,Bin, AU - Bu,Ding-fang, AU - Yuan,Yun, PY - 2010/3/3/entrez PY - 2010/3/3/pubmed PY - 2010/4/28/medline SP - 3328 EP - 31 JF - Zhonghua yi xue za zhi JO - Zhonghua Yi Xue Za Zhi VL - 89 IS - 47 N2 - 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 normal 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. SN - 0376-2491 UR - https://www.unboundmedicine.com/medline/citation/20193560/[Two_novel_mutations_of_GJB1_gene_associated_with_typical_X_linked_Charcot_Marie_Tooth_disease]_ L2 - http://journal.yiigle.com/LinkIn.do?linkin_type=pubmed&issn=0376-2491&year=2009&vol=89&issue=47&fpage=3328 DB - PRIME DP - Unbound Medicine ER -