Novel Missense Mitochondrial ND4L Gene Mutations in Friedreich's Ataxia

Document Type: Original Article

Authors

Department of Biology, Science School, Yazd University, Yazd, Iran.

Abstract

Objective(s)
The mitochondrial defects in Friedreich's ataxia have been reported in many researches. Mitochondrial DNA is one of the candidates for defects in mitochondrion, and complex I is the first and one of the largest catalytic complexes of oxidative phosphorylation (OXPHOS) system.
Materials and Methods
We searched the mitochondrial ND4L gene for mutations by TTGE and sequencing on 30 FRDA patients and 35 healthy controls.
Results
We found 3 missense mutations [m.10506A>G (T13A), m.10530G>A (V21M), and m.10653G>A (A62T)] in four patients whose m.10530G>A and m.10653G>A were not reported previously. In two patients, heteroplasmic m.10530G>A mutation was detected. They showed a very early ataxia syndrome. Our results showed that the number of mutations in FRDA patients was higher than that in the control cases (P= 0.0287).
Conclusion
Although this disease is due to nuclear gene mutation, the presence of these mutations might be responsible for further mitochondrial defects and the increase of the gravity of the disease. Thus, it should be considered in patients with this disorder.

Keywords


1. Harding AE. Friedreich’s ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain 1981; 104:589-620.

2. Mateo I, Llorca J, Volpini V, Corral J, Berciano J, Combarros O. Expanded GAA repreats and clinicls variations in Friedreich’s ataxia. Acta Neurol Scand 2004; 109:75-78.

3. Campuzano V, Monermini L, Molto MD, Pianese L, Cossee M. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996; 271:1423–1427.

4. Campuzano V, Montermini L, Lutz Y, Cova L, Hindelang C, Jiralerspong S, et al. Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet 1997; 6:1771-1780.

5. Tan G, Chen LS, Lonnerdal B, Gellera C, Taroni FA, Cortopassi GA. Frataxin expression rescues mitocondral dysfunctions in FA cells. Hum Mol Genet 2001; 19:2099-20107.

6. Cooper JM, Mann VM, Krige D, Schapira AHV. Human mitochondrial complex I dysfunction. BBA 1992; 1101:198– 203.

7. Kish SJ, Bergeron C, Rajput A, Dozic S, Masdrogiacomo F, Chang L. Brain cytochrome oxidase in Alzheimers disease. J Neurochem. 1992; 59: 776–779.

8. Schapira AHV, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondrial complex I deficiency in Parkinsons disease. J Neurochem. 1990; 54:823– 827.

9. Heales  SJR,  Bolanos  JP,  Stewart  VC,  Brookes  PS,  Land  JM,  Clark  JB.  Nitric  oxiade,  mitochondria  and neurological disease. Biochim Biophys Acta 1999; 1410:215– 228.

10.  Lu F, Selak M, O'Connor J, Croul S, Lorenzana C, Butunoi C, et al. Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in lesions of multiple sclerosis. J Neurol Sci 2000; 177:95– 103.

11. Bradley J, Blake JC, Chamberlain S, Thomas PK, Cooper JM, Schapira AHV. Clinical biochemical and molecular genetic correlations in Friedreich’s ataxia. Hum Mol Gen 2000; 9:275-282.

12.  Heidari MM, Houshmand M, Hosseinkhani S, Nafissi S, Khatami M. Complex I and ATP content deficiency in lymphocytes from Friedreich’s Ataxia. Can J Neurol Sci 2009; 36:26-31.

13. Heidari MM, Houshmand M, Hosseinkhani S, Nafissi S, Scheiber-Mojdehkar B, Khatami M. A novel mitochondrial heteroplasmic C13806A point mutation associated with Iranian Friedreich’s ataxia. Cell Mol Neurobiol 2009; 29:225-233.

14.  Geffroy  G,  Barbeau  A,  Breton  G.  Clinical  description  and  roentgenologic  evaluation  of  patients  with Friedreich’s ataxia. Can J Neurol Sci 1976; 3:279–286.

15.  Anderson S, Bankier AT, Barrel BG, de Bruijn MHL, Coulson AR, Drouin J, et al. Sequence and organization of the human mitochondrial genome. Nature 1981; 290:457-465.

16.  MITOMAP:a human mitochondrial genome database. 2009. Available At: http://www.mitomap.org/.

17.  Garnier J, Osguthorpe DJ, Robson B. Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J Mol Biol 1978; 120:97-120.

18.  Kyte J, Doolittle RF. A simple method for displaying the hydropathic character of a protein. J Mol Biol 1982; 157:105-132.

19. Howell N, Bindoff LA, McCullough DA, Kubacka I, Poulton J, Mackey D, et al. Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. Am J Hum Genet 1991; 49:939–950.

20.  Sternberg D, Danan C, Lombès A, Laforêt P, Girodon E, Goossens M, et al. Exhaustive scanning approach to screen all the mitochondrial tRNA genes for mutations and its application to the investigation of 35 independent patients with mitochondrial disorders. Hum Mol Genet 1998; 7:33-42.

21.  Grantham R. Amino acid difference formula to help explain protein evolution. Science 1974; 185:862–864.

22.  Rötig A, de Lonlay P, Chretien D, Foury F, Koenig M, Sidi D, et al. Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat Genet 1997; 17:215-217.

23.  Wilson RB, Roof DM. Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue. Nat Genet 1997; 16:352– 357.

24.  Lodi R, Cooper JM, Bradley JL, Manners D, Styles P, Taylor DJ, et al. Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci USA 1999; 96:11492-11495.