Clinical and molecular features of adPEO due to mutations in the Twinkle gene

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Abstract

We have analyzed Twinkle, the causative gene for autosomal dominant progressive external ophthalmoplegia (adPEO) on chromosome 10, in 11 Australian autosomal dominant progressive external ophthalmoplegia families of Caucasian origin, and investigated whether there are distinct molecular and clinical features associated with mutations in this gene. We found two new mutations in Twinkle, in 3 of the 11 pedigrees examined. One resides in the linker region of this gene while the other is in the primase domain. Both regions are highly conserved between species. Multiple deletions in the mtDNA from muscle are not always prominent and there are significant variations in the clinical presentation within and between families with mutations in the Twinkle gene. Therefore, genotype/phenotype predictions are difficult. No mutations were found in adenine nucleotide translocator 1 (ANT1), another known adPEO causative gene, in four of the seven remaining families investigated. Thus, Twinkle appears to be the most common gene associated with adPEO in Australian families.

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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