Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion

Hakonen, Anna H.; Isohanni, Pirjo; Paetau, Anders; Herva, Riitta; Suomalainen, Anu; Lönnqvist, Tuula

doi:10.1093/brain/awm242

Cited by 182 publications

(146 citation statements)

References 28 publications

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“…These investigators further demonstrated that recombinant Y508C p72 hexamers have near WT DNA helicase activity with a slight reduction in single-stranded DNA binding affinity (43), results that corroborate the current work. The A318T substitution is only found as a compound heterozygous mutation with Y508C in a severe early onset encephalopathy with liver involvement and depletion of mtDNA in the liver (44,47). These observations that one A318T-, T457I-, or Y508C-substituted copy of C10orf2 is insufficient to induce disease strongly suggests that the remaining WT allele is sufficient for health or is able to rescue any biochemical deficiencies of the protein derived from the mutant allele.…”

Section: Discussionmentioning

confidence: 98%

Disease Variants of the Human Mitochondrial DNA Helicase Encoded by C10orf2 Differentially Alter Protein Stability, Nucleotide Hydrolysis, and Helicase Activity

Longley

Humble

Sharief

et al. 2010

Journal of Biological Chemistry

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Missense mutations in the human C10orf2 gene, encoding the mitochondrial DNA (mtDNA) helicase, co-segregate with mitochondrial diseases such as adult-onset progressive external ophthalmoplegia, hepatocerebral syndrome with mtDNA depletion syndrome, and infantile-onset spinocerebellar ataxia. To understand the biochemical consequences of C10orf2 mutations, we overproduced wild type and 20 mutant forms of human mtDNA helicase in Escherichia coli and developed novel schemes to purify the recombinant enzymes to near homogeneity. A combination of molecular crowding, non-ionic detergents, Mg 2؉ ions, and elevated ionic strength was required to combat insolubility and intrinsic instability of certain mutant variants. A systematic biochemical assessment of the enzymes included analysis of DNA binding affinity, DNA helicase activity, the kinetics of nucleotide hydrolysis, and estimates of thermal stability. In contrast to other studies, we found that all 20 mutant variants retain helicase function under optimized in vitro conditions despite partial reductions in DNA binding affinity, nucleotide hydrolysis, or thermal stability for some mutants. Such partial defects are consistent with the delayed presentation of mitochondrial diseases associated with mutation of C10orf2.Chronic disruption of mitochondrial function can result in a broad array of neuromuscular degenerative disorders known as mitochondrial diseases, including progressive external ophthalmoplegia (PEO), 2 Alpers syndrome, parkinsonism, and several complex ataxia neuropathy syndromes (1-3). A heritable form of PEO was first mapped to a chromosomal interval near position 10q24 in a Finnish pedigree (4). One molecular hallmark of PEO was the age-dependent accumulation of mtDNA deletions in somatic tissues of affected individuals, which suggested that this locus was needed for replication or maintenance of mtDNA (4). In 2001, autosomal dominant PEO with mtDNA deletions was shown to co-segregate with 11 different missense mutations in the C10orf2 gene (5), which encoded a protein containing predicted amino acid sequences homologous to portions of the bacteriophage T7 gene product 4 and other superfamily 4 DNA helicases (5, 6). Since that time, numerous reports have identified 23 additional missense mutations in C10orf2 associated with heritable mitochondrial diseases such as adPEO, hepatocerebral mtDNA depletion syndrome (MDS), and infantile-onset spinocerebellar ataxia (IOSCA) (7, 8) (see Fig. 1).Several lines of evidence more directly link C10orf2 function to maintenance of mtDNA. The C10orf2 gene product dynamically colocalizes with mtDNA in nucleoprotein structures known as mitochondrial nucleoids (5, 9), and knocking down expression of C10orf2 by RNAi results in the rapid decrease in mtDNA copy number in cultured human osteosarcoma (143B) cells (10). Overexpression of catalytic mutants and dominant disease variants of the mtDNA helicase in cultured human or Schneider cells results in stalled mtDNA replication or depletion of mtDNA (11-13), which emulates the...

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Section: Discussionmentioning

confidence: 98%

Disease Variants of the Human Mitochondrial DNA Helicase Encoded by C10orf2 Differentially Alter Protein Stability, Nucleotide Hydrolysis, and Helicase Activity

Longley

Humble

Sharief

et al. 2010

Journal of Biological Chemistry

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“…Hakonen et al described a more severe disease associated with compound heterozygous Twinkle mutations in two brothers, who had very early-onset encephalopathy at around 6 months of age with abnormal eye, face, and limb movements, sensory neuropathy, and hypotonia (Hakonen et al 2007). The evolution was marked by the emergence of intractable epilepsy and liver failure, mimicking Alpers syndrome described in patients with POLG mutations.…”

Section: Discussionmentioning

confidence: 99%

“…The onset of the disease is between 1 and 2 years of age (Koskinen et al 1994). Recently, case studies of two children with early-onset encephalopathy and liver failure associated with Twinkle mutations were reported (Hakonen et al 2007). The phenotype was close to Alpers hepatocerebral syndrome (Alpers 1931), which is caused by mutations in POLG.…”

Section: Introductionmentioning

confidence: 99%

Abnormal Glycosylation Profile and High Alpha-Fetoprotein in a Patient with Twinkle Variants

et al. 2016

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The C10orf2 gene encodes Twinkle, a protein involved in mitochondrial DNA (mtDNA) replication. Twinkle mutations cause mtDNA deletion or depletion and are associated with a large spectrum of clinical symptoms including dominant progressive external ophthalmoplegia (adPEO), infantile-onset spinocerebellar ataxia (IOSCA), and early-onset encephalopathy. The diagnosis remains difficult because of the wide range of symptoms and lack of association with specific metabolic changes. We report herein a child with early-onset encephalopathy, unusual abnormal movements, deafness, and axonal neuropathy. All laboratory investigations were normal with the exceptions of high alpha-fetoprotein levels and an abnormal glycosylation profile. These abnormal parameters resulted in misdiagnosis as a previously unidentified congenital disorder of glycosylation (CDG) type I syndrome. Whole exome sequencing revealed two point mutations in C10orf2 that were confirmed by Sanger sequencing; neither had been previously reported. This report enlarges the clinical phenotype of Twinkle mutations and suggests that an abnormal glycosylation profile suggestive of CDG type I associated with high blood alpha-fetoprotein levels without obvious cause should prompt Twinkle sequencing.

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“…Mutations in C10orf2 have been associated with variable phenotypes, including infantile-onset spinocerebellar ataxia [11,[93][94][95][96][97], autosomal dominant PEO [98][99][100], and hepatocerebral MDS [101,102]. Mutations in C10orf2 are a rare cause of early-onset hepatocerebral MDS that has been reported in 5 children from 2 unrelated families.…”

Section: C10orf2-related Hepatocerebral Mdsmentioning

confidence: 99%

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

2013

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Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2,

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Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion

Cited by 182 publications

References 28 publications

Disease Variants of the Human Mitochondrial DNA Helicase Encoded by C10orf2 Differentially Alter Protein Stability, Nucleotide Hydrolysis, and Helicase Activity

Disease Variants of the Human Mitochondrial DNA Helicase Encoded by C10orf2 Differentially Alter Protein Stability, Nucleotide Hydrolysis, and Helicase Activity

Abnormal Glycosylation Profile and High Alpha-Fetoprotein in a Patient with Twinkle Variants

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

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