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Other entities represented in this entry:
HGNC Approved Gene Symbol: TWNK
SNOMEDCT: 724227000;
Cytogenetic location: 10q24.31 Genomic coordinates (GRCh38) : 10:100,987,543-100,994,403 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q24.31 | Mitochondrial DNA depletion syndrome 7 (hepatocerebral type) | 271245 | Autosomal recessive | 3 |
| Perrault syndrome 5 | 616138 | Autosomal recessive | 3 | |
| Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 | 609286 | Autosomal dominant | 3 |
The TWNK gene encodes a mitochondrial protein with structural similarity to the phage T7 primase/helicase (GP4) and other hexameric ring helicases. The twinkle protein colocalizes with mtDNA in mitochondrial nucleoids, and its name derives from the unusual localization pattern reminiscent of twinkling stars (summary by Spelbrink et al., 2001).
Spelbrink et al. (2001) identified the C10ORF2 gene, which encodes a protein similar to T7 GP4, by searching for open reading frames (ORFs) in a region linked to PEOA3 (609286) on 10q24. C10ORF2 has a mitochondrial targeting sequence at the N terminus. The predicted full-length protein, which the authors designated twinkle, has 684 amino acids with a molecular mass of 77 kD. Spelbrink et al. (2001) identified a splice variant resulting from the use of a downstream exon 4 splice donor site that leads to a 43-bp insertion between the regular exon 4-exon 5 sequence. The protein encoded by the variant mRNA, which the authors called twinky, has a molecular mass of 66 kD and has 582 amino acids; it lacks residues 579 through 684 and terminates with 4 unique amino acids. Both cDNA variants, when expressed transiently in HEK293T cells, directed the synthesis of proteins close to the expected molecular masses. The authors found that C. elegans and Drosophila have similar proteins, also related to T7 GP4. S. pombe has a few homologs with low similarity, but Spelbrink et al. (2001) could not identify a related sequence in S. cerevisiae. Multiple sequence alignment of the various proteins showed greatest similarity in the domain responsible for helicase activity in the phage T7 protein, which is located in its C terminus. The degree of identity between the human and a partial mouse sequence is approximately 85%, whereas the identity between the mammalian and vertebrate sequences is 35 to 40%. Northern blot analysis detected full-length mRNAs of 4 kb, significantly larger than the 2.1-kb ORF. Twinkle was expressed at high relative levels in skeletal muscle and pancreas and at low levels in heart. The relative level of twinkle expression in skeletal muscle was probably underestimated because of the strong crossreacting alpha-actin mRNA species just below the beta-actin mRNA. Twinkle is localized to mitochondrial nucleoids and shows an unusual localization pattern reminiscent of twinkling stars. Cells overexpressing twinkle had a modestly increased mtDNA helicase activity. The function of twinkle was presumed to be critical for lifetime maintenance of human mitochondrial integrity.
Van Hove et al. (2009) noted that the twinkle protein contains 3 functional domains: a 3-prime helicase region, required for mtDNA replication, a linker region involved in oligomerization into a hexamer required for helicase activity, and a 5-primase domain. Most pathogenic mutations occur in the helicase or linker regions.
Farge et al. (2008) showed that purified recombinant human TWINKLE formed hexamers, even in the absence of Mg(2+) or ATP, at high ionic strength. The C-terminal domain of TWINKLE was essential for hexamer formation, but the N-terminal domain also contributed to proper hexamerization. TWINKLE interacted with both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), preferably with long ssDNA or dsDNA. The C-terminal helicase domain of TWINKLE was responsible for DNA binding, but the N-terminal domain specifically contributed to ssDNA-binding activity. ssDNA stimulated the intrinsic ATPase activity of TWINKLE. The N-terminal region of TWINKLE was not absolutely required for its ATPase activity, but it had a positive effect on levels of ATPase activity, as well as ssDNA-dependent stimulation, helicase activity, and DNA synthesis on a duplex DNA template.
