Hereditary Spastic Paraplegia SPG13 Is Associated with a Mutation in the Gene Encoding the Mitochondrial Chaperonin Hsp60

Abstract

SPG13, an autosomal dominant form of pure hereditary spastic paraplegia, was recently mapped to chromosome 2q24-34 in a French family. Here we present genetic data indicating that SPG13 is associated with a mutation, in the gene encoding the human mitochondrial chaperonin Hsp60, that results in the V72I substitution. A complementation assay showed that wild-type HSP60 (also known as "HSPD1"), but not HSP60 (V72I), together with the co-chaperonin HSP10 (also known as "HSPE1"), can support growth of Escherichia coli cells in which the homologous chromosomal groESgroEL chaperonin genes have been deleted. Taken together, our data strongly indicate that the V72I variation is the first disease-causing mutation that has been identified in HSP60.

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].…”

Single-nucleotide variations in the genes encoding the mitochondrial Hsp60/Hsp10 chaperone system and their disease-causing potential

“…Asp, c.1688G>C/p.Gly563Ala), 30 additional, unrelated control individuals from the Danish Cell bank were typed by sequencing the respective regions of the genome. The frequencies for the c.292G>A/p.Val98Ile variations associated with hereditary spastic paraplegia and the c.551A>G (p.Asn184Ser) variation in 400 unrelated control individuals have been determined previously (Hansen et al 2002). For the polymorphic variation c.1688G>C/p.Gly563Ala an additional 114 unrelated control individuals were typed using a PCR/ RFLP assay.…”

“…The non-synonymous variations in the coding region (c.1136A>G/Asp379Gly, c1676G>A/Gly559Asp, and c.1688G>C/Gly563Ala) were introduced, by site-directed mutagenesis (QuikChange or megaprimer PCRmethod), into the prokaryotic expression vector that contains cDNA encoding Hsp10 and the processed form of Hsp60 supplemented with a methionine initiation codon as an operon under control of an IPTGinducible promoter (Hansen et al 2002). Presence of the respective variations and absence of mutagenesisinduced PCR errors was established by sequencing and subcloning.…”

“…Presence of the respective variations and absence of mutagenesisinduced PCR errors was established by sequencing and subcloning. The resulting vectors were used in the genetic complementation assay described previously (Hansen et al 2002;Richardson et al 2001).…”

“…Our genetic investigation of a French family with an autosomal dominant form of spastic paraplegia (SPG13; MIM 605280) identified a missense mutation in the HSPD1 gene (c.292G>A/ p.Val98Ile) that segregated with the disease phenotype and was shown to compromise chaperonin function (Hansen et al 2002).…”