Alternative titles; symbols
HGNC Approved Gene Symbol: SPART
SNOMEDCT: 230264003;
Cytogenetic location: 13q13.3 Genomic coordinates (GRCh38) : 13:36,301,638-36,370,180 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q13.3 | Troyer syndrome | 275900 | Autosomal recessive | 3 |
By positional cloning of a region implicated in Troyer syndrome (SPG20; 275900), Patel et al. (2002) identified a gene designated 'SPG20.' The SPG20 gene produces a 3,402-bp transcript encoding a 72.7-kD, 666-amino acid protein that the authors called spartin (spastic paraplegia autosomal recessive Troyer syndrome). Northern dot blot analysis showed that SPG20 is expressed ubiquitously, with highest expression in adipose tissue. Database analysis indicated that spartin shares sequence similarity with the N-terminal region of spastin (SPAST; 604277), as well as with other proteins involved in the morphology and membrane trafficking of endosomes. One mechanism for endosomal transportation involves microtubules. Spastin, which is commonly mutated in autosomal dominant hereditary spastic paraplegia (SPG4; 182601), associates with the microtubule cytoskeleton. Cells overexpressing spastin mutants show constitutive binding of abnormal spastin to microtubules, leading to redistribution of the microtubule array. The microtubule-binding capability of spastin appears to be located in its N-terminal region, which shares similarity with spartin. Thus, the data implicated spartin in endosomal trafficking, microtubule dynamics, or both, and suggested a functional link between 2 genes responsible for hereditary spastic paraplegia.
Bakowska et al. (2005) noted that in addition to the N-terminal microtubule-interacting and trafficking (MIT) domain, spartin contains a C-terminal plant-related region. By Western blot analysis of HeLa cell lysates, they showed that spartin had an apparent molecular mass of about 84 kD. In fractionated cells, spartin localized mainly to the cytosolic fraction, and a small amount was membrane-associated.
By genomic sequence analysis, Patel et al. (2002) determined that the SPG20 gene contains 9 exons spanning 43.3 kb.
By genomic sequence analysis, Patel et al. (2002) mapped the SPG20 gene to chromosome 13q12.3.
By multiple sequence alignment, Ciccarelli et al. (2003) identified a sequence domain of approximately 80 amino acids in spartin and in spastin. The domain partially resembled that called ESP (Phillips et al., 2001) which is found in proteins with a well established and consistent role in endosomal trafficking. Spastin is likely to be involved in microtubule interaction. Ciccarelli et al. (2003) proposed a more descriptive name, MIT (contained within microtubule-interacting and trafficking molecules), for the domain and predicted endosomal trafficking as the principal functionality of all molecules in which it is present.
By yeast 2-hybrid analysis, Bakowska et al. (2005) found that an N-terminal fragment of spartin interacted with EPS15 (600051), which was confirmed by protein pull-down and cellular redistribution assays. Mutation analysis showed that a 99-residue domain near the N terminus of spartin interacted with the C-terminal 65 amino acids of EPS15.
Using PCR analysis, Manzini et al. (2010) found SPG20 expression at modest levels in fetal and adult human brain, including the amygdala, cortex, and thalamus, with lower levels of expression in the hippocampus and cerebellum. Studies in mouse brain showed similar findings, except for higher expression in the hippocampus and expression in the spinal cord. In the mouse brain, Spg20 was found to be developmentally regulated, as expression was maximal at midgestation and embryonic day 10 and showed a precipitous decline thereafter. In situ studies in adult mouse brain showed Spg20 expression at low levels in neurons and glia of hippocampus and forebrain, and throughout the cerebellum, brainstem, and spinal cord. Shortly after neural tube closure, Spg20 was specifically expressed in the initial frontonasal mass/forebrain, craniofacial structures, aortic arch/heart primordium, and limb buds during morphogenesis, with lowest expression in the heart. These findings implicated a role for Spg20 in morphogenesis and differentiation at these sites.
Renvoise et al. (2010) observed that IST1 (616434) bound with high affinity to spartin and that the 2 proteins colocalized to the ends of Flemming bodies during cytokinesis. Deletion analysis revealed that the N-terminal MIT domain of spartin interacted with the MIM1 domain of IST1. Depletion of IST1 in HeLa cells reduced the localization of both spartin and IST1 at midbodies, but depletion of spartin had little effect on IST1 localization. Depletion of either IST1 or spartin substantially increased the number of multinucleated cells, consistent with a defect in cytokinesis. Live cell imaging showed a failure of abscission with knockdown of either spartin or IST1.
In Amish patients with Troyer syndrome, Patel et al. (2002) identified a homozygous 1-bp deletion (607111.0001) in the SPG20 gene. The findings were consistent with a founder effect.
In affected members of a large Omani kindred with SPG20, Manzini et al. (2010) identified a homozygous 2-bp deletion (607111.0002) in the SPG20 gene.
In 3 patients of Filipino descent, including 2 sisters, Butler et al. (2016) identified a homozygous frameshift mutation in the SPG20 gene (607111.0002). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variant and studies of patient cells were not performed, but the mutation was the same as that identified in Omani and Turkish SPG20 kindreds (Manzini et al., 2010 and Tawamie et al., 2015), confirming the pathogenicity.
