Human Molecular Genetics Advance Access published online on August 31, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi328
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1 National Public Health Institute, Department of Molecular Medicine and University of Helsinki, Department of Medical Genetics, Haartmaninkatu 8, 00290 Helsinki, Finland; MRC Developmental Neurobiology Centre, New Hunt's House, Guy's Hospital Campus, King's College, London SE1 1UL, UK
* To whom correspondence should be addressed. Infantile onset spinocerebellar ataxia (IOSCA; MIM271245) is a severe autosomal recessively inherited neurodegenerative disorder characterized by progressive atrophy of the cerebellum, brain stem and spinal cord, and sensory axonal neuropathy. We report here the molecular background of this disease based on the positional cloning/candidate approach of the defective gene. Having established the linkage to chromosome 10q24, we restricted the critical DNA region using single nucleotide polymorphism-based haplotypes. After analyzing all positional candidate transcripts, we identified two point mutations in the gene C10orf2 encoding Twinkle, a mtDNA specific helicase, and a rarer splice variant Twinky, underlying IOSCA. The founder IOSCA mutation, homozygous in all but one of the patients, leads to an Y508C amino acid change in the polypeptides. One patient, heterozygous for Y508C, carries a silent coding region cytosine to thymine transition mutation in his paternal disease chromosome. This allele is expressed at a reduced level, causing the preponderance of messenger RNAs encoding Y508C polypeptides, and thus leads to the IOSCA disease phenotype. Previously we have shown that different mutations in this same gene cause autosomal dominant progressive external ophthalmoplegia with multiple mtDNA deletions (adPEO; MIM606075), a neuromuscular disorder sharing a spectrum of symptoms with IOSCA. IOSCA phenotype is the first recessive one due to Twinkle and Twinky mutations, the dominant PEO mutations affecting mtDNA maintenance, but in IOSCA mtDNA stays intact. The severe neurological phenotype observed in IOSCA, a result of only a single amino acid substitution in Twinkle and Twinky, suggests these proteins play a crucial role in the maintenance and/or function of specific affected neuronal subpopulations.
Received February 21, 2005
Revised July 29, 2005
Accepted August 24, 2005
Article
Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky
2 University of Helsinki, Programme of Neurosciences, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland
3 National Public Health Institute, Department of Molecular Medicine and University of Helsinki, Department of Medical Genetics, Haartmaninkatu 8, 00290 Helsinki, Finland
4 Institute of Medical Technology and Tampere University Hospital, 33014 University of Tampere, Finland
5 Department of Child Neurology, Hospital for Children and Adolescents, Helsinki University Central Hospital, Stenbäckinkatu, 00250 Helsinki, Finland
Kaisu Nikali, E-mail: kaisu.nikali{at}tiscali.co.uk
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