Abstract
Troyer syndrome is an autosomal recessive form of hereditary spastic paraplegia (HSP) caused by deleterious mutations in the SPG20 gene. Although the disease is associated with a loss of function mechanism of spartin, the protein encoded by SPG20, the precise pathogenesis is yet to be elucidated. Recent data indicated an important role for spartin in both mitochondrial maintenance and function. Here we report a child presenting with progressive spastic paraparesis, generalized muscle weakness, dysarthria, impaired growth, and severe isolated decrease in muscle cytochrome c oxidase (COX) activity. Whole exome sequencing identified the homozygous c.988A>G variant in SPG20 gene (p.Met330Val) resulting in almost complete loss of spartin in skeletal muscle. Further analyses demonstrated significant tissue specific reduction of COX 4, a nuclear encoded subunit of COX, in muscle suggesting a role for spartin in proper mitochondrial respiratory chain function mediated by COX activity. Our findings need to be verified in other Troyer syndrome patients in order to classify it as a form of HSP caused by mitochondrial dysfunction.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Alazami AM, Patel N, Shamseldin HE, Anazi S, Al-Dosari MS, Alzahrani F (2015) Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep 10:148–161
Atorino L, Silvestri L, Koppen M et al (2003) Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia. J Cell Biol 163:777–787
Bakowska JC, Jupille H, Fatheddin P, Puertollano R, Blackstone C (2007) Troyer syndrome protein spartin is mono-ubiquitinated and functions in EGF receptor trafficking. Mol Biol Cell 18:1683–1692
Bakowska JC, Wang H, Xin B, Sumner CJ, Blackstone C (2008) Lack of spartin protein in Troyer syndrome: a loss-of-function disease mechanism? Arch Neurol 65:520–524
Bross P, Naundrup S, Hansen J 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
Butler S, Helbig KL, Alcaraz W, Seaver LH, Hsieh DT, Rohena L (2016) Three cases of Troyer syndrome in two families of Filipino descent. Am J Med Genet A 170(7):1780–1785
Eastman SW, Yassaee M, Bieniasz PD (2009) A role for ubiquitin ligases and Spartin/SPG20 in lipid droplet turnover. J Cell Biol 184:881–894
Hensiek A, Kirker S, Reid E (2015) Diagnosis, investigation and management of hereditary spastic paraplegias in the era of next-generation sequencing. J Neurol 262:1601–1612
Joshi DC, Bakowska JC (2011) SPG20 protein spartin associates with cardiolipin via its plant-related senescence domain and regulates mitochondrial Ca2+ homeostasis. PLoS One 6(4), e19290
Lossos A, Stümpfig C, Stevanin G et al (2015) Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia. Neurology 84:659–667
Lu J, Rashid F, Byrne PC (2006) The hereditary spastic paraplegia protein spartin localises to mitochondria. J Neurochem 98:1908–1919
Manzini MC, Rajab A, Maynard TM et al (2010) Developmental and degenerative features in a complicated spastic paraplegia. Ann Neurol 67:516–525
Patel H, Cross H, Proukakis C et al (2002) SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nat Genet 31:347–348
Saada A, Bar-Meir M, Belaiche C, Miller C, Elpeleg O (2004) Evaluation of enzymatic assays and compounds affecting ATP production in mitochondrial respiratory chain complex I deficiency. Anal Biochem 335:66–72
Shanmughapriya S, Rajan S, Hoffman NE et al (2015) SPG7 is an essential and conserved component of the mitochondrial permeability transition pore. Mol Cell 60:47–62
Shimazaki H, Takiyama Y, Ishiura H et al (2012) A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55). J Med Genet 49:777–784
Stiburek L, Vesela K, Hansikova H et al (2005) Tissue-specific cytochrome c oxidase assembly defects due to mutations in SCO2 and SURF1. Biochem J 392:625–632
Suomalainen A, Elo JM, Pietiläinen KH et al (2011) FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol 10:806–818
Tawamie H, Wohlleber E, Uebe S, Schmäl C, Nöthen MM, Abou Jamra R (2015) Recurrent null mutation in SPG20 leads to Troyer syndrome. Mol Cell Probes 29:315–318
Truong T, Karlinski ZA, O’Hara C, Cabe M, Kim H, Bakowska JC (2015) Oxidative stress in Caenorhabditis elegans: protective effects of spartin. PLoS One 10(6), e0130455
Yang Y, Liu W, Fang Z et al (2016) A newly identified missense mutation in FARS 2 causes autosomal recessive spastic paraplegia. Hum Mutat 37:165–169
Acknowledgements
Corinne Alban is acknowledged for technical assistance. This research was in part funded by the Hadassah Compensatory fund.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Johan Lodewijk Karel Van Hove, MD, PhD
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Table S1
Suspected variants identified by WES (DOCX 29 kb)
Fig. S1
A. Light microscopy showing normal structure of skeletal muscle. H&E stain X200. B. Skeletal muscle immune-histochemistry showing normal COX staining (TIFF 1,200 kb)
Fig. S2
High evolutionary conservation of Met residue at position 330 is illustrated (the mutated residue is marked by black box) (TIFF 256 kb)
Appendices
Authors’ Contributions
Dr. Spiegel leads the composition and evaluation of the manuscript; designed and conceptualized the study, and interpreted the data. Dr. Spiegel serves as guarantor for the article, accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
Dr. Soiferman evaluated the manuscript for content and analyzed and interpreted the biochemical studies as well as Western blot analyses.
Dr. Shaag evaluated the manuscript for content and analyzed and interpreted the genetic data.
Prof. Shalev evaluated the manuscript for content and analyzed and interpreted the clinical data.
Prof. Elpeleg evaluated the manuscript for content, including medical writing for content, analyzed and interpreted the genetic data in particular the exome sequencing.
Prof. Saada leads the composition and evaluation of the manuscript, designed and conceptualized the study, and analyzed and interpreted the biochemical data as well as the Western blot analysis.
Conflict of Interests
Dr Spiegel, Dr. Soiferman, Dr. Shaag, Prof. Shalev, Prof. Elpeleg and Prof. Saada all declare that they have no conflict of interests.
Ethics and Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained accordingly as approved by the local ethical review board.
Rights and permissions
Copyright information
© 2016 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Spiegel, R., Soiferman, D., Shaag, A., Shalev, S., Elpeleg, O., Saada, A. (2016). Novel Homozygous Missense Mutation in SPG20 Gene Results in Troyer Syndrome Associated with Mitochondrial Cytochrome c Oxidase Deficiency. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 33. JIMD Reports, vol 33. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2016_580
Download citation
DOI: https://doi.org/10.1007/8904_2016_580
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-55011-3
Online ISBN: 978-3-662-55012-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)