Using recombinant protein expressed in E. coli, Longley et al. (2010) showed that human C10ORF2, which they called p72, bound both ssDNA and dsDNA, catalyzed DNA unwinding, and required ATP and Mg(2+) for helicase activity.
Sen et al. (2012) showed that recombinant human twinkle formed oligomers spontaneously, but that it formed hexamers specifically in the presence of MgUTP, which appeared to stabilize the hexameric state. Twinkle bound both ssDNA and dsDNA via different binding sites with distinct binding affinities. DNA binding was independent of Mg(2+) or nucleotide triphosphates (NTP). Twinkle showed unwinding activity predominantly with 5-prime-tailed dsDNA substrates in the presence of several NTPs and Mg(2+), and it required its NTPase activity for dsDNA unwinding. Unwinding of dsDNA was facilitated by inclusion of T7 gp2.5 single strand-binding protein or complementary ssDNA to prevent reannealing of the unwound displaced strand. Twinkle also showed UTP-independent DNA annealing of 2 ssDNA strands in the absence of gp2.5 or complementary ssDNA. Sen et al. (2012) concluded that twinkle is a bifunctional helicase with both unwinding and annealing activities.
TWINKLE comprises a DNA helicase domain and a primase domain joined by a flexible linker helix. Using negative stain analysis, Peter et al. (2019) showed that TWINKLE was present as a mixture of hexameric and heptameric species. These oligomers formed star-like structures with the helicase domain forming an internal ring and the primase domain extending into the solvent. TWINKLE underwent conformational changes in the presence of nucleotides, leading to structural compaction and repositioning of the primase domain and the formation of hexamers and heptamers with smaller diameters. The linker helix contacted the neighboring helicase domain, connecting 1 monomer to the next.
Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions, Autosomal Dominant, 3
In a Finnish family and a Pakistani family with autosomal dominant progressive external ophthalmoplegia (PEOA3; 609286), Spelbrink et al. (2001) identified 2 different heterozygous mutations in the C10ORF2 gene (606075.0001 and 606075.0002, respectively). Nine additional heterozygous mutations in the C10ORF2 gene (see, e.g., 606075.0003-606075.0007) were identified in 9 unrelated Italian PEO families and 1 British PEO family out of over 70 PEO families tested.
One of the mutations identified by Spelbrink et al. (2001) was a val368-to-ile (V368I) change, found in 2 Sicilian families with PEO. However, Arenas et al. (2003) reported that they found the same change in 1.2% of a normal control population and concluded that the change is a nonpathogenic polymorphism. A proband from 1 of the families with the mutation was later found to have mutations in the POLG gene (174763), which was presumably the disease-causing gene.
In a patient with sporadic PEO, Van Goethem et al. (2003) identified a heterozygous arg334-to-gln substitution in the C10ORF2 gene (R334Q; 606075.0008) cooccurring with a heterozygous gly848-to-ser mutation in the POLG gene (G848S; 174763.0006). Both mutations were absent in 180 Belgian control chromosomes. No mutations were found in the ANT1 gene (SLC25A4; 103220).
In 5 patients from 2 unrelated French families with autosomal dominant PEOA3, Echaniz-Laguna et al. (2010) identified a heterozygous mutation in the C10ORF2 gene (R374W; 606075.0014). Common features included ptosis, ophthalmoplegia, hearing loss, sensory axonal neuropathy, and proximal muscle weakness. The older patients, including deceased affected family members, developed abnormal gait, dysphagia, dysphonia, and late-onset dementia in their seventies and eighties. The findings expanded the phenotypic spectrum of PEOA3.
Autosomal Recessive Mitochondrial DNA Depletion Syndrome 7 (Hepatocerebral Type)
In Finnish patients with autosomal recessive mitochondrial DNA depletion syndrome-7 (MTDPS7; 271245), manifest as infantile-onset spinocerebellar ataxia (IOSCA), Nikali et al. (2005) identified homozygosity for a founder mutation in the C10ORF2 gene, Y508C (606075.0012). The phenotype was a severe neurodegenerative disorder characterized by progressive atrophy of the cerebellum, brainstem, and spinal cord and sensory axonal neuropathy, Hakonen et al. (2008) found that patients with the Y508C mutation had mtDNA depletion in brain tissue and liver.
