Alternative titles; symbols
HGNC Approved Gene Symbol: SPG11
SNOMEDCT: 1187563003;
Cytogenetic location: 15q21.1 Genomic coordinates (GRCh38) : 15:44,562,696-44,663,662 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q21.1 | Amyotrophic lateral sclerosis 5, juvenile | 602099 | Autosomal recessive | 3 |
| Charcot-Marie-Tooth disease, axonal, type 2X | 616668 | Autosomal recessive | 3 | |
| Spastic paraplegia 11, autosomal recessive | 604360 | Autosomal recessive | 3 |
The SPG11 gene encodes spatacsin, a protein with a role in neuronal axonal growth, function, and intracellular cargo trafficking (summary by Perez-Branguli et al., 2014).
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2001) cloned KIAA1840. The deduced protein contains 1,437 amino acids. RT-PCR ELISA detected moderate expression in all tissues and specific brain regions examined, with highest expression in liver, followed by brain and ovary.
Stevanin et al. (2007) demonstrated that the full-length 8-kb SPG11 transcript encodes a predicted protein of 2,443 amino acids, which they termed spatacsin, after 'spasticity with thin or atrophied corpus callosum syndrome protein.' Human SPG11 shares 85% identity with the homologous protein in dog, 76% with mouse, and 73% with rat. The spatacsin protein includes 4 putative transmembrane domains, suggesting that the protein may be a receptor or transporter, as well as a leucine zipper and coiled-coil domain. It was assigned to the aromatic compound dioxygenase superfamily because of 22% identity with the consensus sequence between residues 2104 and 2381. The SPG11 gene is expressed ubiquitously in the nervous system but most prominently in the cerebellum, cerebral cortex, hippocampus, and pineal gland. Overexpression of a GFP fusion protein in COS-7 cells demonstrated a diffuse and reticular cytosolic and perinuclear distribution, sometimes also present in nuclei. At least 3 alternative transcripts were detected in all structures of adult brain. mRNA in situ hybridization in rat brain detected no expression in newborn rat, but found expression throughout the brain in adult rat.
Perez-Branguli et al. (2014) found expression of the SPG11 gene in human and mouse cortical projection neurons throughout embryonic development and in the adult brain. Spg11 was expressed in axonal and dendritic processes as well as in a punctate cytosolic pattern in mouse cortical neurons and human neurons.
Stevanin et al. (2007) determined that the SPG11 gene contains 40 exons and spans 101 kb.
Stevanin et al. (2007) mapped the SPG11 gene to chromosome 15q21.1 by genomic sequence analysis.
By immunoprecipitation analysis of HeLa cells, Slabicki et al. (2010) showed that KIAA0415 (613653) exists in a core protein complex containing SPG11, SPG15 (270700), C20ORF29 (AP5S1; 614824), and DKFZp761E198 (614367). Knockdown of KIAA0415, C20ORF29, or SPG15 in HeLa cells reduced homologous recombination in a test substrate, whereas knockdown of SPG11 or DKFZp761E198 had no effect.
Spastic Paraplegia 11, Autosomal Recessive
In 11 families with autosomal recessive hereditary spastic paraplegia with thin corpus callosum (SPG11; 604360), Stevanin et al. (2007) found 10 different mutations in the spatacsin gene (see, e.g., 610844.0001-610844.0004; 610844.0011-610844.0013). The mutations were either nonsense or insertions or deletions leading to a frameshift, suggesting a loss-of-function mechanism.
Del Bo et al. (2007) identified a homozygous mutation in the SPG11 gene (733delAT; 610844.0004) in 27-year-old Italian opposite-sex dizygotic twins with autosomal recessive SPG11.
In 9 unrelated families with SPG11, Hehr et al. (2007) identified 11 different mutations, including 10 novel mutations, in the SPG11 gene (see, e.g., 610844.0005-610844.0006) in the homozygous or compound heterozygous state. Four of the families were consanguineous, including 3 Turkish families initially reported by Olmez et al. (2006). Mutations were distributed throughout the entire spatacsin gene without obvious clustering.
Bauer et al. (2009) used high-resolution comparative genomic hybridization (HRCGH) to identify deletions in the SPG11 gene in 3 patients with SPG11 in whom only 1 mutant SPG11 allele had been identified by gene sequencing. HRCGH analysis suggested heterozygous genomic deletion in all 3 patients; however, quantitative PCR confirmed an 8.23-kb deletion in only 1 patient. The 8.23-kb deletion resulted in loss of exons 31 to 34 and was also found in the proband's affected sister and their unaffected father. The clinical features in the brother and sister did not differ from those of patients with point mutations.
