Mitochondrial Hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy
Mitochondrial Hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy
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DOI：
10.1016/j.ajhg.2008.05.016
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发表时间：
2008-07-01
影响因子：
9.8
通讯作者：
Mandel, Hanna
中科院分区：
文献类型：
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作者：
Magen, Daniella;Georgopoulos, Costa;Mandel, Hanna
髓鞘减少性白质营养不良(HMLS)是一种异常髓鞘形成的疾病。原发HMLS的原型是由PLP1突变引起的X连锁Pelizaeus-Merzbacher病(PMD)。最近，在常染色体隐性遗传性Pelizaeus-Merzbacher样病(PMLD)患者中发现了编码连接蛋白47的GJA12纯合子突变。然而，许多PMLD患者无论男女都没有携带PLP1或GJA12突变。我们报告一个以色列贝都因血缘亲属，其临床和放射学结果与PMLD相一致，其中排除了与PLP1和GJA12的连锁。利用纯合图谱和突变分析，我们发现了一个在HSPD1中没有描述的纯合错义突变(D29G)，它编码所有受影响的个体的线粒体热休克蛋白60(Hsp60)。D29G突变与疾病相关表型完全分离。通过体内大肠杆菌互补实验验证了D29G对Hsp60-伴侣蛋白活性的致病作用，这表明D29G-Hsp60突变蛋白支持大肠杆菌存活的能力受到损害，特别是在高温下。这种疾病，我们称之为MitCHAP-60病，可以与另一种与Hsp60相关的常染色体显性遗传性神经退行性疾病-痉挛性截瘫13(SPG13)区分开来，因为它是常染色体-隐性遗传模式，以及它的早发性、深度大脑受累和致命性。我们的发现表明，Hsp60缺陷可以引起不同严重程度的神经退行性病变，这是以前基于SPG13表型而没有怀疑的。这些发现应该有助于阐明Hsp60在髓鞘形成和神经退行性变中的重要作用。
Hypomyelinating leukodystrophies (HMLs) are disorders involving aberrant myelin formation. The prototype of primary HMLs is the X-linked Pelizaeus-Merzbacher disease (PMD) caused by mutations in PLP1. Recently, homozygous mutations in GJA12 encoding connexin 47 were found in patients with autosomal-recessive Pelizaeus-Merzbacher-like disease (PMLD). However, many patients of both genders with PMLD carry neither PLP1 nor GJA12 mutations. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD, in which linkage to PLP1 and GJA12 was excluded. Using homozygosity mapping and mutation analysis, we have identified a homozygous missense mutation (D29G) not previously described in HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60) in all affected individuals. The D29G mutation completely segregates with the disease-associated phenotype. The pathogenic effect of D29G on Hsp60-chaperonin activity was verified by an in vivo E. coli complementation assay, which demonstrated compromised ability of the D29G-Hsp60 mutant protein to support E, coli survival, especially at high temperatures. The disorder, which we have termed MitCHAP-60 disease, can be distinguished from spastic paraplegia 13 (SPG13), another Hsp60-associated autosomal-dominant neurodegenerative disorder, by its autosomal-recessive inheritance pattern, as well as by its early-onset, profound cerebral involvement and lethality. Our findings suggest that Hsp60 defects can cause neurodegenerative pathologies of varying severity, not previously suspected on the basis of the SPG13 phenotype. These findings should help to clarify the important role of Hsp60 in myelinogenesis and neurodegeneration.