Alternative titles; symbols
HGNC Approved Gene Symbol: ACP5
SNOMEDCT: 703523004;
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38): 19:11,574,660-11,578,975 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.2 | Spondyloenchondrodysplasia with immune dysregulation | 607944 | Autosomal recessive | 3 |
Ketcham et al. (1989) cloned a full-length cDNA for type 5 tartrate-resistant acid phosphatase from human placenta and found that it contained an open reading frame of 969 basepairs (corresponding to a protein of 323 amino acids), a putative signal sequence of 19 amino acids, and 2 potential glycosylation sites. The deduced amino acid sequence of the human isozyme is 85% identical to the amino acid sequence of porcine uteroferrin and 82% identical to the corresponding regions of a partial amino acid sequence of the bovine spleen enzyme. The type 5 isozyme of acid phosphatase is the most basic of the acid phosphatases and is the only form insensitive to inhibition by L(+)-tartrate. Normally, it is detected as a minor intracellular component of spleen, lung, liver, and bone. High levels of acid phosphatase-5 are found within the spleen and monocytes of patients with Gaucher disease (230800). The type 5 isozyme is an iron-containing glycoprotein with a molecular mass of approximately 34 kD.
Lord et al. (1990) also isolated a clone for ACP5, which is found principally in resident tissue macrophages. They found that an ACP5 cDNA clone contained an open reading frame of 975 bp, encoded a protein of 325 amino acids, including a single peptide of 19 residues and 2 potential sites for N-glycosylation.
Allen et al. (1989) assigned the ACP5 gene to 15q22-q26 by in situ hybridization both to normal metaphase chromosomes and to the chromosomes of an individual carrying an unbalanced translocation involving chromosome 15. However, Grimes et al. (1993) showed that the Acp5 gene maps to mouse chromosome 9 in a group of genes that are homologous to a group of genes on 19p13.3-p13.1. By Southern blot analysis of somatic cell hybrids and use of a PCR method, Leach et al. (1994) confirmed the assignment of ACP5 to chromosome 19. By isotopic in situ hybridization, Lord et al. (1990) mapped the APC5 gene to 19p13.3-p13.2 with a peak at 19p13.2.
Lord et al. (1990) found that the expression of ACP5 mRNA was restricted to mononuclear phagocytes and that the enzyme was induced more than 20-fold on transformation of normal human monocytes to macrophages by culture in serum-supplemented medium.
In 10 patients with spondyloenchondrodysplasia with immune dysregulation (SPENCDI; 607944) from 8 families, Briggs et al. (2011) identified homozygosity or compound heterozygosity for mutations in the ACP5 gene (see, e.g., 171640.0001-171640.0004 and 171640.0010). In vivo testing confirmed a loss of expressed protein, and all 8 cases assayed showed elevated serum interferon alpha (see IFNA1, 147660) activity, with gene expression profiling in whole blood defining a type I interferon signature.
Simultaneously and independently, Lausch et al. (2011) mapped SPENCDI to chromosome 19p13 and identified homozygous or compound heterozygous mutations in the ACP5 gene in 14 affected individuals from 11 families (see, e.g., 171640.0004-171640.0007). Lausch et al. (2011) demonstrated that the mutations abolished TRAP enzyme function in serum and cells of affected individuals, and that phosphorylated osteopontin accumulated in serum, urine, and cells cultured from TRAP-deficient individuals. Case-derived dendritic cells exhibited an altered cytokine profile and were more potent than matched controls in stimulating allogeneic T-cell proliferation in mixed lymphocyte reactions.
In a girl who had severe immune dysregulation with neurologic impairment and only minor bone changes, Girschick et al. (2015) identified compound heterozygosity for a missense mutation (T44M; 171640.0008) and a 1-bp duplication (171640.0009) in the ACP5 gene. The authors concluded that mutation in ACP5 can cause severe immune dysregulation and neurologic impairment even in the absence of metaphyseal dysplasia.
In a Turkish sister and brother exhibiting spondyloenchondrodysplasia without immune dysregulation or neurologic abnormalities, de Bruin et al. (2016) performed exome sequencing and identified homozygosity for a frameshift mutation in the ACP5 gene (171640.0010).