In 2 Algerian sibs and a first cousin with autosomal recessive mitochondrial DNA deletion syndrome-7, Sarzi et al. (2007) identified a homozygous mutation in the C10ORF2 gene (606075.0011). All 3 patients were born of first-cousin parents and showed a severe hepatocerebral phenotype characterized by neonatal hypotonia, mild liver insufficiency, increased serum and CSF lactate, psychomotor retardation, seizures, and peripheral neuropathy. All 3 patients died by age 3 years. Mitochondrial DNA depletion was severe in 2 patients examined, with mtDNA levels in liver of 8% and 5% of normal, respectively.
Perrault Syndrome 5
In 4 women from 2 unrelated families with Perrault syndrome-5 (PRLTS5; 616138), Morino et al. (2014) identified compound heterozygous mutations in the C10ORF2 gene (606075.0016-606075.0019). The mutations, which were found by exome sequencing, segregated with the disorder in the families. All 4 mutations occurred in the helicase domain and were predicted to adversely affect enzyme activity based on structure, but functional studies of the variants were not performed. The patients presented as teenagers with primary amenorrhea and sensorineural hearing loss, and later developed ataxia and sensory axonal neuropathy. Morino et al. (2014) noted that the report expanded the phenotypic spectrum associated with recessive C10ORF2 mutations to include less severe neurologic involvement compared to MTDPS7 and a clinical presentation consistent with Perrault syndrome.
Functional Studies of Mutant C10ORF2
Longley et al. (2010) assayed the DNA-binding, DNA-unwinding, and ATPase activities of 20 different human p72 mutants, each containing a different amino acid substitution associated with mitochondrial disease. All 20 mutant forms exhibited helicase activity under the standard reaction conditions. Most substitutions altered DNA binding or the kinetics of ATP hydrolysis or helicase activity of the mutant protein, but none profoundly altered p72 function.
Peter et al. (2019) found that TWINKLE with PEOA3-associated mutations in the linker helix could form hexamers and heptamers, albeit at lower levels than wildtype. However, these mutations disrupted subunit flexibility, thereby reducing or eliminating TWINKLE catalytic activity. PEOA3-associated mutations in the TWINKLE primase domain, in close proximity to the primase-linker boundary, targeted the oligomerization process and caused structural and functional changes in TWINKLE.
In a review of 29 pathogenic mutations in the C10ORF2 gene, Van Hove et al. (2009) found that all mutations clustered in a short region between residues arg303 and tyr508, involving the primase domains V and VI, the linker region, and the helicase domain. A phenotypic review of 56 patients with these mutations showed that most develop symptoms as adults between age 17 and 73 years. The most common symptoms were progressive external ophthalmoplegia and ptosis (96%). Almost half (46%) had symptoms of myopathy, usually described as limb-girdle, and 14% had a polyneuropathy. Other common features included brainstem symptoms (18%), depression (13%), and parkinsonism or tremors (13%), with less frequent features including diabetes mellitus, ataxia, cataract, memory loss, hearing loss, and cardiac problems.
Tyynismaa et al. (2004) reported that Twinkle expression patterns are not conserved between human and mouse but are synchronized with the adjacent gene Mrpl43, suggesting a shared promoter. The authors generated 2 transgenic mouse lines overexpressing wildtype Twinkle. Increased expression of Twinkle in muscle and heart increased mtDNA copy number up to 3-fold higher than controls, more than any other factor reported to date. In cultured human cells, reduced expression of Twinkle by RNA interference mediated a rapid drop in mtDNA copy number, further supporting the in vivo results. The authors concluded that Twinkle helicase is essential for mtDNA maintenance and that it may be a key regulator of mtDNA copy number in mammals.
