Alternative titles; symbols
HGNC Approved Gene Symbol: SPG21
SNOMEDCT: 764734003;
Cytogenetic location: 15q22.31 Genomic coordinates (GRCh38): 15:64,963,022-64,989,914 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q22.31 | Mast syndrome | 248900 | Autosomal recessive | 3 |
Using the cytoplasmic tail of CD4 (186940) as bait in a yeast 2-hybrid screen of a Jurkat T-cell cDNA library, followed by PCR, Zeitlmann et al. (2001) cloned ACP33. The deduced 308-amino acid protein contains a cluster of 4 aspartic acids near the N terminus and a structural element conserved in alpha/beta fold bacterial hydrolases. It does not have a localization signal, leader sequence, or transmembrane helix. Northern blot analysis detected a 2.1-kb ACP33 transcript expressed at comparable levels in all tissues examined. Western blot analysis detected ACP33 at an apparent molecular mass of 33 kD in all human and murine cell lines examined. Fractionation of a CD4-positive T-cell line found both endogenous and transiently expressed ACP33 evenly distributed between the soluble cytosolic fraction and the particulate fraction. Immunofluorescence localization showed that ACP33 partially localized in the cytosol and also accumulated in an intracellular vesicular compartment, where it colocalized to a large extent with CD4.
Using Western blot analysis, Hanna and Blackstone (2009) found high expression of endogenous maspardin in HeLa cells. Immunohistochemical analysis localized maspardin throughout the cytoplasm, with clustering at the perinuclear region. Maspardin fractionated with both cytoplasmic and several membrane components, but not with nuclei, and was associated predominantly with markers for the trans-Golgi and endocytic compartment.
By coimmunoprecipitation experiments, Zeitlmann et al. (2001) confirmed that endogenous CD4 interacted with ACP33 in an ACP33-transfected CD4-positive T-cell line. By analyzing the interaction between various truncation and point mutants, they determined that the last 2 conserved hydrophobic amino acids at the C terminus of CD4 and ser109 within the alpha/beta fold of ACP33 were required for the interaction. Truncation of the last 2 amino acids of CD4 enhanced T-cell receptor (see 186880)-induced T-cell activation, suggesting that ACP33 is a negative regulator of CD4 activity. The CD4-ACP33 complex could also coprecipitate LCK (153390). There was no direct interaction between ACP33 and LCK, indicating that ACP33 and LCK interact independently and simultaneously with CD4.
Using coimmunoprecipitation analysis and protein pull-down assays, Hanna and Blackstone (2009) showed that endogenous maspardin and ALDH16A1 (613358) interacted directly.
By genomic sequence analysis, Simpson et al. (2003) mapped the ACP33 gene to chromosome 15q22.31.
In an extensive Amish pedigree segregating Mast syndrome (MASTS; 248900), a 'complicated' form of autosomal recessive hereditary spastic paraplegia associated in more advanced cases with dementia and other CNS abnormalities, Simpson et al. (2003) mapped the disease locus to a small interval of 15q22.31 encompassing 3 genes. Sequence analysis of the 3 transcripts revealed that all 14 affected members were homozygous for a 1-bp insertion in the ACP33 gene (601insA; 608181.0001). Simpson et al. (2003) designated the gene product maspardin (Mast syndrome, spastic paraplegia, autosomal recessive, with dementia).
In 2 Japanese brothers with Mast syndrome, Ishiura et al. (2014) identified a homozygous missense mutation in the ACP33 gene (A108P; 608181.0002). Functional studies of the variant were not performed. The proband was ascertained from a larger cohort of 129 Japanese patients with spastic paraplegia who were analyzed for mutations in candidate spastic paraplegia genes.
In an Italian patient with Mast syndrome, Scarlato et al. (2017) identified a homozygous mutation in the ACP33 gene (c.118delC; 608181.0003). The mutation was predicted to result in loss of the maspardin interaction domain and therefore loss of function.
In 5 patients from 3 unrelated families of Austrian and German origin with Mast syndrome, Amprosi et al. (2022) identified homozygous or compound heterozygous putative loss-of-function nonsense or frameshift mutations in the ACP33 gene (608181.0004-608181.0006). Functional studies of the variants and studies of patient cells were not performed.
Davenport et al. (2016) characterized the neurologic phenotype of a mouse knockout for Spg21 (Spg21 -/-). Twelve-month-old mutant mice had increased slippages on a beam walking test and shorter mean latency to falling on a ledge test compared to wildtype mice, which was suggestive of hindlimb dysfunction. The mutant mice also had an abnormal hindlimb clasp test compared to wildtype mice, consistent with neuronal dysfunction. Davenport et al. (2016) also characterized the phenotype of primary cortical neurons from the Spg21 -/- mice. Neurons from the mutant mice had delayed ganglia network formation and reduced ganglia formation in response to EGF stimulation. Neurons from the mutant mice additionally demonstrated reduced axonal branches. In brain cortex from the mutant mice, Egfr1 (131550) mRNA was increased, and expression of the Egf (131530) targets Rorb (601972), Fyn (137025), and Ets1 (164720) were reduced.
In affected members of the extended Amish pedigree in which Cross and McKusick (1967) first identified the form of complicated spastic paraplegia called Mast syndrome (MASTS; 248900), Simpson et al. (2003) identified a homozygous 1-bp insertion (601insA) in the ACP33 gene, causing a frameshift and premature termination of the protein.
