Clinical and molecular features of adPEO due to mutations in the Twinkle gene
Introduction
Normal human mitochondrial function involves a highly complex interaction between the nuclear and mitochondrial genomes. Hence, mutations in both mitochondrial and nuclear encoded genes can cause mitochondrial dysfunction and disease. A group of autosomally inherited mitochondrial diseases is associated with mtDNA deletions. While progressive external ophthalmoplegia (PEO) is a prominent feature, additional and variable clinical features are usually present, as for example in recessively inherited mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). The mutated gene in MNGIE, thymidine phosphorylase (TP), was identified in 1999 [1].
Autosomal dominant PEO (adPEO) is clinically heterogeneous, and may include other features such as deafness, cataracts, depression, levodopa responsive Parkinsonism and sensory ataxic axonal neuropathy [2], [3], [4]. AdPEO is also genetically heterogeneous. At least three genes are known to cause the disease: adenine nucleotide translocator 1 (ANT1, chromosome 4) [5], DNA polymerase γ (POLG, chromosome 15) [6], and Twinkle (chromosome 10) [7].
Mutations in the Twinkle gene appear to be a common cause of adPEO. We have previously described a family with adPEO linked to chromosome 10 [8]. Here, we report a novel Twinkle gene mutation, S369Y, in this pedigree. This mutation was also found in another, possibly related, pedigree. A second novel mutation, P335L, was identified in another adPEO family. The clinical features are quite variable both within and between families, therefore making any type of genotype/phenotype correlation difficult.
Section snippets
DNA extraction
Genomic DNA was isolated from blood using the salting out lysis procedure [9] and from muscle biopsies using QiaAmp Tissue Kit (Qiagen Australia) according to manufacturer's instructions.
Southern blot analysis
Southern blot analysis of 2.5–5 μg of human genomic lymphoblast and/or muscle DNA was performed as previously described [10].
DNA amplification
All oligonucleotide primers were synthesized by Genset (Singapore). Sequences were as described in Spelbrink et al. [7]. All reactions were cycled on a PC-960G Thermal Cycler machine
Clinical features
Since the previous description of family 1 [8], we have investigated an additional branch of this large family (Fig. 1). A 40-year-old individual (V-31) developed fatigue in his late teens, ptosis in his late twenties, and then ophthalmoplegia. In recent years, he has developed exertional muscle pain and generalized fatigue. Other symptoms are poor balance, blurred vision but no diplopia, and occasional palpitations. An ECG has shown a right bundle branch block. His mother had surgically
Discussion
We have identified mutations in the Twinkle gene in three of 11 Australian adPEO families. We found two novel mutations. One of the new mutations, S369Y, was found in two supposedly unrelated families who do however originate from the same region in Tasmania. Haplotype analysis in II-4 from family 2 and V-13, IV-7, IV-8 and V-31 from family 1 with markers surrounding the Twinkle gene showed a common haplotype, suggesting that the two families are related. A change in the Ser369 residue has also
Acknowledgements
We thank Dr. Martin Delatycki, Dr. David Mackey, Dr. John Christodoulou, Dr. Matt Edwards, Dr. Jane Rice and Professor Phillip Thompson for the referral and examination of patients, Dr. Rosetta Marotta and Dr. David Thorburn for the DNA samples, Mr. Tom Milovac for the assistance with Southern blots and Dr. Shehnaaz Manji for sequencing of some samples. Professor Peter Blumbergs examined the muscle biopsy in family 3 and Dr. Xenia Dennett all other biopsies. This work was supported by the NHMRC
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Two novel mutations in PEO1 (Twinkle) gene associated with chronic external ophthalmoplegia
2011, Journal of the Neurological SciencesCitation Excerpt :Recessive PEO1 mutations result in severe and early clinical presentations such as infantile-onset spinocerebellar ataxia [9] and a hepatocerebral mtDNA depletion disorder [10,11]. Conversely, dominantly inherited mutations account for autosomal dominant progressive external ophthalmoplegia (adPEO) characterised by ptosis and ophthalmoparesis, with COX-deficient and ragged-red fibres and multiple mtDNA deletions in muscle [12]. We previously reported that PEO1 mutations occur in 17.9% of PEO cases in a large cohort of patients with muscle multiple mtDNA deletions [13].
The human mitochondrial replication fork in health and disease
2010, Biochimica et Biophysica Acta - BioenergeticsNovel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia and multisystem failure
2009, Neuromuscular DisordersCitation Excerpt :ANT1 encodes the adenine nucleotide translocator 1, POLG encodes polymerase gamma and PEO1 encodes twinkle which is a hexameric DNA helicase involved in mtDNA replication and stability [2–4]. To date, most mutations in PEO1 have been reported in Caucasians [5–10]. Clinical features range from isolated PEO to multisystem disorders [1].
Phenotype and clinical course in a family with a new de novo Twinkle gene mutation
2008, Neuromuscular DisordersCitation Excerpt :Mutations in PEO1 have been reported in 23 families. In six of these families, clinical findings were reported to range from isolated chronic progressive external ophthalmoplegia (CPEO) to multisystem disorders [3–7]. In vitro[8] and mouse [9] studies suggest that mutations in PEO1 cause a time-dependent accumulation of multiple mtDNA deletions, which points to a progressive nature of the disease.