Tyynismaa et al. (2005) generated transgenic mice overexpressing mouse Twinkle due to mutations corresponding to the PEO-associated mutations ala359 to thr (A359T; 606075.0003) and duplication of amino acids 352 to 364 (606075.0001) in humans. Multiple mtDNA deletions accumulated in the tissues of mutant mice, resulting in progressive respiratory dysfunction and chronic late-onset mitochondrial disease starting at 1 year of age. The muscles of mutant mice faithfully replicated features of PEO patients. These mice had progressive deficiency of cytochrome c oxidase in distinct neuronal populations, but they did not display premature aging.
Goffart et al. (2009) investigated the effects of dominant Twinkle PEO mutations in human cell culture and the Deletor mouse model, which expresses a dominant PEO mutation in Twinkle. Expression of dominant Twinkle mutations led to accumulation of mtDNA replication intermediates in cell culture. This indicated severe replication pausing or stalling and caused mtDNA depletion. Enhanced accumulation of replication intermediates was evident also in 6-week-old Deletor mice compared with wildtype littermates, even though mtDNA deletions accumulated in a late-onset fashion in this model. In vitro assays showed functional defects in the various Twinkle mutants and broadly agreed with the cell culture phenotypes such as the level of mtDNA depletion and the level of accumulation of replication intermediates. The authors suggested that mtDNA replication pausing or stalling is the common consequence of Twinkle PEO mutations that predisposes to multiple deletion formation.
Tyynismaa et al. (2010) studied the skeletal muscle gene expression profiles of mice with late-onset mitochondrial myopathy due to a dominant mutation in twinkle. The global gene expression pattern of the mouse skeletal muscle showed induction of pathways involved in amino acid starvation response and activation of Akt (164730) signaling. Furthermore, the muscle showed induction of a fasting-related hormone, fibroblast growth factor-21 (FGF21; 609436). Fgf21 was also elevated in the mouse serum, and the animals showed widespread changes in their lipid metabolism. The authors proposed that respiratory chain deficiency may induce a mitochondrial stress response, with local and global changes mimicking starvation, in a normal nutritional state, which may have important implications for understanding the metabolic consequences of mitochondrial myopathies.
In affected members of a Finnish family with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), originally reported by Suomalainen et al. (1992), Spelbrink et al. (2001) identified a 39-bp duplication (nucleotides 1053-1092) of the C10ORF2 gene, resulting in a duplication of amino acids 352-364 of twinkle. There was complete segregation of this duplication with the disease phenotype in this pedigree. The mutation was not identified in over 400 Finnish controls. Individuals with this duplication had severe retarded depression and avoidant personality features in addition to PEO. Three autopsies from family members showed the highest amounts of deleted mtDNA in the cerebral cortex and basal ganglia (approximately 60% of total mtDNA), followed by skeletal muscle and heart, with only small amounts in kidney. This distribution, however, did not correspond exactly with the pattern of twinkle expression, arguing for variable sensitivity of different tissues to twinkle dysfunction.
In affected members of a Pakistani family reported by Li et al. (1999) with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), Spelbrink et al. (2001) identified a heterozygous 1423G-C transversion in the C10ORF2 gene, resulting in an ala475-to-pro (A475P) substitution. This mutation was not identified in 194 controls of various ethnic origin, including 88 of Pakistani/Indian origin.
In affected members of a large consanguineous Italian family segregating autosomal dominant progressive ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), Spelbrink et al. (2001) identified an ala359-to-thr (A359T) substitution in the twinkle protein. Two homozygous individuals had a more severe phenotype with earlier onset than their heterozygous relatives. This mutation was not detected in a control group of 100 individuals.
Longley et al. (2010) found that several disease-associated substitutions in p72, including A359T, which is located within the linker region, reduced the stability of the p72 hexamer. A359T also reduced p72 DNA-binding affinity and the velocities of p72 helicase and ATPase activities.
In affected members of a pedigree segregating autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), Spelbrink et al. (2001) identified a trp474-to-cys (W474C) substitution in the twinkle protein. This mutation was not identified in 100 controls.
In affected members of a pedigree segregating autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), Spelbrink et al. (2001) identified a trp315-to-leu (W315L) substitution in the twinkle protein. This mutation was in a moderately conserved segment of the linker region and was not identified in 100 controls.
