Kaisu Nikali

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.

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 (Clarkes 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 Friedreichs ataxia, another recessively inherited usually childhood-onset ataxia.

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 ∼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 mrs3omrs4o 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 REPRESENTS AN ALLELIC DISEASE DISTINCT FROM OTHER HEREDITARY ATAXIAS

ABSTRACT: 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 ataxia 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.

cDNA cloning, expression profile and genomic structure of a novel human transcript on chromosome 10q24, and its analyses as a candidate gene for infantile onset spinocerebellar ataxia ☆

In our search for the disease gene underlying autosomally recessively inherited infantile onset spinocerebellar ataxia (IOSCA), we identified an expressed sequence tag cluster representing a previously uncharacterized transcript in the restricted genomic sequence covering the IOSCA locus on chromosome 10q24, and for mutation analyses in IOSCA patients isolated the corresponding novel human cDNA, C10orf6. Multiple tissue cDNA and Northern analyses showed that this gene is ubiquitously expressed, with expression levels highest in the skeletal muscle and less abundant in the brain, liver, and heart than in other tissues examined. C10orf6 consists of 20 exons forming a 7.3 kb cDNA which is capable of encoding a 1173 amino acid polypeptide and possesses orthologues in other mammals. Sequencing of RT and genomic PCR products of the gene revealed no alterations in IOSCA patients when compared to control subjects, and neither could differences be detected in expression levels between patient and control brain RNA samples, thus excluding mutation(s) in this novel gene as causative for IOSCA. However, this study facilitates future investigations on both the role of C10orf6 gene product in human cells as well as its possible involvement in the pathogenesis of other hereditary diseases mapped to chromosome 10q24.