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Human Molecular Genetics Advance Access originally published online on August 31, 2005
Human Molecular Genetics 2005 14(20):2981-2990; doi:10.1093/hmg/ddi328
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky

Kaisu Nikali1,*,{dagger}, Anu Suomalainen2, Juha Saharinen1, Mikko Kuokkanen1, Johannes N. Spelbrink3, Tuula Lönnqvist4 and Leena Peltonen1

1Department of Molecular Medicine, National Public Health Institute and 2Department of Medical Genetics, Programme of Neurosciences, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland, 3Institute of Medical Technology, Tampere University Hospital, University of Tampere, 33014 Tampere, Finland and 4Department of Child Neurology, Hospital for Children and Adolescents, Helsinki University Central Hospital, Stenbäckinkatu, 00250 Helsinki, Finland

* To whom correspondence should be addressed. Tel: +44 2078486549; Fax: +44 2078486816; Email: kaisu.nikali{at}tiscali.co.uk

Received February 21, 2005; Revised July 29, 2005; Accepted August 24, 2005

Infantile onset spinocerebellar ataxia (IOSCA) (MIM 271245) 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 mitochondrial deoxyribonucleic acid (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 a 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 (adPEO) with multiple mtDNA deletions (MIM 606075), 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 that these proteins play a crucial role in the maintenance and/or function of specific affected neuronal subpopulations.

{dagger} Present address: MRC Developmental Neurobiology Centre, New Hunt's House, Guy's Hospital Campus, King's College, London SE1 1UL, UK.


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