Hayman et al. (1996) observed that mice with a targeted disruption of the Acp5 gene, or Trap, suffered from developmental deformities of the limb and axial skeleton and had osteoclasts defective in bone resorption, resulting in mild osteopetrosis.
Bune et al. (2001) determined that macrophages of Acp5-deficient mice had compensatory acid phosphatase activity attributable to the Acp2 gene (171650) and enhanced proinflammatory responses in vitro. However, mice lacking Acp5 showed delayed clearance of Staphylococcus aureus in vivo, which was associated with reduced numbers of peritoneal macrophages, in spite of normal macrophage and neutrophil phagocytosis and killing in vitro.
In a Turkish brother and sister with spondyloenchondrodysplasia and immune dysregulation (SPENCDI; 607944), born of first-cousin parents, Briggs et al. (2011) identified homozygosity for a 266C-T transition in exon 4 of the ACP5 gene, resulting in a thr89-to-ile (T89I) substitution at a highly conserved residue. The brother, who was previously reported by Navarro et al. (2008), presented at age 22 months with spasticity and a vasculitic skin rash. Upon evaluation at 11 years of age, plasma levels of total TRAP protein were negligible and TRAP 5a protein was undetectable, and he had spasticity and intracranial calcifications, elevated antinuclear antibody and anti-double-stranded DNA antibody titers, and hypocomplementemia. His older sister, who was evaluated at 14 years of age for short stature, had a history of Raynaud phenomenon but did not have elevated ANA or anti-dsDNA titers; she was, however, found to have a high level of interferon-alpha (147660) in serum.
In an 11-year-old Pakistani boy with spondyloenchondrodysplasia and immune dysregulation (SPENCDI; 607944), born of first-cousin parents and previously reported by Renella et al. (2006) as 'patient 10,' Briggs et al. (2011) identified homozygosity for a 667C-T transition in the ACP5 gene, resulting in a gln223-to-ter (Q223X) substitution. Plasma levels of total TRAP protein were negligible and TRAP 5a protein was undetectable in this patient, indicating an almost complete lack of TRAP synthesis or secretion. In addition to skeletal manifestations, the patient had elevated antinuclear antibody and anti-double-stranded DNA antibody titers and autoimmune hemolytic anemia.
In a female patient with spondyloenchondrodysplasia and immune dysregulation (SPENCDI; 607944), who was born of first-cousin parents of Portuguese descent and was originally reported by Roifman and Melamed (2003), Briggs et al. (2011) identified homozygosity for a 791T-A transversion in exon 7 of the ACP5 gene, resulting in a met264-to-lys (M264K) substitution. Computational analysis indicated that this change was likely to destabilize the structure of the protein. In addition to skeletal changes, the patient had a history of recurrent infections, elevated antinuclear antibody and anti-double-stranded DNA antibody titers, thrombocytopenia requiring splenectomy, nonerosive arthropathy, systemic lupus erythematosus, and hypothyroidism.
In a female patient from Mali with spondyloenchondrodysplasia and immune dysregulation (SPENCDI; 607944), Briggs et al. (2011) identified homozygosity for a 643G-A transition in exon 6 of the ACP5 gene, resulting in a gly215-to-arg (G215R) substitution. This patient, who presented at 6 years of age with nephropathy, also had severe short stature with metaphyseal dysplasia, elevated antinuclear antibody and anti-double-stranded DNA antibody titers, and systemic lupus erythematosus with class V lupus nephritis on renal biopsy.
In 2 unrelated girls with spondyloenchondrodysplasia, 14 years and 10 years of age, respectively, Lausch et al. (2011) identified homozygosity for the G215R mutation in the ACP5 gene. In addition to skeletal changes, the older girl had chronic thrombocytopenia, ataxia, leukodystrophy, and basal ganglia calcifications, whereas the younger girl had only calcifications of the left globus pallidus without immunologic or neurologic symptoms. The mutation was not found in 228 control alleles.