In Amish patients with Troyer syndrome (275900), Patel et al. (2002) identified a homozygous 1-bp deletion (1110delA) in exon 4 of the SPG20, predicted to result in a truncated protein. Sequencing of RNA from lymphocytes from affected individuals, carrier parents, and normal controls showed the mutation in the RNA transcripts in individuals with Troyer syndrome. The mutation was not found in 760 normal control chromosomes of mixed Caucasian, Asian, and African descent or in 100 chromosomes from individuals from the same and neighboring Amish communities who were not close relatives of the individuals with Troyer syndrome.
Bakowska et al. (2008) identified the 1110delA mutation in 2 Amish sibs with Troyer syndrome. Studies on patient fibroblasts and lymphoblasts showed spartin mRNA transcripts, but no translated protein, consistent with complete loss of function.
In affected individuals from a large Omani kindred with SPG20 (275900), Manzini et al. (2010) identified a homozygous 2-bp deletion (c.364_365delAT) in the first coding exon of the SPG20 gene, resulting in a frameshift and premature termination. Unaffected family members were heterozygous for the mutation, which was not found in 96 controls. The phenotype included lower limb spasticity and hyperreflexia, short stature, dysarthria, and delayed motor and cognitive development. Studies in patient lymphoblastoid cells confirmed lack of the protein consistent with a null mutation.
Tawamie et al. (2015) identified a homozygous c.364_365delAT mutation (c.364delAT, NM_001142294) (Met122ValfsTer2) in exon 2 of the SPG20 gene in 2 sibs, born of consanguineous Turkish parents, with SPG20. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was filtered against the 1000 Genomes Project and Exome Variant Server database and over 600 in-house exomes. The variant was present as a heterozygous variant in 6 individuals from the ExAC database. Functional studies and studies of patient cells were not performed. Haplotype analysis indicated that the mutation occurred independently from that in the Omani patients reported by Manzini et al. (2010).
Butler et al. (2016) identified a homozygous c.364_365delAT mutation in 2 sisters and an unrelated boy, all of Filipino descent, with SPG20. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variant and studies of patient cells were not performed.
Bakowska, J. C., Jenkins, R., Pendleton, J., Blackstone, C. The Troyer syndrome (SPG20) protein spartin interacts with Eps15. Biochem. Biophys. Res. Commun. 334: 1042-1048, 2005. [PubMed: 16036216] [Full Text: https://doi.org/10.1016/j.bbrc.2005.06.201]
Bakowska, J. C., Wang, H., Xin, B., Sumner, C. J., Blackstone, C. Lack of spartin protein in Troyer syndrome: a loss-of-function disease mechanism? Arch. Neurol. 65: 520-524, 2008. [PubMed: 18413476] [Full Text: https://doi.org/10.1001/archneur.65.4.520]
Butler, S., Helbig, K. L., Alcaraz, W., Seaver, L. H., Hsieh, D. T., Rohena, L. Three cases of Troyer syndrome in two families of Filipino descent. Am. J. Med. Genet. 170A: 1780-1785, 2016. [PubMed: 27112432] [Full Text: https://doi.org/10.1002/ajmg.a.37658]
Ciccarelli, F. D., Proukakis, C., Patel, H., Cross, H., Azam, S., Patton, M. A., Bork, P., Crosby, A. H. The identification of a conserved domain in both spartin and spastin, mutated in hereditary spastic paraplegia. Genomics 81: 437-441, 2003. [PubMed: 12676568] [Full Text: https://doi.org/10.1016/s0888-7543(03)00011-9]
Manzini, M. C., Rajab, A., Maynard, T. M., Mochida, G. H., Tan, W.-H., Nasir, R., Hill, R. S., Gleason, D., Al Saffar, M., Partlow, J. N., Barry, B. J., Vernon, M., LaMantia, A.-S., Walsh, C. A. Developmental and degenerative features in a complicated spastic paraplegia. Ann. Neurol. 67: 516-525, 2010. [PubMed: 20437587] [Full Text: https://doi.org/10.1002/ana.21923]
Patel, H., Cross, H., Proukakis, C., Hershberger, R., Bork, P., Ciccarelli, F. D., Patton, M. A., McKusick, V. A., Crosby, A. H. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nature Genet. 31: 347-348, 2002. [PubMed: 12134148] [Full Text: https://doi.org/10.1038/ng937]
Phillips, S. A., Barr, V. A., Haft, D. H., Taylor, S. I., Haft, C. R. Identification and characterization of SNX15, a novel sorting nexin involved in protein trafficking. J. Biol. Chem. 276: 5074-5084, 2001. [PubMed: 11085978] [Full Text: https://doi.org/10.1074/jbc.M004671200]
Renvoise, B., Parker, R. L., Yang, D., Bakowska, J. C., Hurley, J. H., Blackstone, C. SPG20 protein spartin is recruited to midbodies by ESCRT-III protein Ist1 and participates in cytokinesis. Molec. Biol. Cell 21: 3293-3303, 2010. [PubMed: 20719964] [Full Text: https://doi.org/10.1091/mbc.E09-10-0879]
Tawamie, H., Wohlleber, E., Uebe, S., Schmal, C., Nothen, M. M., Jamra, R. A. Recurrent null mutation in SPG20 leads to Troyer syndrome. Molec. Cell. Probes 29: 315-318, 2015. [PubMed: 26003402] [Full Text: https://doi.org/10.1016/j.mcp.2015.05.006]