Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature - PubMed (original) (raw)

doi: 10.1038/ng.748. Epub 2011 Jan 9.

Gillian I Rice, Sarah Daly, Jill Urquhart, Hannah Gornall, Brigitte Bader-Meunier, Kannan Baskar, Shankar Baskar, Veronique Baudouin, Michael W Beresford, Graeme C M Black, Rebecca J Dearman, Francis de Zegher, Emily S Foster, Camille Francès, Alison R Hayman, Emma Hilton, Chantal Job-Deslandre, Muralidhar L Kulkarni, Martine Le Merrer, Agnes Linglart, Simon C Lovell, Kathrin Maurer, Lucile Musset, Vincent Navarro, Capucine Picard, Anne Puel, Frederic Rieux-Laucat, Chaim M Roifman, Sabine Scholl-Bürgi, Nigel Smith, Marcin Szynkiewicz, Alice Wiedeman, Carine Wouters, Leo A H Zeef, Jean-Laurent Casanova, Keith B Elkon, Anthony Janckila, Pierre Lebon, Yanick J Crow

Affiliations

Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature

Tracy A Briggs et al. Nat Genet. 2011 Feb.

Abstract

We studied ten individuals from eight families showing features consistent with the immuno-osseous dysplasia spondyloenchondrodysplasia. Of particular note was the diverse spectrum of autoimmune phenotypes observed in these individuals (cases), including systemic lupus erythematosus, Sjögren's syndrome, hemolytic anemia, thrombocytopenia, hypothyroidism, inflammatory myositis, Raynaud's disease and vitiligo. Haplotype data indicated the disease gene to be on chromosome 19p13, and linkage analysis yielded a combined multipoint log(10) odds (LOD) score of 3.6. Sequencing of ACP5, encoding tartrate-resistant acid phosphatase, identified biallelic mutations in each of the cases studied, and in vivo testing confirmed a loss of expressed protein. All eight cases assayed showed elevated serum interferon alpha activity, and gene expression profiling in whole blood defined a type I interferon signature. Our findings reveal a previously unrecognized link between tartrate-resistant acid phosphatase activity and interferon metabolism and highlight the importance of type I interferon in the genesis of autoimmunity.

PubMed Disclaimer

Figures

Figure 1

Figure 1. Bone, brain and skin involvement in patients with mutations in ACP5

Enchondromatous lesions are seen in the distal ulna and radius of patient 1, with sclerosis and irregularity of the metaphyseal plate (panel a). Lateral spine radiographs demonstrate platyspondyly and irregularity of the vertebral endplates in patient 4 (panel b). Dense calcification of the basal ganglia, thalami and deep gyri is observed in patient 1 (panel c). The hands of patient 1 illustrate significant sclerotic changes (panel d). Note the loss of tissue from several digits. Severe gangrenous changes led to amputation of the left index finger.

Figure 2

Figure 2. Summary of mutation data

Panel a shows the AutoSNPa output for Chromosome 19p generated from whole-genome SNP analysis of five unrelated individuals (P denotes patient). A shared region of homozygosity (indicated by the red box) was identified in three patients (4, 6 and 7) born to consanguineous parents, between base-pair positions 10,527,380-13,214,722 (black and yellow bars indicate homozygous and heterozygous SNPs respectively). Within this homozygous region, patient 1 demonstrated a failure of hybridization for a copy number probe and an adjacent SNP probe. QMPSF was performed to confirm the presence of the putative deletion in this patient (panel b). Representative data from an analysis of exons 4 and 6 indicates that no products were seen using DNA from the proband (predicted copy number of 0), consistent with a homozygous ACP5 gene deletion, whilst her mother carries a heterozygous deletion as expected (predicted copy number of 1, compared to predicted copy number of 2 in the control). DNA from the father was unavailable. A schematic of the disease critical interval on chromosome 19p is shown in panel c. The deleted region included sequence for the gene ACP5, in which single base-pair mutations, a frame shift mutation and two gene deletions were identified. Deletions are indicated by solid lines and double arrows indicate extension beyond the coordinates shown. No other genes were involved in either of these deletions.