In 2 Senegalese sibs with spondyloenchondrodysplasia and autoantibodies, Briggs et al. (2016) identified homozygosity for the G215R mutation in ACP5. Both sibs had elevated antinuclear antibody titers and serum interferon-alpha activity levels; 1 sib also showed elevated anti-dsDNA antibody titers, whereas the other had antiplatelet antibodies and presented at 5 years of age with cerebral hemorrhage.
In 2 sibs with spondyloenchondrodysplasia and immune dysregulation (SPENCDI; 607944), Lausch et al. (2011) identified homozygosity for a c.325G-A transition (c.325G-A, ENST00000218758) in exon 7 of the ACP5 gene, resulting in a gly109-to-arg (G109R) substitution. In addition to skeletal changes, both sibs had systemic lupus erythematosus, the older sib also had arthralgia and vitiligo, and the younger sib had arthritis; the older sib also had mild developmental delay and diffuse intracranial calcifications as well as of the basal ganglia, and the younger sib had basal ganglia and right frontal lobe calcifications, but neither sib displayed neurologic signs. In 2 additional affected individuals from unrelated families, 1 of whom was the patient originally reported by Scharer (1958), Lausch et al. (2011) identified compound heterozygosity for the G109R mutation and another mutation in the ACP5 gene (see 171640.0006 and 171640.0007). None of the mutations was found in 228 control alleles.
In a 36-year-old Iraqi Jewish woman and a 35-year-old Arab man with spondyloenchondrodysplasia, both originally reported by Frydman et al. (1990), Briggs et al. (2016) identified homozygosity for the G109R mutation in ACP5. Neither patient exhibited clinical autoimmune disease, although the woman had a positive interferon-stimulated genes (ISG) score, and autoantibodies had not been assessed in the man. In addition to typical skeletal findings of spondyloenchondrodysplasia, the man had spasticity, moderate mental retardation, and basal ganglia calcification.
In a 64-year-old Ashkenazi Jewish man with spondyloenchondrodysplasia and immune dysregulation (SPENCDI; 607944), who was originally reported by Scharer (1958) and later studied by Renella et al. (2006), Lausch et al. (2011) identified compound heterozygosity for mutations in the ACP5 gene: a 3-bp deletion (c.831delCTA, ENST00000218758) in exon 7, resulting in deletion of tyrosine at codon 278 (Y278del), and a G109R substitution (171640.0005). The patient was diagnosed with systemic lupus erythematosus at 9.5 years of age but was subsequently lost to follow-up; the diagnosis of spondyloenchondrodysplasia was made 40 years later upon reevaluation of his radiographs. In adulthood he had continued to have recurrent fevers and arthralgias and developed antiphospholipid syndrome, steroid-dependent neutropenia, and thrombocytopenia.
In a 12-year-old patient with spondyloenchondrodysplasia and immune dysregulation (SPENCDI; 607944), Lausch et al. (2011) identified compound heterozygosity for mutations in the ACP5 gene: a c.602T-C transition (c.602T-C, ENST00000218758) in exon 6, resulting in a leu201-to-pro (L201P) substitution, and a G109R substitution (171640.0005). In addition to skeletal manifestations, the patient had thrombocytopenia, leukopenia, hepatosplenomegaly, elevated antinuclear antibody titers, childhood-onset spastic diplegia, and calcification of the basal ganglia and frontal subcortical area.
In a 9-year-old girl who had spasticity, multisystem inflammation, autoimmunity, and immunodeficiency, with only minimal metaphyseal changes (SPENCDI; 607944), Girschick et al. (2015) identified compound heterozygosity for a c.131C-T transition in the ACP5 gene, resulting in a thr44-to-met (T44M) substitution, and a 1-bp duplication (c.816dupC), causing a frameshift predicted to result in a premature termination codon (Lys272GlnfsTer14). Tartrate-resistant acid phosphatase (TRAP) activity was biochemically undetectable in the patient. Her unaffected parents were each heterozygous for 1 of the mutations, and both had markedly decreased TRAP levels.
