Mitochondrial hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain...

Area of Science:

• Neurogenetics
• Molecular Biology
• Cellular Biology

Background:

• Hypomyelinating leukodystrophies (HMLs) are a group of rare genetic disorders characterized by abnormal myelin formation.
• Pelizaeus-Merzbacher disease (PMD) and autosomal-recessive Pelizaeus-Merzbacher-like disease (PMLD) are primary HMLs linked to mutations in PLP1 and GJA12, respectively.
• However, numerous PMLD cases remain genetically unexplained, indicating other causative genes.

Purpose of the Study:

• To identify the genetic cause of an unexplained autosomal-recessive leukodystrophy in a consanguineous kindred.
• To investigate the role of mitochondrial heat-shock protein 60 (Hsp60) in the pathogenesis of this novel leukodystrophy.

Main Methods:

• Homozygosity mapping and mutation analysis were employed to identify the causative gene.
• A homozygous missense mutation (D29G) in the HSPD1 gene, encoding Hsp60, was identified.
• Functional validation of the mutation's pathogenicity was performed using an in vivo E. coli complementation assay.

Main Results:

• A novel homozygous missense mutation (D29G) in HSPD1 was identified in affected individuals, segregating with the disease phenotype.
• The D29G mutation impaired Hsp60 chaperonin activity, as evidenced by compromised E. coli survival, particularly at elevated temperatures.
• The identified disorder, termed MitCHAP-60 disease, presents with early-onset, severe cerebral involvement and lethality, distinguishing it from SPG13.

Conclusions:

• Defects in Hsp60 can cause severe autosomal-recessive neurodegenerative disorders, including a novel form of hypomyelinating leukodystrophy.
• This finding highlights the critical role of Hsp60 in myelinogenesis and neuroprotection.
• The study expands the spectrum of Hsp60-associated neurodegenerative pathologies.