Mitochondrial Hsp60 Chaperonopathy Causes an Autosomal-Recessive Neurodegenerative Disorder Linked to Brain Hypomyelination and Leukodystrophy

Pediatric Nephrology Unit, Rambam Health Care Campus, Haifa 31096, Israel.
The American Journal of Human Genetics (Impact Factor: 10.93). 08/2008; 83(1):30-42. DOI: 10.1016/j.ajhg.2008.05.016
Source: PubMed


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.

Download full-text


Available from: Karl Skorecki, Jul 24, 2015
  • Source
    • "These patients are suffering from Pelizaeus– Merzbacher-like disease (PMLD). PMLD has been linked to a mutation in HSPD1 (Magen et al., 2008), to various autosomal recessive mutations in GJC2 and to several mutations in the GJC2 promoter (Table 2 and Figure 3; Orthmann-Murphy et al., 2007; Henneke et al., 2008; Al-Yahyaee et al., 2012; Yalcinkaya et al., 2012; Biancheri et al., 2013; Kammoun Jellouli et al., 2013; Shimojima et al., 2013). In addition , mutations in GJC2 are linked to hereditary spastic paraplegia; a milder but similar phenotype (Orthmann-Murphy et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Connexins (Cxs) form a family of transmembrane proteins comprising 21 members in humans. Cxs differ in their expression patterns, biophysical properties and ability to combine into homomeric or heteromeric gap junction channels between neighboring cells. The permeation of ions and small metabolites through gap junction channels or hemichannels confers a crucial role to these proteins in intercellular communication and in maintaining tissue homeostasis. Among others, Cx37, Cx40, Cx43, Cx45 and Cx47 are found in heart, blood- and lymphatic vessels. Mutations or polymorphisms in the genes coding for these Cxs have not only been implicated in cardiovascular pathologies but also in a variety of other disorders. While mutations in Cx43 are mostly linked to oculodentodigital dysplasia, Cx47 mutations are associated with Pelizaeus-Merzbacher-like disease and lymphedema. Cx40 mutations are principally linked to atrial fibrillation. Mutations in Cx37 have not yet been described, but polymorphisms in the Cx37 gene have been implicated in the development of arterial disease. This review addresses current knowledge on gene mutations in cardiovascular Cxs systematically and links them to alterations in channel properties and disease.This article is protected by copyright. All rights reserved
    Biology of the Cell 06/2014; 106(9). DOI:10.1111/boc.201400038 · 3.51 Impact Factor
  • Source
    • "SPG13 is a pure form of HSP that presents late onset and a slow progression (Hansen et al., 2002). In contrast, the white matter disorder MitCHAP60 disease is a fatal disorder that is characterized by a strikingly deficient formation of myelin (Magen et al., 2008). On basis of these observations, it is clear that mitochondrial Hsp60 plays a particularly important role in neuronal cell survival and disturbances in its function are primarily associated with human inherited diseases of the nervous system. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cells rely on efficient protein quality control systems (PQCs) to maintain proper activity of mitochondrial proteins. As part of this system, the mitochondrial chaperone Hsp60 assists folding of matrix proteins and it is an essential protein in all organisms. Mutations in HSPD1, the gene encoding Hsp60, are associated with two human inherited diseases of the nervous system, a dominantly inherited form of spastic paraplegia (SPG13) and an autosomal recessively inherited white matter disorder termed MitCHAP60 disease. Although the connection between mitochondrial failure and neurodegeneration is well known in many neurodegenerative disorders, such as Huntington´s disease, Parkinson´s disease, and hereditary spastic paraplegia, the molecular basis of the neurodegeneration associated with these diseases is still ill-defined. Here, we investigate mice heterozygous for a knockout allele of the Hspd1 gene encoding Hsp60. Our results demonstrate that Hspd1 haploinsufficiency is sufficient to cause a late onset and slowly progressive deficit in motor functions in mice. We furthermore emphasize the crucial role of the Hsp60 chaperone in mitochondrial function by showing that the motor phenotype is associated with morphological changes of mitochondria, deficient ATP synthesis, and in particular, a defect in the assembly of the respiratory chain complex III in neuronal tissues. In the current study, we propose that our heterozygous Hsp60 mouse model is a valuable model system for the investigation of the link between mitochondrial dysfunction and neurodegeneration.
    Neurobiology of Disease 03/2013; 54. DOI:10.1016/j.nbd.2013.02.012 · 5.08 Impact Factor
  • Source
    • "); Mit-CHAP60, AR (Magen et al, 2008) "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuronal survival critically depends on the integrity and functionality of mitochondria. A hierarchical system of cellular surveillance mechanisms protects mitochondria against stress, monitors mitochondrial damage and ensures the selective removal of dysfunctional mitochondrial proteins or organelles. Mitochondrial proteases emerge as central regulators that coordinate different quality control (QC) pathways within an interconnected network of mechanisms. A failure of this system causes neuronal loss in a steadily increasing number of neurodegenerative disorders, which include Parkinson's disease, spinocerebellar ataxia, spastic paraplegia and peripheral neuropathies. Here, we will discuss the role of the mitochondrial QC network for neuronal survival and neurodegeneration.
    The EMBO Journal 02/2012; 31(6):1336-49. DOI:10.1038/emboj.2012.38 · 10.43 Impact Factor
Show more