Copyright © 2002 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 70, Issue 5, 1328-1332, 1 May 2002
doi:10.1086/339935
Report
Hereditary Spastic Paraplegia SPG13 Is Associated with a Mutation in the Gene Encoding the Mitochondrial Chaperonin Hsp60
Jens Jacob Hansen1, Alexandra Dürr2, 3, 4, Isabelle Cournu-Rebeix5, Costa Georgopoulos6, Debbie Ang6, Marit Nyholm Nielsen1, Claire-Sophie Davoine5, Alexis Brice2, 3, 4, Bertrand Fontaine2, 5, Niels Gregersen1 and Peter Bross1, 
, 
1 Research Unit for Molecular Medicine, Århus University Hospital and Faculty of Health Sciences, Århus, Denmark
2 Fédération de Neurologie, Groupe Hospitalier Pitié-Salpêtrière, Paris
3 INSERM U289, Groupe Hospitalier Pitié-Salpêtrière, Paris
4 Département de Génétique, Cytogénétique et Embryologie, Groupe Hospitalier Pitié-Salpêtrière, and
5 INSERM U546, Faculté de Médecine et Groupe Hospitalier Pitié-Salpêtrière, Paris
6 Biochimie Médicale, Centre Médical Universitaire, Geneva
Address for correspondence and reprints: Dr. Peter Bross, Research Unit for Molecular Medicine, Skejby Sygehus, Brendstrupgaardsvej, 8200 Århus N, DenmarkAbstract
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.
Article Information
PubMed
Related Articles
- Mitochondrial Hsp60 Chaperonopathy Causes an Autosomal-Reces...Mitochondrial Hsp60 Chaperonopathy Causes an Autosomal-Recessive Neurodegenerative Disorder Linked to Brain Hypomyelination and Leukodystrophy
The American Journal of Human Genetics, Volume 83, Issue 1, 11 July 2008, Pages 30-42
Daniella Magen, Costa Georgopoulos, Peter Bross, Debbie Ang, Yardena Segev, Dorit Goldsher, Alexandra Nemirovski, Eli Shahar, Sarit Ravid, Anthony Luder, Bayan Heno, Ruth Gershoni-Baruch, Karl Skorecki and Hanna Mandel
AbstractHypomyelinating 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.
Abstract | | - Is the Transportation Highway the Right Road for Hereditary ...Is the Transportation Highway the Right Road for Hereditary Spastic Paraplegia?
The American Journal of Human Genetics, Volume 71, Issue 5, 1 November 2002, Pages 1009-1016
Andrew H. Crosby and Christos Proukakis
AbstractThe term “hereditary spastic paraplegia” (HSP) refers to a genetically and clinically diverse group of disorders whose primary feature is progressive spasticity of the lower extremities. The condition arises because of degeneration of the longest motor and sensory axons on the spinal cord, which appear to be most sensitive to the underlying mutations. The marked genetic heterogeneity in HSP, with 20 loci chromosomally mapped and eight genes now identified, suggests that a number of defective cellular processes may be shown to result in the disease. Although previous studies have suggested a mitochondrial basis for at least one form of the disease, a mechanism common to a number of the other genes mutated in HSP has remained elusive until now. The identification of the most recent genes for the condition suggests that aberrant cellular-trafficking dynamics may be a common process responsible for the specific pattern of neurodegeneration seen in HSP.
Abstract | | - The Yeast Connection to Friedreich AtaxiaThe Yeast Connection to Friedreich Ataxia
The American Journal of Human Genetics, Volume 64, Issue 2, 1 February 1999, Pages 365-371
Simon A.B. Knight, Roy Kim, Debkumar Pain and Andrew Dancis
| - …more