In affected members of an Italian family segregating autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), Spelbrink et al. (2001) identified a 1061G-C transversion in the C10ORF2 gene, resulting in an arg354-to-pro (R354P) substitution. This mutation was not identified in 100 normal controls.
In affected members of an Italian family segregating autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), Spelbrink et al. (2001) identified a 1442T-C transition in the C10ORF2 gene, resulting in a leu381-to-pro (L381P) substitution. This mutation segregated strictly with the disease in this family and was not identified in 100 controls.
Longley et al. (2010) found that several disease-associated substitutions in p72, including L381P, which is located between the linker region and helicase domain, reduced the stability of the p72 hexamer. L381P also increased the rate of ATP hydrolysis by p72 over that measured for wildtype p72. However, elevated ATP hydrolysis was not accompanied by proportionately higher DNA helicase activity, implying that nucleotide hydrolysis and DNA translocation may be partially uncoupled by the L381P substitution.
In a sporadic case of progressive external ophthalmoplegia (see 609286 and 157640), Van Goethem et al. (2003) identified heterozygosity for a 1031G-A transition in the C10ORF2 gene, resulting in an arg334-to-gln (R334Q) mutation, and heterozygosity for a gly884-to-ser mutation in the POLG gene (G884S; 174763.0006), indicating a digenic mode of inheritance. Clinical onset in the patient was at 52 years of age with blepharoptosis, depression, and levodopa-responsive Parkinson disease. Later she suffered from severe dysphagia leading to cachexia and necessitating enteric feeding. Sudden death, attributed to cardiac arrest, occurred at age 66 years.
In affected members of a large family with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), Lewis et al. (2002) identified a heterozygous 1106C-A transversion in the C10ORF2 gene, resulting in a ser369-to-tyr (S369Y) substitution in the linker region of the protein. Affected members of a second presumably unrelated family were found to have the same mutation. Both families originated from the same region in Tasmania, and haplotype analysis showed a common haplotype. The S369Y mutation was not identified in 100 control individuals.
In 2 sibs with autosomal dominant progressive external ophthalmoplegia with mitochondrial deletions-3 (PEOA3; 609286), Hudson et al. (2005) identified a heterozygous 955A-G transition in the C10ORF2 gene, resulting in a lys319-to-glu (K319E) substitution. The 45-year-old proband had ptosis, external ophthalmoplegia, moderate proximal weakness of the legs, severe sensory ataxia, and moderate dementia. His sister had ptosis, ophthalmoplegia, proximal leg weakness, dysarthria, ataxia, and signs of a sensory neuropathy. She subsequently developed dementia, diabetes, and seizures. At age 41 she developed status epilepticus and died. The mutation was not identified in the parents' blood, hair follicles, buccal mucosa, or urinary epithelium, indicating germline mosaicism. Hudson et al. (2005) emphasized that the findings broadened the phenotype associated with C10ORF2 mutations, and noted the phenotypic overlap with sensory ataxia neuropathy, dysarthria, and ophthalmoparesis (SANDO; 607459), The authors also noted that the mutation caused the replacement of a basic amino acid with an acidic amino acid in a conserved region of the protein, which may have accounted for the more severe phenotype observed in their patients compared to other patients with C10ORF2 mutations.
In 2 Algerian sibs and a first cousin with autosomal recessive mitochondrial DNA depletion syndrome-7 (MTDPS7; 271245), Sarzi et al. (2007) identified a homozygous 1370C-T transition in the C10ORF2 gene, resulting in a thr457-to-ile (T457I) substitution. All 3 patients were born of first-cousin parents and showed a severe hepatocerebral phenotype characterized by neonatal hypotonia, mild liver insufficiency, increased serum and CSF lactate, psychomotor retardation, seizures, and peripheral neuropathy. All 3 patients died by age 3 years. Mitochondrial DNA depletion was severe in 2 patients examined, with mtDNA levels in liver of 8% and 5% of normal, respectively. Molecular modeling predicted that the mutation is located in the interface between 2 monomers of the hexameric enzyme. In vitro functional expression studies showed that the T457I mutant protein had a more than 50% reduction in helicase activity. Family members who were presumed obligate carriers were unaffected.
