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

Abstract

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.

Redox regulation of cellular stress response in multiple sclerosis

“…Mutations in the HSPD1 gene encoding Hsp60 have recently been found to underlie spastic paraplegia 13 (SPG13 [MIM 605280]), an autosomal-dominant spinal-cord neurodegenerative disorder of late onset, characterized by progressive weakness and spasticity of the lower limbs, and, more recently, a homozygous missense mutation, D29G, in HSPD1, encoding the mitochondrial Hsp60 chaperonin, causing a mitochondrial Hsp60 chaperonopathy linked to brain hypomyelination and leukodystrophy. This finding provides evidence for the pivotal role of the mitochondrial Hsp60 chaperonin in the process of normal brain myelination and in the pathogenesis of hypomyelinating neurodegenerative disease [58]. Notably, we found increased expression of thioredoxin in MS as compared to control subjects.…”

Proteostasis impairment in protein-misfolding and -aggregation diseases

“…Mutations of the mitochondrial chaperonin Hsp60 cause autosomal dominant spastic paraplegia [82] and an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy [83].…”

Functional single-nucleotide variant of HSPD1 in sudden infant death syndrome

“…The present study, therefore focuses on an SNV in the coding region of the gene for Hsp60, HSPD1, that creates a bona fide amino acid change in the protein and that has already been shown to cause manifest disease if present in a homozygous genotype (25). In addition, evidence for functional impairment of Hsp60 by this SNV has been produced by demonstrating reduced survival in transgenic Escherichia coli, especially when confronted with heat stress (25).…”

“…In addition, evidence for functional impairment of Hsp60 by this SNV has been produced by demonstrating reduced survival in transgenic Escherichia coli, especially when confronted with heat stress (25).…”

“…This study is the first to examine in a substantially larger number of cases whether the nonsynonymous and known to be pathogenic (25) rare variant rs72466451 in the gene for Hsp60 is associated with the occurrence of SIDS. Table 1 shows the results of the distribution analysis of the allelic variants of the HSPD1 SNV in controls and cases of SIDS.…”