Perez-Branguli et al. (2014) found that neuronal cultures derived from pluripotent stem cells of 2 SPG11 patients showed profound reductions in the neuritic complexity and severely impaired axonal process outgrowth compared to controls. Knockdown of Spg11 in mouse cortical neurons resulted in a reduction of neurite length and complexity associated with a decrease in acetylated stabilized tubulin. Studies in mouse brain showed that Spg11 colocalized with the vesicle marker VAMP2 (185881) and the presynaptic marker SNAP25 (600322), consistent with a role in synaptic vesicles. Knockdown of Spg11 in mouse neurons causes a decrease in synaptic vesicles in neurites and disrupted anterograde axonal transport. SPG11 patient-derived neurons showed similar defects in anterograde axonal transport as well as large numbers of inclusions, membrane-encircled structures, and vacuoles within neurites, suggesting alterations in the transport of membranous organelles. The findings suggested that axonal dysfunction underlies the disorder.
Juvenile Amyotrophic Lateral Sclerosis 5
In affected members of 10 unrelated families with a protracted course of autosomal recessive juvenile-onset amyotrophic lateral sclerosis-5 (ALS5; 602099), Orlacchio et al. (2010) identified homozygous or compound heterozygous mutations in the SPG11 gene (see, e.g., 610844.0003-610844.0004, 610844.0010-610844.0013). All of the families were consanguineous and of different ethnic backgrounds, including Italian, Japanese, Turkish, Brazilian, and Canadian. Most of the mutations resulted in a truncated protein, and all but 1 of the 12 different mutations identified had previously been reported in patients with spastic paraplegia-11. However, the patients reported by Orlacchio et al. (2010) had a slightly different phenotype, namely the absence of cognitive impairment, thin corpus callosum, and ocular abnormalities. In addition, most ALS5 patients had bulbar symptoms. Postmortem examination of 1 patient showed typical pathologic features of ALS, including small pyramids, loss of anterior horn large motor neurons and loss of large myelinated fibers in the anterolateral columns. Remaining neurons showed central chromatolysis, pigmentary degeneration, and round hyaline inclusions; Bunina bodies were not observed. Functional studies of the variants and studies of patient cells were not performed. The 10 families with ALS5 were ascertained from a cohort of 25 families who underwent SPG11 gene sequencing, thus accounting for 40% of families. Orlacchio et al. (2010) did not speculate on why the same mutations led to a slightly different phenotype more consistent with ALS than SPG, but noted that the common finding of axonal involvement in both ALS and SPG suggested a common pathologic pathway in both disorders. The findings expanded the phenotype associated with SPG11 gene mutations to included autosomal recessive juvenile ALS with long-term survival.
Charcot-Marie-Tooth Disease Type 2X
In affected members of 12 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease type 2X (CMT2X; 616668), Montecchiani et al. (2016) identified 15 different biallelic mutations in the SPG11 gene (see, e.g., 610844.0001-610844.0003; 610844.0014-610844.0015). Thirteen mutations had previously been reported as causative of SPG11 or ALS5; 2 mutations were novel. Montecchiani et al. (2016) noted that identical mutations can cause different phenotypes, indicating that genotype/phenotype correlations for SPG11 mutations are often unpredictable. All mutations except 1 were predicted to result in a truncated protein with loss of function; functional studies of the variants were not performed. The mutations, which were found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the families. The families showed different ethnic origins, including Italy, Brazil, Canada, England, Iran, and Japan.
In 3 consanguineous North African kindreds, Stevanin et al. (2007) found that a homozygous 6100C-T transition in exon 32 of the SPG11 gene, resulting in an arg2034-to-stop substitution (R2034X), segregated with spastic paraplegia with thin corpus callosum (SPG11; 604360). If not rapidly degraded, the predicted protein would be truncated by 27% of its normal size.
Boukhris et al. (2008) identified a homozygous R2034X mutation in affected members of 2 Tunisian families of Arab origin with SPG11.