For discussion of the c.816dupC mutation in the ACP5 gene, causing a frameshift predicted to result in a premature termination codon (Lys272GlnfsTer14), that was found in compound heterozygous state in a patient with spondyloenchondrodysplasia with immune dysregulation (SPENCDI; 607944) by Girschick et al. (2015), see 171640.0008.
In an 11-year-old Egyptian girl with spondyloenchondrodysplasia and immune dysregulation (SPENCDI; 607944), Briggs et al. (2011) identified homozygosity for a 19-bp deletion (c.772_790del) in exon 7 of the ACP5 gene, causing a frameshift predicted to result in a premature termination codon (Ser258TrpfsTer39). The patient's features included elevated elevated antinuclear antibody and anti-dsDNA antibody titers, microglobulinemia, and rheumatic fever with hypogammaglobulinemia.
In a Turkish sister and brother with spondyloenchondrodysplasia without immune dysregulation or neurologic abnormalities, de Bruin et al. (2016) identified homozygosity for the c.772_790del (c.772_790del, ENST00000218758.5) frameshift mutation in the ACP5 gene. Brain MRI was normal in both patients, and laboratory evaluation revealed no evidence for subclinical autoimmune dysfunction.
Allen, B. S., Ketcham, C. M., Roberts, R. M., Nick, H. S., Ostrer, H. Localization of the human type 5, tartrate-resistant acid phosphatase gene by in situ hybridization. Genomics 4: 597-600, 1989. [PubMed: 2473026] [Full Text: https://doi.org/10.1016/0888-7543(89)90284-x]
Bilginer, Y., Duzova, A., Topaloglu, R., Batu, E. D., Boduroglu, K., Gucer, S., Bodur, I., Alanay, Y. Three cases of spondyloenchondrodysplasia (SPENCD) with systemic lupus erythematosus: a case series and review of the literature. Lupus 25: 760-765, 2016. [PubMed: 26854080] [Full Text: https://doi.org/10.1177/0961203316629000]
Briggs, T. A., Rice, G. I., Adib, N., Ades, L., Barete, S., Baskar, K., Baudouin, V., Cebeci, A. N., Clapuyt, P., Coman, D., De Somer, L., Finezilber, Y., and 19 others. Spondyloenchondrodysplasia due to mutations in ACP5: a comprehensive survey. J. Clin. Immun. 36: 220-234, 2016. Note: Erratum: J. Clin. Immun. 36: 529-530, 2016. [PubMed: 26951490] [Full Text: https://doi.org/10.1007/s10875-016-0252-y]
Briggs, T. A., Rice, G. I., Daly, S., Urquhart, J., Gornall, H., Bader-Meunier, B., Baskar, K., Baskar, S., Baudouin, V., Beresford, M. W., Black, G. C. M., Dearman, R. J., and 28 others. Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nature Genet. 43: 127-131, 2011. [PubMed: 21217755] [Full Text: https://doi.org/10.1038/ng.748]
Bune, A. J., Hayman, A. R., Evans, M. J., Cox, T. M. Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disordered macrophage inflammatory responses and reduced clearance of the pathogen, Staphylococcus aureus. Immunology 102: 103-113, 2001. [PubMed: 11168643] [Full Text: https://doi.org/10.1046/j.1365-2567.2001.01145.x]
de Bruin, C., Orbak, Z., Andrew, M., Hwa, V., Dauber, A. Severe short stature in two siblings as the presenting sign of ACP5 deficiency. Horm. Res. Paediat. 85: 358-362, 2016. [PubMed: 26789720] [Full Text: https://doi.org/10.1159/000443684]
Frydman, M., Bar-Ziv, J., Preminger-Shapiro, R., Brezner, A., Brand, N., Ben-Ami, T., Lachman, R. S., Gruber, H. E., Rimoin, D. L. Possible heterogeneity in spondyloenchondrodysplasia: quadriparesis, basal ganglia calcifications, and chondrocyte inclusions. Am. J. Med. Genet. 36: 279-284, 1990. [PubMed: 2363422] [Full Text: https://doi.org/10.1002/ajmg.1320360306]
