Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A novel homozygous missense mutation in the FASTKD2 gene leads to Lennox-Gastaut syndrome

Journal of Human Genetics (2022)Cite this article

Subjects

Abstract

FASTKD2 encodes an RNA-binding protein, which is a key post-transcriptional regulator of mitochondrial gene expression. Mutations in FASTKD2 have recently been found in mitochondrial encephalomyopathy, which is characterized by a deficiency in mitochondrial function. To date, seven patients have been reported. Six patients were identified with nonsense or frameshift mutations in the FASTKD2 gene, and only one patient harbored a missense mutation and a nonsense mutation. Here, we identified a novel FASTKD2 homozygous mutation, c.911 T > C, in a patient diagnosed with Lennox-Gastaut syndrome. We observed that the expression of FASTKD2 and the levels of mitochondrial 16 S rRNA were lower in the patient than in the unaffected controls. In conclusion, the missense mutation c.911 T > C caused loss of function in FASTKD2, which was associated with a new phenotype, Lennox-Gastaut syndrome.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3

References

  1. Ohkubo A, Van Haute L, Rudler DL, Stentenbach M, Steiner FA, Rackham O. et al. The FASTK family proteins fine-tune mitochondrial RNA processing. Plos Genet. 2021;17:e1009873. https://doi.org/10.1371/journal.pgen.1009873.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Popow J, Alleaume AM, Curk T, Schwarzl T, Sauer S, Hentze MW. FASTKD2 is an RNA-binding protein required for mitochondrial RNA processing and translation. RNA. 2015;21:1873–84. https://doi.org/10.1261/rna.052365.115.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Jourdain AA, Popow J, de la Fuente MA, Martinou JC, Anderson P, Simarro M. The FASTK family of proteins: emerging regulators of mitochondrial RNA biology. Nucleic Acids Res. 2017;45:10941–7. https://doi.org/10.1093/nar/gkx772.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Boehm E, Zaganelli S, Maundrell K, Jourdain AA, Thore S, Martinou JC. FASTKD1 and FASTKD4 have opposite effects on expression of specific mitochondrial RNAs, depending upon their endonuclease-like RAP domain. Nucleic Acids Res. 2017;45:6135–46. https://doi.org/10.1093/nar/gkx164.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Boehm E, Zornoza M, Jourdain AA, Delmiro Magdalena A, García-Consuegra I, Torres Merino R. et al. Role of FAST Kinase Domains 3 (FASTKD3) in Post-transcriptional regulation of mitochondrial gene expression. J Biol Chem. 2016;291:25877–87. https://doi.org/10.1074/jbc.M116.730291.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Jourdain AA, Koppen M, Rodley CD, Maundrell K, Gueguen N, Reynier P. et al. A mitochondria-specific isoform of FASTK is present in mitochondrial RNA granules and regulates gene expression and function. Cell Rep. 2015;10:1110–21. https://doi.org/10.1016/j.celrep.2015.01.063.

    CAS  Article  PubMed  Google Scholar 

  7. Ghezzi D, Saada A, D’Adamo P, Fernandez-Vizarra E, Gasparini P, Tiranti V. et al. FASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency. Am J Hum Genet. 2008;83:415–23. https://doi.org/10.1016/j.ajhg.2008.08.009.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Simarro M, Gimenez-Cassina A, Kedersha N, Lazaro JB, Adelmant GO, Marto JA. et al. Fast kinase domain-containing protein 3 is a mitochondrial protein essential for cellular respiration. Biochem Biophys Res Commun. 2010;401:440–6. https://doi.org/10.1016/j.bbrc.2010.09.075.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Lee I, Hong W. RAP-a putative RNA-binding domain. Trends Biochem Sci. 2004;29:567–70. https://doi.org/10.1016/j.tibs.2004.09.005.

    CAS  Article  PubMed  Google Scholar 

  10. Das S, Yeung KT, Mahajan MA, Samuels HH. Fas Activated Serine-Threonine Kinase Domains 2 (FASTKD2) mediates apoptosis of breast and prostate cancer cells through its novel FAST2 domain. BMC Cancer. 2014;14:852. https://doi.org/10.1186/1471-2407-14-852

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. https://doi.org/10.1038/gim.2015.30.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chomczynski P, Sacchi N. The single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction: twenty-something years on. Nat Protoc. 2006;1:581–5. https://doi.org/10.1038/nprot.2006.83.

    CAS  Article  PubMed  Google Scholar 

  13. Wei X, Du M, Li D, Wen S, Xie J, Li Y. et al. Mutations in FASTKD2 are associated with mitochondrial disease with multi-OXPHOS deficiency. Hum Mutat. 2020;41:961–72. https://doi.org/10.1002/humu.23985.

    CAS  Article  PubMed  Google Scholar 

  14. Yoo DH, Choi YC, Nam DE, Choi SS, Kim JW, Choi BO. et al. Identification of FASTKD2 compound heterozygous mutations as the underlying cause of autosomal recessive MELAS-like syndrome. Mitochondrion. 2017;35:54–58. https://doi.org/10.1016/j.mito.2017.05.005.

    CAS  Article  PubMed  Google Scholar 

  15. Benkirane M, Marelli C, Guissart C, Roubertie A, Ollagnon E, Choumert A. et al. High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families. Genet Med. 2021;23:2160–70. https://doi.org/10.1038/s41436-021-01250-6.

    CAS  Article  PubMed  Google Scholar 

  16. Arzimanoglou A, French J, Blume WT, Cross JH, Ernst JP, Feucht M. et al. Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. Lancet Neurol. 2009;8:82–93. https://doi.org/10.1016/S1474-4422(08)70292-8.

    Article  PubMed  Google Scholar 

  17. Lee S, Baek MS, Lee YM. Lennox-Gastaut syndrome in mitochondrial disease. Yonsei Med J. 2019;60:106–14. https://doi.org/10.3349/ymj.2019.60(1).1.106.

    Article  PubMed  Google Scholar 

  18. Antonicka H, Shoubridge EA. Mitochondrial RNA granules are centers for posttranscriptional rna processing and ribosome biogenesis. Cell Rep. 2015;10:920–32. https://doi.org/10.1016/j.celrep.2015.01.030.

    CAS  Article  PubMed  Google Scholar 

  19. Perks KL, Rossetti G, Kuznetsova I, Hughes LA, Ermer JA, Ferreira N. et al. PTCD1 is required for 16s rrna maturation complex stability and mitochondrial ribosome assembly. Cell Rep. 2018;23:127–42. https://doi.org/10.1016/j.celrep.2018.03.033.

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the patients and their families for their participation in the study. We would like to thank Editage (www.editage.cn) for the English language editing.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Xiangya Hospital Central South University, Changsha, 410008, China

    Tenghui Wu, Leilei Mao, Chen Chen, Fei Yin & Jing Peng

  2. Hunan Children’s Mental Disorders Research Center, XiangYa Hospital, Central South University, Changsha, 410008, China

    Tenghui Wu, Leilei Mao, Chen Chen, Fei Yin & Jing Peng

Authors
  1. Tenghui Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leilei Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fei Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jing Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TW drafted the manuscript and performed the experiments. LM and FY performed patient clinical management and analyzed the clinical data. CC analyzed the EEG data. JP supervised the work and designed of the research.

Corresponding author

Correspondence to Jing Peng.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

This study was approved by the Ethics Committee of Xiangya Hospital of Central South University, China (Human study/protocol #201605585).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wu, T., Mao, L., Chen, C. et al. A novel homozygous missense mutation in the FASTKD2 gene leads to Lennox-Gastaut syndrome. J Hum Genet (2022). https://doi.org/10.1038/s10038-022-01056-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s10038-022-01056-7

Search

Advanced search

Quick links