Abstract
Primary deficiency of coenzyme Q10 (CoQ10 ubiquinone), is classified as a mitochondrial respiratory chain disorder with phenotypic variability. The clinical manifestation may involve one or multiple tissue with variable severity and presentation may range from infancy to late onset. ADCK3 gene mutations are responsible for the most frequent form of hereditary CoQ10 deficiency (Q10 deficiency-4 OMIM #612016) which is mainly associated with autosomal recessive spinocerebellar ataxia (ARCA2, SCAR9). Here we provide the clinical, biochemical and genetic investigation for unrelated three nuclear families presenting an autosomal form of Spino-Cerebellar Ataxia due to novel mutations in the ADCK3 gene. Using next generation sequence technology we identified a homozygous Gln343Ter mutation in one family with severe, early onset of the disease and compound heterozygous mutations of Gln343Ter and Ser608Phe in two other families with variable manifestations. Biochemical investigation in fibroblasts showed decreased activity of the CoQ dependent mitochondrial respiratory chain enzyme succinate cytochrome c reductase (complex II + III). Exogenous CoQ slightly improved enzymatic activity, ATP production and decreased oxygen free radicals in some of the patient’s cells. Our results are presented in comparison to previously reported mutations and expanding the clinical, molecular and biochemical spectrum of ADCK3 related CoQ10 deficiencies.
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References
Quinzii CM, DiMauro S, Hirano M (2007) Human coenzyme Q10 deficiency. Neurochem Res 32:723–727. https://doi.org/10.1097/WCO.0b013e32834ab528
Emmanuele V, López LC, Berardo A, Naini A, Tadesse S, Wen B, D’Agostino E, Solomon M, DiMauro S, Quinzii C, Hirano M (2012) Heterogeneity of coenzyme Q10 deficiency: patient study and literature review. Arch Neurol 69:978–983. https://doi.org/10.1001/archneurol.2012.206
Laredj LN, Licitra F, Puccio HM (2014) The molecular genetics of coenzyme Q biosynthesis in health and disease. Biochimie 100:78–87. https://doi.org/10.1016/j.biochi.2013.12.006
Quinzii CM, Emmanuele V, Hirano M (2014) Clinical presentations of coenzyme q10 deficiency syndrome. Mol Syndromol 5:141–146. https://doi.org/10.1159/000360490
Lagier-Tourenne C, Tazir M, López LC et al (2008) ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency. Am J Hum Genet 82:661–672. https://doi.org/10.1016/j.ajhg.2007.12.024
Mollet J, Delahodde A, Serre V, Chretien D, Schlemmer D, Lombes A, Boddaert N, Desguerre I, de Lonlay P, de Baulny HO, Munnich A, Rötig A (2008) CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures. Am J Hum Genet 82:623–630. https://doi.org/10.1016/j.ajhg.2007.12.022
Stefely JA, Licitra F, Laredj L et al (2016) Cerebellar ataxia and coenzyme Q deficiency through loss of unorthodox kinase activity. Mol Cell 63:608–620. https://doi.org/10.1016/j.molcel.2016.06.030
Gerards M, van den Bosch B, Calis C, Schoonderwoerd K, van Engelen K, Tijssen M, de Coo R, van der Kooi A, Smeets H (2010) Nonsense mutations in CABC1/ADCK3 cause progressive cerebellar ataxia and atrophy. Mitochondrion 10:510–515. https://doi.org/10.1016/j.mito.2010.05.008
Horvath R, Czermin B, Gulati S, Demuth S, Houge G, Pyle A, Dineiger C, Blakely EL, Hassani A, Foley C, Brodhun M, Storm K, Kirschner J, Gorman GS, Lochmüller H, Holinski-Feder E, Taylor RW, Chinnery PF (2012) Adult-onset cerebellar ataxia due to mutations in CABC1/ADCK3. J Neurol Neurosurg Psychiatry 83:174–178. https://doi.org/10.1136/jnnp-2011-301258
Blumkin L, Leshinsky-Silver E, Zerem A, Yosovich K, Lerman-Sagie T, Lev D (2014) Heterozygous mutations in the ADCK3 gene in siblings with cerebellar atrophy and extreme phenotypic variability. JIMD Rep 12:103–107. https://doi.org/10.1007/8904_2013_251
