Mitochondrial hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy.
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.
Magen
Daniella
D
Pediatric Nephrology Unit, Rambam Health Care Campus, Haifa 31096, Israel.
Georgopoulos
Costa
C
Bross
Peter
P
Ang
Debbie
D
Segev
Yardena
Y
Goldsher
Dorit
D
Nemirovski
Alexandra
A
Shahar
Eli
E
Ravid
Sarit
S
Luder
Anthony
A
Heno
Bayan
B
Gershoni-Baruch
Ruth
R
Skorecki
Karl
K
Mandel
Hanna
H
D000595:Amino Acid Sequence; D016022:Case-Control Studies; D018834:Chaperonin 60 / Q000032:analysis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002889:Chromosomes, Human, Pair 2; D003241:Consanguinity; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005804:Genes, Lethal; D005808:Genes, Recessive; D008040:Genetic Linkage; D005819:Genetic Markers; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007223:Infant; D008297:Male; D018895:Microsatellite Repeats; D024101:Mitochondrial Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010375:Pedigree; D020161:Physical Chromosome Mapping; D012150:Polymorphism, Restriction Fragment Length; D011859:Radiography; D017386:Sequence Homology, Amino Acid
D018834:Chaperonin 60; D029968:Escherichia coli Proteins; D005819:Genetic Markers; D024101:Mitochondrial Proteins