缝隙连接蛋白B1基因新突变导致X连锁腓骨肌萎缩症的临床和病理特点

目的 报道2个缝隙连接蛋白B1(GJB1)基因新突变导致的X连锁腓骨肌萎缩症(CMT1X)家系的临床、电生理以及病理特点.方法 对两个家系的先证者行神经电图和腓肠神经活检,对先证者及家系中部分成员和100名健康人行GJB1基因测序.结果 2个家系先证者的周围神经传导速度中度减慢,腓肠神经活检可见有髓神经纤维中度减少、薄髓纤维、轴索变性及再生簇等病理改变,免疫组化染色在神经内衣及神经束衣可见CD68阳性细胞.在先证者和家系患者中分别检测到GJB1基因c.379A>T(I127F)和c.533A>G(D178G)突变,家系正常人和100名健康对照无此突变.结论 GJB1基因的I127F和D178G突变导致典型的CMT1X,临床表现具有异质性,免疫因素可能参与了致病过程.

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

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 CMT1 X 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.