In 2 Japanese brothers with Mast syndrome (MASTS; 248900), Ishiura et al. (2014) identified a homozygous c.322G-C transversion in exon 4 of the ACP33 gene, resulting in an ala108-to-pro (A108P) substitution at a highly conserved residue next to the active site of the alpha/beta hydrolase domain. Functional studies of the variant were not performed. The proband was ascertained from a larger cohort of 129 Japanese patients with spastic paraplegia who were analyzed for mutations in candidate spastic paraplegia genes. The brothers had onset of gait disturbances due to spasticity in their fifties and sixties, much later than that in the Amish patients reported by Cross and McKusick (1967) and Simpson et al. (2003) who had a different ACP33 mutation (608181.0001). Both had cognitive decline and apraxia, and brain MRI of the proband showed thin corpus callosum and frontotemporal atrophy. Neither patient had extrapyramidal, cerebellar, or bulbar signs, which also differed from that observed in the Amish patients.
In an Italian patient with Mast syndrome (MASTS; 248900), Scarlato et al. (2017) identified homozygosity for a 1-bp deletion (c.118delC) in the ACP33 gene, predicted to result in a frameshift and premature termination (Arg40GlufsTer27). The mutation was predicted to result in loss of the protein interaction domain and therefore loss of function. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the patient's mother and healthy sister. The patient's father was not available for testing. The patient had early school difficulties and motor problems; in his early twenties, he had progressive speech limitation and executive dysfunction and personality disturbances, followed by spastic paraparesis and extrapyramidal features.
In an Austrian woman (family 1) with onset of Mast syndrome (MASTS; 248900) at age 35 years, Amprosi et al. (2022) identified a homozygous 1-bp deletion (c.487delA) in the ACP33 gene, resulting in a frameshift and premature truncation (Ile163Ter). The frequency of this allele in the non-Finnish European population in gnomAD was 1.8 x 10(-5). Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function. The patient had a progressive disease course and was wheelchair-bound with dementia at age 50.
In 2 Austrian sibs (family 2) with Mast syndrome (MASTS; 248900), Amprosi et al. (2022) identified compound heterozygous mutations in exon 3 of the ACP33 gene: a c.118C-T transition resulting in an arg40-to-ter (R40X) substitution, and a 1-bp deletion (c.153delT; 608181.0006) resulting in a frameshift (Val52fs). One patient had onset of 30 years, whereas the other had onset at age 10 years. Two affected sibs from another family (family 3) of German descent were found to be homozygous for the R40X mutation. One patient in this family had onset at age 20 years, whereas the other had onset at age 40 years. Functional studies of the variants and studies of patient cells were not performed, but they were predicted to result in a loss of function.
For discussion of the 1-bp deletion (c.153delT) in the ACP33 gene, resulting in a frameshift (Val52fs), that was found in compound heterozygous state 2 sibs with Mast syndrome (MASTS; 248900) by Amprosi et al. (2022), see 608181.0005.
Amprosi, M., Indelicato, E., Nachbauer, W., Hussl, A., Stendel, C., Eigentler, A., Gallenmuller, C., Boesch, S., Klopstock, T. Mast syndrome outside the Amish community: SPG21 in Europe. Front. Neurol. 12: 799953, 2022. [PubMed: 35111129] [Full Text: https://doi.org/10.3389/fneur.2021.799953]
Cross, H. E., McKusick, V. A. The Mast syndrome: a recessively inherited form of presenile dementia with motor disturbances. Arch. Neurol. 16: 1-13, 1967. [PubMed: 6024251] [Full Text: https://doi.org/10.1001/archneur.1967.00470190005001]
Davenport, A., Bivona, A., Latson, W., Lemanski, L. F., Cheriyath, V. Loss of maspardin attenuates the growth and maturation of mouse cortical neurons. Neurodegener. Dis. 16: 260-272, 2016. [PubMed: 26978163] [Full Text: https://doi.org/10.1159/000443666]
Hanna, M. C., Blackstone, C. Interaction of the SPG21 protein ACP33/maspardin with the aldehyde dehydrogenase ALDH16A1. Neurogenetics 10: 217-228, 2009. [PubMed: 19184135] [Full Text: https://doi.org/10.1007/s10048-009-0172-6]
Ishiura, H., Takahashi, Y., Hayashi, T., Saito, K., Furuya, H., Watanabe, M., Murata, M., Suzuki, M., Sugiura, A., Sawai, S., Shibuya, K., Ueda, N., Ichikawa, Y., Kanazawa, I., Goto, J., Tsuji, S. Molecular epidemiology and clinical spectrum of hereditary spastic paraplegia in the Japanese population based on comprehensive mutational analyses. J. Hum. Genet. 59: 163-172, 2014. [PubMed: 24451228] [Full Text: https://doi.org/10.1038/jhg.2013.139]
Scarlato, M., Citterio, A., Barbieri, A., Godi, C., Panzeri, E., Bassi, M. T. Exome sequencing reveals a novel homozygous mutation in ACP33 gene in the first Italian family with SPG21. J. Neurol. 264: 2021-2023, 2017. [PubMed: 28752238] [Full Text: https://doi.org/10.1007/s00415-017-8558-0]
Simpson, M. A., Cross, H., Proukakis, C., Pryde, A., Hershberger, R., Chatonnet, A., Patton, M. A., Crosby, A. H. Maspardin is mutated in Mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. Am. J. Hum. Genet. 73: 1147-1156, 2003. [PubMed: 14564668] [Full Text: https://doi.org/10.1086/379522]
Zeitlmann, L., Sirim, P., Kremmer, E., Kolanus, W. Cloning of ACP33 as a novel intracellular ligand of CD4. J. Biol. Chem. 276: 9123-9132, 2001. [PubMed: 11113139] [Full Text: https://doi.org/10.1074/jbc.M009270200]