In 3 sibs, born of consanguineous Italian parents (family RM-888), with axonal Charcot-Marie-Tooth disease type 2X (CMT2X; 616668) Montecchiani et al. (2016) identified compound heterozygous mutations in the SPG11 gene: R2034X and a 1-bp duplication in exon 36 (c.6632dupG; 610844.0014), resulting in a frameshift and premature termination (Pro2212fsTer5). The mutations, which were found by linkage analysis and candidate gene sequencing, segregated with the disorder in the family and were not found in 300 control chromosomes. Functional studies of the variants were not performed.
In 2 Portuguese families, Stevanin et al. (2007) found that a 5-bp deletion in exon 3 of the SPG11 gene, 529_533delATATT, in homozygosity segregated with spastic paraplegia with thin corpus callosum (SPG11; 604360). The mutation was predicted to lead to a frameshift with early termination at amino acid residue 179 (I177_I178delfsX).
In 3 Italian sibs (family RM-801) with axonal Charcot-Marie-Tooth disease type 2X (CMT2X; 616668), Montecchiani et al. (2016) identified compound heterozygous mutations in the SPG11 gene: c.529_533delATATT, predicted to result in a frameshift and premature termination (Ile177SerfsTer2), and a c.592C-T transition in exon 3 of the SPG11 gene, resulting in a gln198-to-ter substitution (Q198X; 610844.0015). The patients also had thin corpus callosum and mild cognitive impairment. The mutation, which was found by linkage analysis and candidate gene sequencing, segregated with the disorder in the family and was not found in 300 control chromosomes. Functional studies of the variants were not performed.
In a brother and sister from a consanguineous Israeli family, Stevanin et al. (2007) found that spastic paraplegia with thin corpus callosum (SPG11; 604360) was associated with a homozygous 118C-T transition in exon 1 of the SPG11 gene that resulted in premature termination of the protein at gln40 (Q40X).
In 2 sisters, born of consanguineous Italian parents (family RM306), with a protracted course of autosomal recessive juvenile amyotrophic lateral sclerosis-5 (ALS5; 602099), Orlacchio et al. (2010) identified compound heterozygous truncating mutations in the SPG11 gene: Q40X and a c.267G-A transition in exon 2, resulting in a trp89-to-ter substitution (W89X; 610844.0010). Functional studies of the variants and studies of patient cells were not performed.
In 2 sibs, born of consanguineous Italian parents (family RM-626), with axonal Charcot-Marie-Tooth disease type 2X (CMT2X; 616668), Montecchiani et al. (2016) identified a homozygous Q40X mutation in the SPG11 gene. Functional studies of the variant were not performed.
In 27-year-old Italian opposite-sex dizygotic twins with autosomal recessive spastic paraplegia-11 (SPG11; 604360), Del Bo et al. (2007) identified a homozygous 2-bp deletion (733delAT) in exon 4 of the SPG11 gene, resulting in a frameshift and premature termination at codon 247. The sibs had onset of ataxia and cognitive impairment at ages 12 and 15 years, respectively. The disorder progressed rapidly, leading to spastic paraplegia, dysarthria, and peripheral neuropathy. Both were wheelchair-bound in their early twenties. Brain MRI showed thin corpus callosum and cortical atrophy in both sibs. Both parents were healthy and came from the same small town in Sicily but denied consanguinity.
In a Spanish patient with SPG11, Hehr et al. (2007) identified compound heterozygosity for the 733delAT mutation and 1-bp insertion (2472insT; 610844.0005) of exon 14 of the SPG11 gene, resulting in frameshift and premature termination.
Boukhris et al. (2008) identified a homozygous 733delAT mutation in affected members of 3 Tunisian families of Arab origin with SPG11.
In 2 French sibs (family FSP117) with spastic paraplegia-11, Stevanin et al. (2007) identified compound heterozygous mutations in the SPG11 gene: a 2-bp deletion (c.733_734delAT) in exon 4, predicted to result in a frameshift and premature termination (Met245ValfsTer), and R1992X (610844.0011).
In 2 Japanese sibs, born of consanguineous parents (family TK005), with autosomal recessive juvenile amyotrophic lateral sclerosis-5 (ALS5; 602099), Orlacchio et al. (2010) identified compound heterozygosity for the R1992X and c.733_734delAT mutations in the SPG11 gene. Functional studies of the variants and studies of patient cells were not performed.
For discussion of the 1-bp insertion in the SPG11 gene (2472insT) that was found in compound heterozygous state in a patient with autosomal recessive spastic paraplegia-11 (SPG11; 604360) by Hehr et al. (2007), see 610844.0004.