Li H, Durbin R (2010) Fast and accurate long-read alignment with Burrows–Wheeler transform. Bioinformatics 26:589–595. https://doi.org/10.1093/bioinformatics/btp698
Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, 1000 Genome Project Data Processing Subgroup (2009) The sequence alignment/map format and SAMtools. Bioinformatics 25:2078–2079. https://doi.org/10.1093/bioinformatics/btp352
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA (2010) The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20:1297–1303. https://doi.org/10.1101/gr.107524.110
McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, Flicek P, Cunningham F (2016) The ensembl variant effect predictor. Genome Biol 17:122. https://doi.org/10.1186/s13059-016-0974-4
Ben-Meir A, Yahalomi S, Moshe B, Shufaro Y, Reubinoff B, Saada A (2015) Coenzyme Q-dependent mitochondrial respiratory chain activity in granulosa cells is reduced with aging. Fertil Steril 104:724–727. https://doi.org/10.1016/j.fertnstert.2015.05.023
Reisch AS, Elpeleg O (2007) Biochemical assays for mitochondrial activity: assays of TCA cycle enzymes and PDHc. Methods Cell Biol 80:199–222. https://doi.org/10.1016/S0091-679X(06)80010-5
Golubitzky A, Dan P, Weissman S, Link G, Wikstrom JD, Saada A (2011) Screening for active small molecules in mitochondrial complex I deficient patient’s fibroblasts, reveals AICAR as the most beneficial compound. PLoS ONE 6:e26883. https://doi.org/10.1371/journal.pone.0026883
Douiev L, Soiferman D, Alban C, Saada A (2016) The effects of ascorbate, N-acetylcysteine, and resveratrol on fibroblasts from patients with mitochondrial disorders. J Clin Med. 6pii:E1. https://doi.org/10.3390/jcm6010001
Yu-Wai-Man P, Soiferman D, Moore DG, Burté F, Saada A (2017) Evaluating the therapeutic potential of idebenone and related quinone analogues in Leber hereditary optic neuropathy. Mitochondrion 36:36–42. https://doi.org/10.1016/j.mito.2017.01.004
Hikmat O, Tzoulis C, Knappskog PM, Johansson S, Boman H, Sztromwasser P, Lien E, Brodtkorb E, Ghezzi D, Bindoff LA (2016) ADCK3 mutations with epilepsy, stroke-like episodes and ataxia: A POLG mimic? Eur J Neurol 23:1188–1194. https://doi.org/10.1111/ene.13003
Pronicka E, Piekutowska-Abramczuk D, Ciara E, Trubicka J, Rokicki D, Karkucińska-Więckowska A, Pajdowska M, Jurkiewicz E, Halat P, Kosińska J, Pollak A, Rydzanicz M, Stawinski P, Pronicki M, Krajewska-Walasek M, Płoski R (2016) New perspective in diagnostics of mitochondrial disorders: two years’ experience with whole-exome sequencing at a national paediatric centre. J Transl Med 14:174. https://doi.org/10.1186/s12967-016-0930-9
Yubero D, Allen G, Artuch R, Montero R (2017) The value of coenzyme Q10 determination in mitochondrial patients. J Clin Med 6pii:E37. https://doi.org/10.3390/jcm6040037
Web Resources
The Human Genome Mutation Database, http://www.hgmd.cf.ac.uk/ac/all.php
The Clinical Variants database, https://www.ncbi.nlm.nih.gov/clinvar
The gene cards database, https://www.genecards.org
Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim
UCSC Genome Browser, http://www.genome.ucsc.edu
Acknowledgements
AS is supported by the Pakula family, via the American Friends of the Hebrew University of Jerusalem. The molecular genetics evaluation is supported by Ginatuna Association, Sakhnin City, POB 1115, Israel.
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Shalata, A., Edery, M., Habib, C. et al. Primary Coenzyme Q deficiency Due to Novel ADCK3 Variants, Studies in Fibroblasts and Review of Literature. Neurochem Res 44, 2372–2384 (2019). https://doi.org/10.1007/s11064-019-02786-5
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DOI: https://doi.org/10.1007/s11064-019-02786-5