Mutations in the mitochondrial tRNA(Ser(AGY)) gene are associated with deafness, retinal degeneration, myopathy and epilepsy

作者：Tuppen Helen A L; Naess Karin; Kennaway Nancy G; Al Dosary Mazhor; Lesko Nicole; Yarham John W; Bruhn Helene; Wibom Rolf; Nennesmo Inger; Weleber Richard G; Blakely Emma L; Taylor Robert W; McFarland Robert^*

来源：European Journal of Human Genetics, 2012, 20(8): 897-904.

DOI：10.1038/ejhg.2012.44

• deafness
• retinitis pigmentosa
• mt-tRNA(Ser(AGY))
• mutation

Although over 200 pathogenic mitochondrial DNA (mtDNA) mutations have been reported to date, determining the genetic aetiology of many cases of mitochondrial disease is still not straightforward. Here, we describe the investigations undertaken to uncover the underlying molecular defect(s) in two unrelated Caucasian patients with suspected mtDNA disease, who presented with similar symptoms of myopathy, deafness, neurodevelopmental delay, epilepsy, marked fatigue and, in one case, retinal degeneration. Histochemical and biochemical evidence of mitochondrial respiratory chain deficiency was observed in the patient muscle biopsies and both patients were discovered to harbour a novel heteroplasmic mitochondrial tRNA (mt-tRNA)(Ser(AGY)) (MTTS2) mutation (m.12264C %26gt; T and m.12261T %26gt; C, respectively). Clear segregation of the m.12261T %26gt; C mutation with the biochemical defect, as demonstrated by single-fibre radioactive RFLP, confirmed the pathogenicity of this novel variant in patient 2. However, unusually high levels of m.12264C %26gt; T mutation within both COX-positive (98.4 +/- 1.5%) and COX-deficient (98.2 +/- 2.1%) fibres in patient 1 necessitated further functional investigations to prove its pathogenicity. Northern blot analysis demonstrated the detrimental effect of the m.12264C %26gt; T mutation on mt-tRNA(Ser(AGY)) stability, ultimately resulting in decreased steady-state levels of fully assembled complexes I and IV, as shown by blue-native polyacrylamide gel electrophoresis. Our findings expand the spectrum of pathogenic mutations associated with the MTTS2 gene and highlight MTTS2 mutations as an important cause of retinal and syndromic auditory impairment. European Journal of Human Genetics (2012) 20, 897-904; doi:10.1038/ejhg.2012.44; published online 29 February 2012

• 出版日期2012-8