In affected members of a consanguineous Turkish family with autosomal recessive spastic paraplegia-11 (SPG11; 604360), Hehr et al. (2007) identified a homozygous G-to-C transversion in the donor splice site of intron 2 of the SPG11 gene. The family was previously reported by Olmez et al. (2006).
In a 48-year-old Swedish patient with autosomal recessive spastic paraplegia-11 (SPG11; 604360) and central retinal dystrophy, Orlen et al. (2009) identified a homozygous G-to-C transversion in intron 39 (7152-1G-C) of the SPG11 gene, resulting in loss of the splice acceptor site and predicting a loss of function. An unrelated 41-year-old Swedish patient with SPG11 had the splice site mutation in compound heterozygosity with a 5623C-T transition in exon 30 of the SPG11 gene, resulting in a gln1875-to-ter (Q1875X; 610844.0008) substitution. Haplotype analysis indicated a founder effect for 7152-1G-C mutation, which was found in 2 (1.8%) of 216 Swedish control chromosomes. Both patients were wheelchair-bound due to lower limb spasticity, had amyotrophy of the hands, sphincter disturbances, thin corpus callosum, and late-onset progressive central retinal degeneration.
For discussion of the gln1875-to-ter (Q1875X) mutation in the SPG11 gene that was found in compound heterozygous state in a patient with autosomal recessive spastic paraplegia-11 (SPG11; 604360) and central retinal dystrophy by Orlen et al. (2009), see 610844.0007.
In 2 sibs, born of consanguineous Iranian parents, with autosomal recessive spastic paraplegia-11 (SPG11; 604360), Orlen et al. (2009) identified a homozygous 1-bp duplication (3067dupA) in exon 17 of the SPG11 gene, resulting in a frameshift and premature termination. The patients were 14 and 29 years old, respectively, at the time of the report. Both had onset at age 3 to 4 years, but the younger brother had a milder phenotype. The older sister was wheelchair-bound due to lower limb spasticity, had amyotrophy of the hands, learning disability, thin corpus callosum, and central retinal degeneration.
For discussion of the c.267G-A transition in exon 2 of the SPG11 gene resulting in a trp89-to-ter (W89X) substitution that was found in compound heterozygous state in 2 Italian sisters with a protracted course of autosomal recessive juvenile amyotrophic lateral sclerosis-5 (ALS5; 602099) by Orlacchio et al. (2010), see 610844.0003.
In a French teenaged boy (family FSP117) with spastic paraplegia-11 (SPG11; 604360), Stevanin et al. (2007) identified compound heterozygous mutations in the SPG11 gene: a c.5974C-T transition in exon 31, resulting in an arg1992-to-ter (R1992X) substitution, and a 2-bp deletion (c.733_734delAT; 610844.0004) in exon 4, resulting in a frameshift and premature termination (Met245ValfsTer). He had a similarly affected sister who was not genetically tested.
In 2 Japanese brothers, born of consanguineous parents (family TK005), with a protracted course of autosomal recessive juvenile amyotrophic lateral sclerosis-5 (ALS5; 602099), Orlacchio et al. (2010) identified compound heterozygosity for the R1992X and c.733_734delAT mutations in the SPG11 gene. Functional studies of the variants and studies of patient cells were not performed.
In a boy, born of consanguineous Italian parents (family OS), with spastic paraplegia-11 (SPG11; 604360), Stevanin et al. (2007) identified a homozygous c.2198T-G transversion in exon 11 of the SPG11 gene, resulting in a leu733-to-ter (L733X) substitution. Each unaffected parent was heterozygous for the mutation.
Orlacchio et al. (2010) identified a homozygous L733X mutation in 2 sibs, born of consanguineous Italian parents (family RM168), with a protracted course of autosomal recessive juvenile amyotrophic lateral sclerosis-5 (ALS5; 602099). Functional studies of the variants and studies of patient cells were not performed.
In a teenaged girl, born of consanguineous Tunisian parents (family FSP515), with spastic paraplegia-11 (SPG11; 604360), Stevanin et al. (2007) identified a homozygous 1-bp insertion (c.7029_7030insT) in exon 39, resulting in a frameshift and premature termination (Val2344CysfsTer).