Figure 3

Figure 3. Levels of TRAP protein and interferon alpha activity in patients with mutations in ACP5

We used monoclonal antibodies to measure levels of total TRAP protein and TRAP isoform 5a in plasma from six patients with ACP5 mutations, and compared them with levels in age and sex-matched control samples (panel a). We also tested an unaffected sibling to patients 2 and 3 who was homozygous for the wild-type allele on gene sequencing (designated control 001). All six patients demonstrated only background levels of total protein and an absence of 5a protein. Serum samples were obtained from eight patients with mutations in ACP5, and interferon alpha levels measured using a biological assay of antiviral activity (panel b). Five patients were assayed serially, at greater than one month intervals between assay points. On only one occasion was the level of interferon alpha within the normal range (< 2 IU/ml) in any of the patients sampled.

Figure 4

Figure 4. Computational analysis of missense mutations in the context of protein structure

Each of the four missense mutations was modelled in the context of the crystal structure. Interactions between the mutated side chains and the rest of the protein are indicated; pink and yellow spikes indicate destabilising van der Waals overlaps, green lenses represent stablising hydrogen bonds. Van der Waals contacts are omitted for clarity. The least destabilising side chain conformation (“rotamer”) is shown in each case. Insets illustrate the wild type residues and their interactions with the rest of the protein shown from the same viewpoint. Panel a illustrates the mutation of Ile 89 to Thr; panel b the mutation of Gly 215 to Arg; panel c the mutation of Asp 241 to Asn and panel d the mutation of Met 264 to Lys. For each mutation, van der Waals overlaps are large enough that they are likely to substantially destabilise the structure. In addition, for panel c there is loss of a hydrogen bond that is stabilising in the wild type, and for panel d the charged NH3 group of the lysine is buried from solvent and not able to make a neutralising charge-charge interaction, further destablising the mutant structure.

Figure 5

Figure 5. Gene expression analysis in patients with TRAP deficiency

Whole transcriptome microarray expression analysis was undertaken in three patients, and compared to the data derived from three age-matched control samples (panel a). We identified a subset of 18 genes that were four or more fold up-regulated in patients, with a significance level for the comparisons of p<0.0005 and a false discovery value of <0.2 (Supplementary Fig. 3). Fifteen of these genes are known to be interferon stimulated, characteristic of a type I interferon signature. The intensity plot was generated from the gene expression values (log 2) that had been standardized (for each gene the mean set to zero, standard deviation to 1) using Partek Genomics Solution (version 6.5, Copyright 2010, Partek Inc., St. Charles, MO, USA). Panel b shows qPCR data for a representative sample of these up-regulated genes Ly6E, Mx1, USP18, RSAD2, OAS1, IFI44L, IL-10 and IL-12. All genes assessed in the patient group were significantly up-regulated (p<0.001) compared to controls, except for IL-10 and IL-12, confirming the type 1 interferon signature seen on microarray analysis and showing an absence of up- or down-regulation of IL-10 and IL-12. RQ is equal to 2−ΔΔCt with ΔΔCt +/− SDs. i.e. the normalized fold change relative to a calibrator.

Comment in

Similar articles

Cited by

References

    1. Schorr S, Legum C, Ochshorn M. SPONDYLOENCHONDRODYSPLASIA - enchondromatosis with severe platyspondyly in 2 brothers. Radiology. 1976;118:133–9. - PubMed
    1. Renella R, et al. SPONDYLOENCHONDRODYSPLASIA with spasticity, cerebral calcifications, and immune dysregulation: Clinical and radiographic delineation of a pleiotropic disorder. Am. J. Med. Genet. A. 2006;140A:541–50. - PubMed
    1. Navarro V, et al. TWO further cases of spondyloenchondrodysplasia (SPENCD) with immune dysregulation. Am. J. Med. Genet. A. 2008;146A:2810–5. - PubMed
    1. Tan EM, et al. THE 1982 revised criteria for the classification of Systemic Lupus Erythematosus. Arthritis Rheum. 1982;25:1271–77. - PubMed
    1. Raymond AA, Zariah AA, Samad SA, Chin CN, Kong NC. BRAIN calcification in patients with cerebral lupus. Lupus. 1996;5:123–8. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources