A novel missense mutation (c.1006C>T) of SPG20 gene associated with Troyer syndrome

Abstract

The number of gene mutations involved in the hereditary spastic paraplegias is rapidly growing due to the expansion of the frontiers of genomic research by next-generation DNA sequencing platforms. Nevertheless, a comprehensive genetic diagnosis method remains yet unavailable for these diseases. In the current research, an 8-year-old boy with short stature and developmental delay impairment, from a nonconsanguineous family, was referred to our genetic lab. Firstly, based on the physician recommendation, the patient was evaluated by tandem mass spectrometry (MS/MS) for the quantitative examination of amino acids, and then the patient was genetically investigated by karyotype analysis and whole-exome sequencing (WES) technique. Subsequently, targeted Sanger sequencing was applied to confirm the presence of the candidate variant in all the members of the family and screening the other patients for Troyer syndrome. Analysis of inherited metabolic disorders by tandem MS/MS showed the state of all the family members as normal and also karyotyping indicated no chromosomal aberration in the patient. Further investigation by WES technique indicated a homozygous missense variant in the SPG20 gene, c.1006C>T. Targeted sequencing result of the mutation confirmed homozygote state for the affected case and a heterozygote genotype for his parents. The mutation was classified as pathogenic. Detection of novel variants especially pathogenic variant in the SPG20 gene was associated with Troyer syndrome, which encodes a multifunctional protein termed Spartin, assist in improving genotype‒phenotype correlation of genetic variants and may facilitate initial diagnosis of Troyer syndrome.

This is a preview of subscription content, log in to check access.

Figure 1
Figure 2
Figure 3

Reference

  1. Alazami A. M., Patel N., Shamseldin H. E., Anazi S., Al-Dosari M. S. Alzahrani F et al. 2015 Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 10, 148–161.

    CAS  Article  Google Scholar 

  2. Bakowska J. C., Wang H., Xin B., Sumner C. J. and Blackstone C. 2008 Lack of spartin protein in Troyer syndrome: a loss-of-function disease mechanism? Arch. Neurol. 65, 520–524.

    Article  Google Scholar 

  3. Bross P., Naundrup S., Hansen J., Nielsen M. N., Christensen J. H., Kruhøffer M. et al. 2008 The Hsp60-(p. V98I) mutation associated with hereditary spastic paraplegia SPG13 compromises chaperonin function both in vitro and in vivo. J. Biol. Chem.283, 15694–15700.

    CAS  Article  Google Scholar 

  4. Butler S., Helbig K. L., Alcara W., Seaver L. H., Hsieh D. T. et al. 2016 Three cases of Troyer syndrome in two families of Filipino descent. Am. J. Med. Genet. Part A170, 1780–1785.

    Article  Google Scholar 

  5. Dardour L., Roelens F., Race V., Souche E., Holvoet M. and Devriendt K. 2017 SPG20 mutation in three siblings with familial hereditary spastic paraplegia. Cold Spring Harb. Mol. Case Stud. 3, a001537.

    Article  Google Scholar 

  6. Diquigiovanni C., Bergamini C., Diaz R., Liparulo I., Bianco F., Masin M. et al. 2018 In Troyer syndrome Spartin loss induces complex I impairments and alters pyruvate metabolism. bioRxiv: 488239.

  7. Eastman S. W., Yassaee M. and Bieniasz P. D. 2009 A role for ubiquitin ligases and Spartin/SPG20 in lipid droplet turnover. J. Cell Biol. 184, 881–894.

    CAS  Article  Google Scholar 

  8. Karlsson A. B., Washington J., Dimitrova V., Hooper C., Shekhtman A. and Bakowska J. C. 2014 The role of spartin and its novel ubiquitin binding region in DALIS occurrence. Mol. Biol. Cell25, 1355–1365.

    Article  Google Scholar 

  9. Lossos A., Stümpfig C., Stevanin G., Gaussen M., Zimmerman B.-E. and Mundwiller E. et al. 2015 Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia. Neurology84, 659–667.

    CAS  Article  Google Scholar 

  10. Manzini M. C., Rajab A., Maynard T. M., Mochida G. H., Tan W. H., Nasir R. et al. 2010 Developmental and degenerative features in a complicated spastic paraplegia. Ann. Neurol. 67, 516–525.

    CAS  Article  Google Scholar 

  11. Patel H., Cross H., Proukakis C., Hershberger R., Bork P. et al. 2002 SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nat. Genet.31, 347.

    CAS  Article  Google Scholar 

  12. Proukakis C., Cross H., Patel H., Patton M. A., Valentine A., Crosby A. H. et al. 2004 Troyer syndrome revisited. J. Neurol. 251, 1105–1110.

    Article  Google Scholar 

  13. Renvoisé B., Parker R. L., Yang D., Bakowska J. C., Hurley J. H., Blackstone C. et al. 2010 SPG20 protein spartin is recruited to midbodies by ESCRT-III protein Ist1 and participates in cytokinesis. Mol. Biol. Cell21, 3293–3303.

    Article  Google Scholar 

  14. Renvoisé B., Stadler J., Singh R., Bakowska J. C. and Blackstone C. 2012 Spg20−/− mice reveal multimodal functions for Troyer syndrome protein spartin in lipid droplet maintenance, cytokinesis and BMP signaling. Hum. Mol. Genet. 21, 3604–3618.

    Article  Google Scholar 

  15. Shanmughapriya S., Rajan S., Hoffman N. E., Higgins A. M., Tomar D., Nemani N. et al. 2015 SPG7 is an essential and conserved component of the mitochondrial permeability transition pore. Mol. Cell60, 47–62.

    CAS  Article  Google Scholar 

  16. Shimazaki H., Takiyama Y., Ishiura H., Sakai C., Matsushima Y., Hatakeyama H. et al. 2012 A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55). J. Med. Genet. 49, 777–784.

    CAS  Article  Google Scholar 

  17. Spiegel R., Soiferman D., Shaag A., Shalev S., Elpeleg O. and Saada A. et al. 2016 Novel homozygous missense mutation in SPG20 gene results in Troyer syndrome associated with mitochondrial cytochrome c oxidase deficiency. JIMD Rep.33, 55–60.

    Article  Google Scholar 

  18. Tawamie H., Wohlleber E., Uebe S., Schmäl C., Nöthen M. M., Jamra R. A. et al. 2015 Recurrent null mutation in SPG20 leads to Troyer syndrome. Mol. Cell. Probes29, 315–318.

    CAS  Article  Google Scholar 

  19. Yang D., Rismanchi N., Renvoisé B., Lippincott-Schwartz J., Blackstone C., Hurley J. H. et al. 2008 Structural basis for midbody targeting of spastin by the ESCRT-III protein CHMP1B. Nat. Struct. Mol. Biol. 15, 1278.

    CAS  Article  Google Scholar 

  20. Yang Y., Liu W., Fang Z., Shi J., Che F., He C. et al. 2016 A newly identified missense mutation in FARS2 causes autosomal-recessive spastic paraplegia. Hum. Mut. 37, 165–169.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to M. R. Mahdavi.

Additional information

Corresponding editor: S. Ganesh

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Khoshaeen, A., Najafi, M., Mahdavi, M.R. et al. A novel missense mutation (c.1006C>T) of SPG20 gene associated with Troyer syndrome. J Genet 99, 55 (2020). https://doi.org/10.1007/s12041-020-01210-0

Download citation

Keywords

  • tandem mass spectrometry
  • karyotype analysis
  • whole-exome sequencing
  • hereditary spastic paraplegias
  • developmental delay.