OBJECTIVES: Non-syndromic hearing loss (NSHL) is a genetically heterogeneous disorder with mostly autosomal recessive inheritance. So far 40 genes and the same amount of loci with as yet unknown genes were described with autosomal recessive NSHL. PATIENTS AND METHODS: A consanguineous Czech family with a child with NSHL was genotyped using SNP array and homozygous regions were compared with previously reported DFNB loci. RESULTS: GRXCR1 and ESRRB genes associated with autosomal recessive NSHL were located in two of the eight homozygous regions detected by SNP array genotyping. Mutation p.R291L in a homozygous state was found in the deaf child, the parents were heterozygous. The entire coding region of the ESRRB gene was sequenced in additional 39 patients of Czech origin with early NSHL and only two variants, p.V413I and p.P386S, were found in homozygous state, but are considered to be polymorphisms. CONCLUSION: Homozygosity mapping is a powerful method for identification of genes in heterogeneous recessive diseases. This is the first report of DFNB35 mutations in the Czech Republic and it seems to be a rare cause of NSHL. Additional mutations in ESRRB gene were reported in Pakistan, Tunisia and Turkey.
- MeSH
- detekce genetických nosičů MeSH
- exony MeSH
- genotyp MeSH
- glutaredoxiny genetika MeSH
- hluchota genetika MeSH
- homozygot MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- mutace * MeSH
- pokrevní příbuzenství MeSH
- receptory pro estrogeny genetika MeSH
- rodokmen MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
The highly reduced mitochondria (mitosomes) of Giardia intestinalis are recently discovered organelles for which, it was suggested, iron-sulfur cluster assembly was their only conserved function. However, only an incomplete set of the components required for FeS cluster biogenesis was localized to the mitosomes. Via proteomic analysis of a mitosome-rich cellular fraction together with immunofluorescence microscopy, we identified a novel mitosomal protein homologous to monothiol glutaredoxins containing a CGFS motif at the active site. Sequence analysis revealed the presence of long nonconserved N-terminal extension of 77 amino acids, which was absent in the mature protein. Expression of the complete and N-terminally truncated forms of the glutaredoxin indicated that the extension is involved in glutaredoxin import into mitosomes. However, the mechanism of preprotein processing is unclear, as the mitosomal processing peptidase is unable to cleave this type of extension. The recombinant mature protein was shown to form a homodimeric structure, which binds a labile FeS cluster. The cluster is stabilized by glutathione and dithiothreitol. Phylogenetic analysis showed that giardial glutaredoxin is related to the mitochondrial monothiol glutaredoxins involved in FeS cluster assembly. The identification of a mitochondrial-type monothiol glutaredoxin in the mitosomes of G. intestinalis thus completes the mitosomal FeS cluster biosynthetic pathway and provides further evidence for the mitochondrial origin of these organelles.