In Finnish patients with mitochondrial DNA depletion syndrome-7 (MTDPS7; 271245) manifest as infantile-onset autosomal recessive spinocerebellar ataxia, Nikali et al. (2005) identified homozygosity for a founder mutation in exon 3 of the C10ORF2 gene: a 1708A-G transition resulting in a tyr508-to-cys (Y508C) substitution in the twinkle and twinky proteins. One other Finnish patient was compound heterozygous for Y508C inherited from his mother and a silent mutation (1472C-T) in exon 2 of C10ORF2 inherited from his father that affected allelic expression levels. Carrier frequency for the mutation peaked at approximately 2.5% in south central Finland. The Y508C mutation was not found in unaffected family members, 712 Finnish control samples, or 95 non-Finnish controls; the silent mutation was not found in 207 Finnish or 95 foreign controls.
In a 71-year-old woman who developed autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286) at age 51, Van Hove et al. (2009) identified a heterozygous 908G-A transition in exon 1 of the TWNK gene, resulting in an arg303-to-gln (R303Q) substitution in the first amino acid of primase motif V. The mutation was not found in 250 control chromosomes. Other clinical features included cataracts, adult-onset diabetes mellitus, distal paresthesias, sensorineural hearing loss, mild sensory ataxia, and chronic progressive limb-girdle muscle weakness. Brain MRI showed scattered white matter changes in the subcortical and periventricular regions. Skeletal muscle biopsy showed a few ragged-red fibers and multiple mtDNA deletions.
In 5 patients from 2 unrelated French families with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), Echaniz-Laguna et al. (2010) identified a heterozygous 1120C-T transition in the C10ORF2 gene, resulting in an arg374-to-trp (R374W) substitution in the linker region. Common features included ptosis, ophthalmoplegia, hearing loss, sensory axonal neuropathy, and proximal muscle weakness. The older patients, including deceased affected family members, developed abnormal gait, dysphagia, dysphonia, and late-onset dementia in their seventies and eighties.
In 2 Finnish sibs with mtDNA depletion syndrome-7 (MTDPS7; 271245), manifest as infantile-onset spinocerebellar ataxia, Hakonen et al. (2007) identified compound heterozygosity for 2 mutations in the C10ORF2 gene: a 952G-A transition, resulting in an ala318-to-thr (A318T) substitution, and the Y508C mutation (606075.0012). The phenotype was severe, showing hypotonia, athetosis, sensory neuropathy, ataxia, hearing deficit, ophthalmoplegia, and refractory epilepsy. The older sib died at age 4.5 years of status epilepticus. One patient had mtDNA depletion in the liver. Each unaffected parent was heterozygous for 1 of the mutations. The A318T mutation was not present in 120 Finnish control chromosomes. Hakonen et al. (2007) noted that the phenotype was reminiscent of Alpers syndrome (MTDPS4B; 203700), which is caused by mutation in the POLG gene (174763).
In 2 Japanese sisters with Perrault syndrome-5 (PRLTS5; 616138), Morino et al. (2014) identified compound heterozygous mutations in the C10ORF2 gene: a c.1172G-A transition resulting in an arg391-to-his (R391H) substitution at a less conserved residue, and a c.1754A-G transition resulting in an asn585-to-ser (N585S; 606075.0017) substitution at a conserved residue. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project databases and were absent from in-house control exomes. Both mutations occurred in the helicase domain and were predicted to adversely affect enzyme activity based on structure, but functional studies of the variants were not performed.
For discussion of the asn585-to-ser (N585S) mutation in the C10ORF2 gene that was found in 2 sisters with Perrault syndrome-5 (PRLTS5; 616138) by Morino et al. (2014), see 606075.0016.
