SPG20 explained

Spartin is a protein that in humans is encoded by the SPG20 gene.^{[1] [2] [3]}

This gene encodes a protein that contains a MIT (Microtubule Interacting and Trafficking molecule) domain. This protein may be involved in endosomal trafficking, microtubule dynamics, or both functions. Spartin loss has been associated to mitochondrial dysfunction, impaired complex I activity and altered pyruvate metabolism.^[4] Frameshift mutations associated with this gene cause autosomal recessive spastic paraplegia 20 (Troyer syndrome).^[3] Troyer syndrome (SPG20) is a complicated type of hereditary spastic paraplegias (HSPs).^[5] HSP is a category of neurological disorder characterized by spasticity and muscle weakness in the lower limbs.

Background

The original description of this gene mutation and associated symptoms were described in 1967.^[6] This mutation is commonly found in high frequency with the Amish population. Newer studies have found that the mutation is not isolated to the Amish population, but also resides in the Omani population.

Presentation

This syndrome is not only characterized by spasticity and weakness in the lower limbs, but also with dysarthria, mental retardation or mild developmental delay, and muscle wasting or muscle atrophy.

Physical

Individuals appear to have difficulty walking, and report a clumsy, spastic gait which worsens over time. Some additional common physical features include overgrowth of the jaw bone, hammer toes, hand and feet abnormalities, and pes cavus.

Cognitive

Cognitive challenges, including developmental delay and difficulty with performance in school, may affect individuals with this syndrome.

Neurologic

Neurologic examination of individuals with this mutation may show dysmetria in the upper extremities, hyperreflexia, distal amyotrophy and ankle clonus, in addition to spasticity, weakness and dysarthria.

Diagnostic Imaging

The cerebellar vermis may present with mild atrophy and a loss of white matter volume.

Through Lifespan

Facial dysmorphism and subtle skeletal features are common in younger children. The condition progressively worsens, as spasticity and distal amyotrophy symptoms are revealed more in teenage years. SPG20 expression in the adult is relatively modest, however it is widespread in the nervous system. Longitudinal comparison of magnetic resonance imaging concluded that there was a progression of the syndrome; thus, the condition appears to worsen over time.

