Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria.

The gene products involved in mammalian mitochondrial DNA (mtDNA) maintenance and organization remain largely unknown. We report here a novel mitochondrial protein, Twinkle, with structural similarity to phage T7 gene 4 primase/helicase and other hexameric ring helicases. Twinkle colocalizes with mtDNA in mitochondrial nucleoids. Screening of the gene encoding Twinkle in individuals with autosomal dominant progressive external ophthalmoplegia (adPEO), associated with multiple mtDNA deletions, identified 11 different coding-region mutations co-segregating with the disorder in 12 adPEO pedigrees of various ethnic origins. The mutations cluster in a region of the protein proposed to be involved in subunit interactions. The function of Twinkle is inferred to be critical for lifetime maintenance of human mtDNA integrity.

Characterization of a novel human putative mitochondrial transporter homologous to the yeast mitochondrial RNA splicing proteins 3 and 4.

We report here a novel human gene, hMRS3/4, encoding a putative mitochondrial transporter structurally and functionally homologous to the yeast mitochondrial RNA splicing proteins 3 and 4. These proteins belong to the family of mitochondrial carrier proteins (MCF) and are likely to function as solute carriers. hMRS3/4 spans approximately 10 kb of genomic DNA on chromosome 10q24 and consists of four exons that encode a 364-aa protein with six transmembrane domains. A putative splice variant, encoding a 177-aa protein with three transmembrane domains, was also identified. hMRS3/4 has a well-conserved signature sequence of MCF and is targeted into the mitochondria. When expressed in yeast, hMRS3/4 efficiently restores the mitochondrial functions in mrs3(o)mrs4(o) knock-out mutants. Ubiquitous expression in human tissues and a well-conserved structure and function suggest an important role for hMRS3/4 in human cells.

Infantile onset spinocerebellar ataxia with sensory neuropathy (IOSCA): neuropathological features.

Infantile onset spinocerebellar ataxia (IOSCA, MIM 271245) is a recessively inherited, progressive neurological disease, which we have described in 19 Finnish patients. The clinical symptoms of IOSCA include ataxia, athetosis, hypotonia, hearing deficit, ophthalmoplegia, sensory neuropathy, female hypogonadism, and epilepsy as a late manifestation. We have mapped the IOSCA locus to 10q24. In our two autopsy cases of IOSCA, the neuropathological findings were almost uniform. The cerebral hemispheres were quite well preserved, but the brain stem and the cerebellum were moderately atrophic. The most severe atrophic changes were seen in the spinal cord: in the dorsal roots, the posterior columns and the posterior spinocerebellar tracts. There was a severe neuronal loss in the dorsal nucleus (Clarke's column) of both cases and slight atrophy of the intermediolateral column in one case. The cerebellar peduncles, the inferior olives, the accessory cuneate nuclei and especially the dentate nuclei were atrophic and gliotic. The eighth cranial nerve and nucleus were atrophic. The ventral pontine nuclei and transverse fibers were slightly affected. Tegmental nuclei and tracts, especially sensory structures, were more severely affected. In mesencephalon, there was atrophy of the oculomotor nuclear complex and periaqueductal gray matter. The cerebellar cortex showed patchy atrophy. Degenerative changes were seen in dorsal root ganglia, and there was a severe axonal loss in the sural nerve. The neuropathological picture of IOSCA thus seems close to that reported in Friedreich's ataxia, another recessively inherited usually childhood-onset ataxia.

Toward cloning of a novel ataxia gene: refined assignment and physical map of the IOSCA locus (SCA8) on 10q24.

Infantile onset spinocerebellar ataxia (IOSCA) is a progressive neurological disorder of unknown etiology. It is inherited as an autosomal recessive trait and has so far been reported in just 19 Finnish patients in 13 separate families. We have previously assigned the IOSCA locus (HGMW-approved symbol SCA8) to chromosome 10q, where no previously identified ataxia loci are located. Haplotype analysis combined with genealogical data provided evidence that all the IOSCA cases in Finland originate from a single 30- to 40-generation-old founder mutation. By analyzing extended disease haplotypes observed today, the IOSCA locus can now be restricted to a region between two adjacent microsatellites, D10S192 and D10S1265, with no genetic intermarker distance. We have constructed a detailed physical map of this 270-kb IOSCA region and cytogenetically localized it to 10q24. We have also assigned two previously known genes, PAX2 and CYP17, more precisely into this region, but the sequence analysis of coding regions of these two genes has not revealed mutations in an IOSCA patient. The obtained long-range clones will form the basis for the isolation of a novel ataxia gene.

Tracing an ancestral mutation: genealogical and haplotype analysis of the infantile onset spinocerebellar ataxia locus.

Infantile onset spinocerebellar ataxia (IOSCA) is a progressive neurological syndrome exhibiting an autosomal recessive pattern of inheritance. The characteristic features were described in Finland in the beginning of 1990s. Having shown that IOSCA does not segregate with any of the markers linked to other hereditary ataxias and thus represents a genetically distinct disease, we assigned the locus of this new hereditary ataxia to 10q23.3-q24.1. To approximate the age of the Finnish IOSCA mutation and to investigate the possible existence of more than one mutation underlying the disease, the ancestors of 13 IOSCA families were identified by use of church records dating back to the 1500s. The IOSCA pedigrees were frequently merged, providing support for these having one common ancestor. Analysis of the extended IOSCA haplotypes exposed ancient recombination events and revealed one core haplotype of four markers on a region of approximately 2 cM, which was unequivocally present in 92% of disease chromosomes. Both genealogical and haplotype data thus suggest that a single IOSCA ancestral mutation was introduced into the Finnish population most probably approximately 30-40 generations ago before the time when the general east-west migration took place within Finland.

Random search for shared chromosomal regions in four affected individuals: the assignment of a new hereditary ataxia locus.

Infantile-onset spinocerebellar ataxia (IOSCA) is an autosomal recessively inherited progressive neurological disorder of unknown etiology. This ataxia, identified so far only in the genetically isolated Finnish population, does not share gene locus with any of the previously identified hereditary ataxias, and a random mapping approach was adopted to assign the IOSCA locus. Based on the assumption of one founder mutation, a primary screening of the genome was performed using samples from just four affected individuals in two consanguineous pedigrees. The identification of a shared chromosomal region in these four patients provided the first evidence that the IOSCA gene locus is on chromosome 10q23.3-q24.1, which was confirmed by conventional linkage analysis in the complete family material. Strong linkage disequilibrium observed between IOSCA and the linked markers was utilized to define accurately the critical chromosomal region. The results showed the power of linkage disequilibrium in the locus assignment of diseases with very limited family materials.

Infantile onset spinocerebellar ataxia represents an allelic disease distinct from other hereditary ataxias.

Hereditary ataxias are a heterogeneous group of progressive neurodegenerative disorders characterized by symptoms and signs originating mainly in the CNS. A new representative of this disease group is infantile onset spinocerebellar ataxia, an autosomal recessively inherited syndrome so far reported only in the genetically isolated Finnish population. The etiology of hereditary ataxias still remains unknown, but the gene loci behind many of them have been mapped to different chromosomal regions. We have carried out linkage analyses with markers on the regions of the previously identified ataxia loci to determine whether the infantile onset spinocerebellar ataxia syndrome represents the same allelic disease as any of the previously identified hereditary ataxias. Here we report that the infantile onset spinocerebellar ataxias syndrome does not segregate with any of the markers closely linked to the other hereditary ataxias. Consequently, it represents a genetically distinct disease, the gene locus of which still has to be identified.