|Itkis YS, Rudenskaya GE, Tsygankova PG, Zakharova EY, Mikhailova SV (2010) Rare mitochondrial mutations in cases of Leigh disease. Abstract MiP2010.|
Link: Abstracts Session 3
Leigh syndrome, a case of mitochondrial disease, is a subacute necrotising encephalomyopathy frequently ascribed to mitochondrial respiratory chain deficiency in muscles and in a wide variety of tissues . Defects of mitochondrial function are genetically unique because the different components involved in this process are encoded by nuclear and mitochondrial genome. The clinical manifestation of this disease is extremely heterogeneous [2,3]. It depends on the severity of oxidative phosphorylation (OXPHOS) damage and on the ATP requirement of different organs and tissues. The aetiology of a mutation and a proportion of mutant mitochondrial DNA (mtDNA) in a cell define the severity of a disease. Thus, point mutations in mtDNA can lead to clinical polymorphism, affecting young and adult patients at any age . Very often in such cases it is difficult to predict a causative mutation .
Last year in our laboratory we performed mtDNA sequence analysis in blood cells of a small group of patients with Leigh-like phenotype and with excluded mutations in SURF1 gene and common mutations in mtDNA (such as T8993C/G substitution). We identified a total four different substitutions in five patients. Among these, in two different families it was the same substitution (13094T>C, ND5 region) but in patients with unlike manifestation. In the third patient we have found a mutation 13513G>A (ND5), which is reported as a frequent cause of Leigh-like syndrome . Also two unknown mutations (14441T>C in ND6 region and 8839G>C in ATP6) were found. However, here a supplementary investigation was required to prove these substitutions being pathogenic mutations but not rare polymorphisms [5,6].
Nowadays, detection of mutations is usually limited to frequent mutations in nuclear genes (genes SURF1, NDUFV1, NDUFS4, NDUFS7, etc.) and common mutations in the mitochondrial DNA. However, mutations in other mtDNA regions can be an important cause of oxidative phosphorylation disease as well and contributes to clinical variability of Leigh syndrome. Thus, it is recommended to deploy an analysis of mtATP6, ND1-ND6 regions of mtDNA as a routine screening for mitochondrial disorders with Leigh (Leigh-like) phenotype, because very often there is no evidence of causative mutation, if frequent mutations are excluded.
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2. Zeviani M, Di Donato S (2004) Mitochondrial disorders. Brain 127: 2153–2172.
3. Scheffler IE (2001) A century of mitochondrial research: achievements and perspectives. Mitochondrion 1: 3-31.
4. Chinnery PF (1993-2000) Mitochondrial Disorders Overview. GeneReviews [Internet].
5. Chinnery PF, Howell N, Andrews RM, Turnbull DM (1999) Mitochondrial DNA analysis: polymorphisms and pathogenicity. J. Med. Genet. 36: 505-510.
6. Mitchell AL, Elson JL, Howell N, Taylor RW, Turnbull DM (2006) Sequence variation in mitochondrial Complex I genes: mutation or polymorphism? J. Med. Genet. 43: 175–179.
• O2k-Network Lab: RU Moscow Itkis YS
Labels: MiParea: mtDNA;mt-genetics, nDNA;cell genetics, mt-Medicine, Patients Pathology: Inherited
Organism: Human Tissue;cell: Blood cells