External links

• GeneReviews/NCBI/NIH/UW entry on Troyer Syndrome **

Further reading

• Hillier LD, Lennon G, Becker M, etal . Generation and analysis of 280,000 human expressed sequence tags. . Genome Res. . 6 . 9 . 807–28 . 1997 . 8889549 . 10.1101/gr.6.9.807 . free .
• Nagase T, Ishikawa K, Miyajima N, etal . Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. . DNA Res. . 5 . 1 . 31–9 . 1998 . 9628581 . 10.1093/dnares/5.1.31 . free .
• Auer-Grumbach M, Fazekas F, Radner H, etal . Troyer syndrome: a combination of central brain abnormality and motor neuron disease? . J. Neurol. . 246 . 7 . 556–61 . 1999 . 10463356 . 10.1007/s004150050403 . 22666392 .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Ciccarelli FD, Proukakis C, Patel H, etal . The identification of a conserved domain in both spartin and spastin, mutated in hereditary spastic paraplegia. . Genomics . 81 . 4 . 437–41 . 2003 . 12676568 . 10.1016/S0888-7543(03)00011-9 .
• Ota T, Suzuki Y, Nishikawa T, etal . Complete sequencing and characterization of 21,243 full-length human cDNAs. . Nat. Genet. . 36 . 1 . 40–5 . 2004 . 14702039 . 10.1038/ng1285 . free .
• Dunham A, Matthews LH, Burton J, etal . The DNA sequence and analysis of human chromosome 13. . Nature . 428 . 6982 . 522–8 . 2004 . 15057823 . 10.1038/nature02379 . 2665288 . 2004Natur.428..522D .
• Liu M, Liu Y, Cheng J, etal . Transactivating effect of hepatitis C virus core protein: a suppression subtractive hybridization study. . World J. Gastroenterol. . 10 . 12 . 1746–9 . 2004 . 15188498 . 4572261 . 10.3748/wjg.v10.i12.1746 . free .
• Colland F, Jacq X, Trouplin V, etal . Functional proteomics mapping of a human signaling pathway. . Genome Res. . 14 . 7 . 1324–32 . 2004 . 15231748 . 10.1101/gr.2334104 . 442148 .
• Gerhard DS, Wagner L, Feingold EA, etal . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• Bakowska JC, Jenkins R, Pendleton J, Blackstone C . The Troyer syndrome (SPG20) protein spartin interacts with Eps15. . Biochem. Biophys. Res. Commun. . 334 . 4 . 1042–8 . 2005 . 16036216 . 10.1016/j.bbrc.2005.06.201 .
• Lu J, Rashid F, Byrne PC . The hereditary spastic paraplegia protein spartin localises to mitochondria. . J. Neurochem. . 98 . 6 . 1908–19 . 2006 . 16945107 . 10.1111/j.1471-4159.2006.04008.x . free .
• Bakowska JC, Jupille H, Fatheddin P, etal . Troyer syndrome protein spartin is mono-ubiquitinated and functions in EGF receptor trafficking. . Mol. Biol. Cell . 18 . 5 . 1683–92 . 2007 . 17332501 . 10.1091/mbc.E06-09-0833 . 1855030 .
• Bakowska, J.C. . Jenkins, R. . Pendleton, J. . Blackstone, C. . The Troyer syndrome (SPG20) protein interacts with Eps15 . Biochemical and Biophysical Research Communications . 334 . 1042–1048 . 2005 . 16036216. 10.1016/j.bbrc.2005.06.201. 4.
• Manzini, M. C. . Rajab, A. . Maynard, T. M. . Mochida, G. H. . Tan, W. . Nasir, R. . etal . Developmental and degenerative features in a complicated spastic paraplegic. . Annals of Neurology . 67 . 4 . 516–525 . 2010 . 20437587. 10.1002/ana.21923. 3027847.
• Ciccarelli, F. D. . Patton, M. A. . McKusick, V. A. . Crosby, A. H. . SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. . Nature Genetics . 31 . 347–348. 2002 . 12134148. 10.1038/ng937. 4. 23051225 .

Notes and References

1. Cross HE, McKusick VA . The Troyer syndrome. A recessive form of spastic paraplegia with distal muscle wasting . Arch Neurol . 16 . 5 . 473–85 . Jun 1967 . 6022528 . 10.1001/archneur.1967.00470230025003.
2. Patel H, Cross H, Proukakis C, Hershberger R, Bork P, Ciccarelli FD, Patton MA, McKusick VA, Crosby AH . SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia . Nat Genet . 31 . 4 . 347–8 . Jul 2002 . 12134148 . 10.1038/ng937 . 23051225 .
3. Web site: Entrez Gene: SPG20 spastic paraplegia 20, spartin (Troyer syndrome).
4. Chiara Diquigiovanni . Christian Bergamini . Rebeca Diaz . Irene Liparulo . Francesca Bianco . Luca Masin . Vito Antonio Baldassarro . Nicola Rizzardi . Antonia Tranchina . Francesco Buscherini . Anita Wischmeijer . Tommaso Pippucci . Emanuela Scarano . Duccio Maria Cordelli . Romana Fato . Marco Seri . Silvia Paracchini . Elena Bonora . A novel mutation in SPART gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism. FASEB Journal. 7 August 2019. 33. 10. 11284–11302. 10.1096/fj.201802722R. 31314595. free. 10023/18172 . free .
5. Bakowska, J.C. . Jenkins, R. . Pendleton, J. . Blackstone, C. . The Troyer syndrome (SPG20) protein interacts with Eps15 . Biochemical and Biophysical Research Communications . 334 . 1042–1048 . 2005 . 16036216. 10.1016/j.bbrc.2005.06.201. 4.
6. Manzini, M. C. . Rajab, A. . Maynard, T. M. . Mochida, G. H. . Tan, W. . Nasir, R. . etal . Developmental and degenerative features in a complicated spastic paraplegic. . Annals of Neurology . 67 . 4 . 516–525 . 2010 . 20437587. 10.1002/ana.21923. 3027847.