Mutations in the gene encoding gap junction protein α12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease
Mutations in the gene encoding gap junction protein α12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease
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DOI：
10.1086/422763
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发表时间：
2004-08-01
影响因子：
9.8
通讯作者：
Gärtner, J
中科院分区：
文献类型：
--
作者：
Uhlenberg, B;Schuelke, M;Gärtner, J
低髓素性脑白质营养不良X连锁Pelizaeus-Merzbacher病(PMD)和Pelizaeus-Merzbacher样疾病(PMLD)以眼球震颤、进行性痉挛和共济失调为特征。在一个有PMLD血缘关系的家系中，我们使用基因芯片图谱EA 10K阵列(Affymetrix)进行了全基因组连锁扫描，并在染色体1q41-q42上检测到一个单基因位点。该区域含有GJA12基因，编码缝隙连接蛋白α12(或连接蛋白46.6)。缝隙连接蛋白组装成细胞间通道，通过该通道信号离子和小分子进行交换。GJA12在少突胶质细胞中高表达，因此，它是PMLD中低髓鞘抑制的一个很好的候选基因。在6个PMLD家族中的3个中，我们检测到5种不同的GJA12突变，包括错义突变、无义突变和移码突变。因此，我们证实了之前的假设，即PMLD是遗传异质性的。虽然小鼠Gja12同源基因在坐骨神经中不表达，但我们通过逆转录聚合酶链式反应在人类坐骨神经和腓肠神经组织中检测到GJA12转录本。这些结果与PMLD患者运动和感觉神经传导速度减慢的电生理学发现是一致的，这证明了一种脱髓鞘神经病。在这项研究中，我们证明了GJA12在中枢髓鞘形成中起关键作用，并参与人类的外周髓鞘形成。
The hypomyelinating leukodystrophies X-linked Pelizaeus-Merzbacher disease (PMD) and Pelizaeus-Merzbacher like disease (PMLD) are characterized by nystagmus, progressive spasticity, and ataxia. In a consanguineous family with PMLD, we performed a genomewide linkage scan using the GeneChip Mapping EA 10K Array (Affymetrix) and detected a single gene locus on chromosome 1q41-q42. This region harbors the GJA12 gene, which encodes gap junction protein alpha12 (or connexin 46.6). Gap junction proteins assemble into intercellular channels through which signaling ions and small molecules are exchanged. GJA12 is highly expressed in oligodendrocytes, and, therefore, it serves as an excellent candidate for hypomyelination in PMLD. In three of six families with PMLD, we detected five different GJA12 mutations, including missense, nonsense, and frameshift mutations. We thereby confirm previous assumptions that PMLD is genetically heterogeneous. Although the murine Gja12 ortholog is not expressed in sciatic nerve, we did detect GJA12 transcripts in human sciatic and sural nerve tissue by reverse-transcriptase polymerase chain reaction. These results are in accordance with the electrophysiological finding of reduced motor and sensory nerve conduction velocities in patients with PMLD, which argues for a demyelinating neuropathy. In this study, we demonstrate that GJA12 plays a key role in central myelination and is involved in peripheral myelination in humans.