Orlacchio et al. (2010) identified a homozygous c.7029_7030insT mutation in 2 sibs, born of consanguineous Canadian parents (family TOR015) with a protracted course of autosomal recessive amyotrophic lateral sclerosis-5 (ALS5; 602099). Functional studies of the variants and studies of patient cells were not performed.
For discussion of the 1-bp duplication (c.6632dupG) in exon 36 of the SPG11 gene, resulting in a frameshift and premature termination (Pro2212fsTer5), that was found in compound heterozygous state in 3 sibs with axonal Charcot-Marie-Tooth disease type 2X (CMT2X; 616668) by Montecchiani et al. (2016), see 610844.0001.
For discussion of the c.592C-T transition in exon 3 of the SPG11 gene, resulting in a gln198-to-ter (Q198X) substitution, that was found in compound heterozygous state in 3 sibs with axonal Charcot-Marie-Tooth disease type 2X (CMT2X; 616668) by Montecchiani et al. (2016), see 610844.0002.
Bauer, P., Winner, B., Schule, R., Bauer, C., Hafele, V., Hehr, U., Bonin, M., Walter, M., Karle, K., Ringer, T. M., Riess, O., Winkler, J., Schols, L. Identification of a heterozygous genomic deletion in the spatacsin gene in SPG11 patients using high-resolution comparative genomic hybridization. Neurogenetics 10: 43-48, 2009. [PubMed: 18787847] [Full Text: https://doi.org/10.1007/s10048-008-0144-2]
Boukhris, A., Stevanin, G., Feki, I., Denis, E., Elleuch, N., Miladi, M. I., Truchetto, J., Denora, P., Belal, S., Mhiri, C., Brice, A. Hereditary spastic paraplegia with mental impairment and thin corpus callosum in Tunisia. Arch. Neurol. 65: 393-402, 2008. [PubMed: 18332254] [Full Text: https://doi.org/10.1001/archneur.65.3.393]
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Hehr, U., Bauer, P., Winner, B., Schule, R., Olmez, A., Koehler, W., Uyanik, G., Engel, A., Lenz, D., Seibel, A., Hehr, A., Ploetz, S., and 13 others. Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia. Ann. Neurol. 62: 656-665, 2007. [PubMed: 18067136] [Full Text: https://doi.org/10.1002/ana.21310]
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Nagase, T., Nakayama, M., Nakajima, D., Kikuno, R., Ohara, O. Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 8: 85-95, 2001. [PubMed: 11347906] [Full Text: https://doi.org/10.1093/dnares/8.2.85]
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Orlen, H., Melberg, A., Raininko, R., Kumlien, E., Entesarian, M., Soderberg, P., Pahlman, M., Darin, N., Kyllerman, M., Holmberg, E., Engler, H., Eriksson, U., Dahl, N. SPG11 mutations cause Kjellin syndrome, a hereditary spastic paraplegia with thin corpus callosum and central retinal degeneration. Am. J. Med. Genet. 150B: 984-992, 2009. [PubMed: 19194956] [Full Text: https://doi.org/10.1002/ajmg.b.30928]
Perez-Branguli, F., Mishra, H. K., Prots, I., Havlicek, S., Kohl, Z., Saul, D., Rummel, C., Dorca-Arevalo, J., Regensburger, M., Graef, D., Sock, E., Blasi, J., Groemer, T. W., Schlotzer-Schrehardt, U., Winkler, J., Winner, B. Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia. Hum. Molec. Genet. 23: 4859-4874, 2014. [PubMed: 24794856] [Full Text: https://doi.org/10.1093/hmg/ddu200]
Slabicki, M., Theis, M., Krastev, D. B., Samsonov, S., Mundwiller, E., Junqueira, M., Paszkowski-Rogacz, M., Teyra, J., Heninger, A.-K., Poser, I., Prieur, F., Truchetto, J., and 9 others. A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia. PLoS Biol. 8: e1000408, 2010. Note: Electronic Article. [PubMed: 20613862] [Full Text: https://doi.org/10.1371/journal.pbio.1000408]
Stevanin, G., Santorelli, F. M., Azzedine, H., Coutinho, P., Chomilier, J., Denora, P. S., Martin, E., Ouvrard-Hernandez, A.-M., Tessa, A., Bouslam, N, Lossos, A., Charles, P., and 13 others. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nature Genet. 39: 366-372, 2007. [PubMed: 17322883] [Full Text: https://doi.org/10.1038/ng1980]