In 2 sisters of paternal Greek ancestry and maternal mixed European ancestry with Perrault syndrome-5 (PRLTS5; 616138), Morino et al. (2014) identified compound heterozygous mutations in the C10ORF2 gene: a c.1321T-G transversion resulting in a trp441-to-gly (W441G) substitution at a conserved residue, and a c.1519G-A transition resulting in a val507-to-ile (V507I; 606075.0019) substitution at a less well-conserved residue. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project databases and were absent from in-house control exomes: V507I was found once in the Exome Sequencing Project database. Both mutations occurred in the helicase domain and were predicted to adversely affect enzyme activity based on structure, but functional studies of the variants were not performed.
For discussion of the val507-to-ile (V507I) mutation in the C10ORF2 gene that was found in 2 sisters with Perrault syndrome-5 (PRLTS5; 616138) by Morino et al. (2014), see 606075.0018.
Arenas, J., Briem, E., Dahl, H., Hutchison, W., Lewis, S., Martin, M. A., Spelbrink, H., Tiranti, V., Jacobs, H., Zeviani, M. The V368I mutation in twinkle does not segregate with adPEO. (Letter) Ann. Neurol. 53: 278 only, 2003. [PubMed: 12557300] [Full Text: https://doi.org/10.1002/ana.10430]
Echaniz-Laguna, A., Chanson, J. B., Wilhelm, J. M., Sellal, F., Mayencon, M., Mohr, M., Tranchant, C., de Camaret, B. M. A novel variation in the Twinkle linker region causing late-onset dementia. Neurogenetics 11: 21-25, 2010. [PubMed: 19513767] [Full Text: https://doi.org/10.1007/s10048-009-0202-4]
Farge, G., Holmlund, T., Khvorostova, J., Rofougaran, R., Hofer, A., Falkenberg, M. The N-terminal domain of TWINKLE contributes to single-stranded DNA binding and DNA helicase activities. Nucleic Acids Res. 36: 393-403, 2008. [PubMed: 18039713] [Full Text: https://doi.org/10.1093/nar/gkm1025]
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Li, F. Y., Tariq, M., Croxen, R., Morten, K., Squier, W., Newsom-Davis, J., Beeson, D., Larsson, C. Mapping of autosomal dominant progressive external ophthalmoplegia to a 7-cM critical region on 10q24. Neurology 53: 1265-1271, 1999. [PubMed: 10522883] [Full Text: https://doi.org/10.1212/wnl.53.6.1265]
Longley, M. J., Humble, M. M., Sharief, F. S., Copeland, W. C. Disease variants of the human mitochondrial DNA helicase encoded by C10orf2 differentially alter protein stability, nucleotide hydrolysis, and helicase activity. J. Biol. Chem. 285: 29690-29702, 2010. [PubMed: 20659899] [Full Text: https://doi.org/10.1074/jbc.M110.151795]
Morino, H., Pierce, S. B., Matsuda, Y., Walsh, T., Ohsawa, R., Newby, M., Hiraki-Kamon, K., Kuramochi, M., Lee, M. K., Klevit, R. E., Martin, A., Maruyama, H., King, M.-C., Kawakami, H. Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features. Neurology 83: 2054-2061, 2014. [PubMed: 25355836] [Full Text: https://doi.org/10.1212/WNL.0000000000001036]
Nikali, K., Suomalainen, A., Saharinen, J., Kuokkanen, M., Spelbrink, J. N., Lonnqvist, T., Peltonen, L. Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins twinkle and twinky. Hum. Molec. Genet. 14: 2981-2990, 2005. [PubMed: 16135556] [Full Text: https://doi.org/10.1093/hmg/ddi328]
Peter, B., Farge, G., Pardo-Hernandez, C., Tangefjord, S., Falkenberg, M. Structural basis for adPEO-causing mutations in the mitochondrial TWINKLE helicase. Hum. Molec. Genet. 28: 1090-1099, 2019. Note: Erratum: Hum. Molec. Genet. 29: 528 only, 2020. [PubMed: 30496414] [Full Text: https://doi.org/10.1093/hmg/ddy415]
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