Orthmann-Murphy Jennifer L, Salsano Ettore, Abrams Charles K, Bizzi Alberto, Uziel Graziella, Freidin Mona M, Lamantea Eleonora, Zeviani Massimo, Scherer Steven S, Pareyson Davide
Department of Neurology, University of Pennsylvania School of Medicine, Room 464 Stemmler Hall, Philadelphia, PA 19104-6077, USA.
Brain. 2009 Feb;132(Pt 2):426-38. doi: 10.1093/brain/awn328. Epub 2008 Dec 4.
Recessive mutations in GJA12/GJC2, the gene that encodes the gap junction protein connexin47 (Cx47), cause Pelizaeus-Merzbacher-like disease (PMLD), an early onset dysmyelinating disorder of the CNS, characterized by nystagmus, psychomotor delay, progressive spasticity and cerebellar signs. Here we describe three patients from one family with a novel recessively inherited mutation, 99C>G (predicted to cause an Ile>Met amino acid substitution; I33M) that causes a milder phenotype. All three had a late-onset, slowly progressive, complicated spastic paraplegia, with normal or near-normal psychomotor development, preserved walking capability through adulthood, and no nystagmus. MRI and MR spectroscopy imaging were consistent with a hypomyelinating leukoencephalopathy. The mutant protein forms gap junction plaques at cell borders similar to wild-type (WT) Cx47 in transfected cells, but fails to form functional homotypic channels in scrape-loading and dual whole-cell patch clamp assays. I33M forms overlapping gap junction plaques and functional channels with Cx43, however, I33M/Cx43 channels open only when a large voltage difference is applied to paired cells. These channels probably do not function under physiological conditions, suggesting that Cx47/Cx43 channels between astrocytes and oligodendrocytes are disrupted, similar to the loss-of-function endoplasmic reticulum-retained Cx47 mutants that cause PMLD. Thus, GJA12/GJC2 mutations can result in a milder phenotype than previously appreciated, but whether I33M retains a function of Cx47 not directly related to forming functional gap junction channels is not known.
编码缝隙连接蛋白连接蛋白47（Cx47）的基因GJA12/GJC2中的隐性突变会导致佩利措伊斯-默茨巴赫样病（PMLD），这是一种中枢神经系统的早发性脱髓鞘疾病，其特征为眼球震颤、精神运动发育迟缓、进行性痉挛和小脑体征。在此，我们描述了来自一个家族的三名患者，他们携带一种新的隐性遗传突变，即99C>G（预计会导致异亮氨酸>甲硫氨酸氨基酸替换；I33M），该突变导致一种较轻的表型。所有三名患者均表现为迟发性、缓慢进展的复杂性痉挛性截瘫，精神运动发育正常或接近正常，成年后仍保留行走能力，且无眼球震颤。磁共振成像（MRI）和磁共振波谱成像与低髓鞘性白质脑病一致。在转染细胞中，突变蛋白在细胞边界形成与野生型（WT）Cx47相似的缝隙连接斑，但在刮片加载和双全细胞膜片钳试验中未能形成功能性同型通道。然而，I33M与Cx43形成重叠的缝隙连接斑和功能性通道，不过，I33M/Cx43通道仅在对配对细胞施加较大电压差时才会打开。这些通道在生理条件下可能不起作用，这表明星形胶质细胞和少突胶质细胞之间的Cx47/Cx43通道被破坏，类似于导致PMLD的功能丧失的内质网滞留Cx47突变体。因此，GJA12/GJC2突变可导致比先前认识到的更轻的表型，但I33M是否保留了与形成功能性缝隙连接通道不直接相关的Cx47功能尚不清楚。
