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Mitochondrial Medicine & Neurogenetics (MMN)

Quest for Novel Genes

The MMN is actively engaged in the search for new genes causing mitochondrial and other types of neurological disease. It is from this work that the PITRM1 project was generated.

So far, PITRM1 is the only truly novel mitochondrial gene discovered by this work. Although the gene itself had been recognised and linked to a mitochondrial function, namely the digestion of mitochondrial targeting sequences after cleavage by the mitochondrial matrix peptidase, its role in causing disease had never been shown.

These studies have been performed in collaboration with colleagues from the Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway, particularly: Per Knappskog, Stefan Johansson and Helge Boman.

Some of our other projects:

  1. PNKP Mutations Identified by Whole-Exome Sequencing in a Norwegian Patient with Sporadic Ataxia and Edema. Cerebellum 2016 May 10. Using exome sequencing, we identified PNKP mutations in a Norwegian woman with ataxia and ocular apraxia (AOA). This patient had the typical findings with cognitive dysfunction, peripheral neuropathy, cerebellar dysarthria, horizontal nystagmus, oculomotor apraxia, and severe truncal and appendicular ataxia. In addition, she had hypoalbuminemia and massive lower limb edema which showed some improvement with treatment. Sequencing identified two heterozygous mutations, one in exon 14 (c.1196T>C, p.Leu399Pro) and one in exon 16 (c.1393_1396del, p.Glu465*). This is the first non-Portuguese patient with AOA due to PNKP mutations and provides independent verification that PNKP mutations cause AOA.
  2. ADCK3 mutations with epilepsy, stroke-like episodes and ataxia: a POLG mimic? Eur J Neurol. 2016 Jul;23(7):1188-94. We used exome sequencing to investigate 3 new patients with a phenotype resembling POLG. Mutations were identified by whole exome sequencing and in two measurement of skeletal muscle CoQ10 was performed. All patients presented with childhood-onset epilepsy and progressive cerebellar ataxia and 3 had epilepsia partialis continua and stroke-like episodes affecting the posterior brain. Electroencephalography showed focal epileptic activity in the occipital and temporal lobes. Genetic investigation revealed ADCK3 mutations in all patients including a novel change in exon 15: c.T1732G, p.F578V. There was no apparent genotype-phenotype correlation. With this work we showed that ADCK3 mutations can cause a combination of progressive ataxia and acute epileptic encephalopathy with stroke-like episodes. The clinical, radiological and electrophysiological features of this disorder mimic the phenotype of polymerase gamma (POLG) related encephalopathy and it is therefore suggested that ADCK3 mutations be considered in the differential diagnosis of mitochondrial encephalopathy with POLG-like features.
  3. Novel SLC19A3 Promoter Deletion and Allelic Silencing in Biotin-Thiamine-Responsive Basal Ganglia Encephalopathy. PLoS One. 2016 Feb 10;11(2):e0149055. We investigated two siblings with early-onset encephalopathy dystonia and epilepsy and using whole-exome sequencing revealed a novel single heterozygous SLC19A3 mutation (c.337T>C). Although Sanger-sequencing and copy-number analysis revealed no other aberrations, RNA-sequencing in brain tissue suggested the second allele was silenced. Whole-genome sequencing resolved the genetic defect by revealing a novel 45,049 bp deletion in the 5'-UTR region of the gene abolishing the promoter. High dose thiamine and biotin therapy was started in the surviving sibling who remains stable. In another patient two novel compound heterozygous SLC19A3 mutations were found. He improved substantially on thiamine and biotin therapy.