Girschick, H., Wolf, C., Morbach, H., Hertzberg, C., Lee-Kirsch, M. A. Severe immune dysregulation with neurological impairment and minor bone changes in a child with spondyloenchondrodysplasia due to two novel mutations in the ACP5 gene. Pediat. Rheum. Online J. 13: 37, 2015. [PubMed: 26346816] [Full Text: https://doi.org/10.1186/s12969-015-0035-7]
Grimes, R., Reddy, S. V., Leach, R. J., Scarcez, T., Roodman, G. D., Sakaguchi, A. Y., Lalley, P. A., Windle, J. J. Assignment of the mouse tartrate-resistant acid phosphatase gene (Acp5) to chromosome 9. Genomics 15: 421-422, 1993. [PubMed: 8449511] [Full Text: https://doi.org/10.1006/geno.1993.1079]
Hayman, A. R., Jones, S. J., Boyde, A., Foster, D., Colledge, W. H., Carlton, M. B., Evans, M. J., Cox, T. M. Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis. Development 122: 3151-3162, 1996. [PubMed: 8898228] [Full Text: https://doi.org/10.1242/dev.122.10.3151]
Ketcham, C. M., Roberts, R. M., Simmen, R. C., Nick, H. S. Molecular cloning of the type 5, iron-containing, tartrate-resistant acid phosphatase from human placenta. J. Biol. Chem. 264: 557-563, 1989. [PubMed: 2909539]
Lausch, E., Janecke, A., Bros, M., Trojandt, S., Alanay, Y., De Laet, C., Hubner, C. A., Meinecke, P., Nishimura, G., Matsuo, M., Hirano, Y., Tenoutasse, S., and 9 others. Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity. Nature Genet. 43: 132-137, 2011. [PubMed: 21217752] [Full Text: https://doi.org/10.1038/ng.749]
Leach, R. J., Reus, B. E., Hundley, J. E., Johnson-Pais, T. L., Windle, J. J. Confirmation of the assignment of the human tartrate-resistant acid phosphatase gene (ACP5) to chromosome 19. Genomics 19: 180-181, 1994. [PubMed: 8188227] [Full Text: https://doi.org/10.1006/geno.1994.1037]
Lord, D. K., Cross, N. C. P., Bevilacqua, M. A., Rider, S. H., Gorman, P. A., Groves, A. V., Moss, D. W., Sheer, D., Cox, T. M. Type 5 acid phosphatase: sequence, expression and chromosomal localization of a differentiation-associated protein of the human macrophage. Europ. J. Biochem. 189: 287-293, 1990. Note: Erratum: Europ. J. Biochem. 191: 775 only, 1990. [PubMed: 2338077] [Full Text: https://doi.org/10.1111/j.1432-1033.1990.tb15488.x]
Navarro, V., Scott, C., Briggs, T. A., Barete, S., Frances, C., Lebon, P., Maisonobe, T., Rice, G. I., Wouters, C. H., Crow, Y. J. Two further cases of spondyloenchondrodysplasia (SPENCD) with immune dysregulation. Am. J. Med. Genet. 146A: 2810-2815, 2008. [PubMed: 18924170] [Full Text: https://doi.org/10.1002/ajmg.a.32518]
Renella, R., Schaefer, E., LeMerrer, M., Alanay, Y., Kandemir, N., Eich, G., Costa, T., Ballhausen, D., Boltshauser, E., Bonafe, L., Giedion, A., Unger, S., Superti-Furga, A. Spondyloenchondrodysplasia with spasticity, cerebral calcifications, and immune dysregulation: clinical and radiologic delineation of a pleiotropic disorder. Am. J. Med. Genet. 140A: 541-550, 2006. [PubMed: 16470600] [Full Text: https://doi.org/10.1002/ajmg.a.31081]
Roifman, C. M., Melamed, I. A novel syndrome of combined immunodeficiency, autoimmunity and spondylometaphyseal dysplasia. Clin. Genet. 63: 522-529, 2003. [PubMed: 12786759] [Full Text: https://doi.org/10.1034/j.1399-0004.2003.00033.x]
Scharer, K. A case of infantile generalized lupus erythematosus with unusual bone changes. Helv. Paediat. Acta 13: 40-68, 1958. [PubMed: 13524805]