SPG11-gene

The SPG11 gene (SPG11 is the acronym for Spastic paraplegia 11 protein) is located on chromosome 15q21.1 (Stevanin et al. 2007). The gene contains 40 exons, spans 101 kb and codes for spatacsin (spasticity with thin or atrophied corpus callosum syndrome protein), a protein that contains 2443 amino acids and is ubiquitously detectable in the organism with the highest expression in the liver, followed by the brain and ovary (Stevanin et al. 2007). The SPG11 gene is ubiquitously expressed in the nervous system, but most prominently in the cerebellum, cerebral cortex, hippocampus and pineal gland.

Human SPG11 is 85% identical to the homologous canine protein, 76% identical to the mouse protein, and 73% identical to the rat protein. The spatacsin protein contains 4 putative transmembrane domains, suggesting that the protein may be a receptor or transporter. 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.

Stevanin et al. (2007) found 10 different mutations in the spatacsin gene in 11 families with autosomal recessive hereditary spastic paraplegia with thin corpus callosum (SPG11; 604360). 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 fraternal twins with autosomal recessive SPG11. Hehr et al. (2007) found 11 different mutations, including 10 novel mutations, in the SPG11 gene in 9 unrelated families with SPG11.

Perez-Branguli et al. (2014) found that neuronal cultures derived from pluripotent stem cells from 2 SPG11 patients showed a profound reduction in neuritic complexity and severely impaired outgrowth of axonal processes compared to controls. Knockdown of Spg11 in mouse cortical neurons resulted in a reduction in neurite length and complexity that was accompanied by a decrease in acetylated stabilized tubulin.

The following (autosomal recessive) diseases are associated with mutations in the SPG11 gene:

• Amyotrophic lateral sclerosis 5, juvenile (OMIM: 602099)
• Charcot-Marie-Tooth disease, axonal, type 2X (OMIM: 616668)
• Spastic paraplegia 11, autosomal recessive (OMIM: 604360)

1. Bauer P et al. (2009) Identification of a heterozygous genomic deletion in the spatacsin gene in SPG11 patients using high-resolution comparative genomic hybridization. Neurogenetics 10: 43-48
2. Del Bo R et al (2007) SPG11: a consistent clinical phenotype in a family with homozygous spatacsin truncating mutation. Neurogenetics 8: 301-305
3. Hehr U et al (2007) Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia. Ann Neuro. 62: 656-665
4. Perez-Branguli F et al (2014) Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia. Hum Molec Genet 23: 4859-4874
5. Stevanin G et al (2007) Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nature Genet 39: 366-372