Identification of RELN variant p.(Ser2486Gly) in an Iranian family with ankylosing spondylitis; the first association of RELN and AS

Abstract

Ankylosing spondylitis (AS) is a common complex inflammatory disease; however, up to now distinct genes with monogenic pattern have not been reported for this disease. In the present study, we report a large Iranian family with several affected members with AS. DNAs of the three affected and two healthy cases were chosen for performing whole-exome sequencing (WES). After several filtering steps, candidate variants in the following genes were detected: RELN, DNMT1, TAF4β, MUC16, DLG2, and FAM208. However, segregation analysis confirmed the association of only one variant, c.7456A>G; p.(Ser2486Gly) in the RELN gene with AS in this family. In addition, in silico predictions supported the probable pathogenicity of this variant. In this study, for the first time, we report a novel variant in the RELN gene, c.7456A>G; p.(Ser2486Gly), which completely co-segregates with AS. This association suggests potential insights into the pathophysiological bases of AS and it could broaden horizons toward new therapeutic strategies.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Pedigree of the family with AS.
Fig. 2
Fig. 3

Data availability

Human variant and phenotypes have been reported to ClinVar (Accession number: SCV000930629; www.ncbi.nlm.nih.gov/clinvar) and LOVD (Individual ID: 00250194). Whole-exome sequencing data produced in the current study have been deposited in the NCBI Sequence Read Archive (SRA) with accession numbers SAMN12565062, SAMN12565063, SAMN12565064, SAMN12565065, and SAMN12565066 and URL: https://dataview.ncbi.nlm.nih.gov/object/PRJNA558631. Also, bioproject is accessible by PRJNA558631 as an accession number and the following URL: https://www.ncbi.nlm.nih.gov/bioproject/PRJNA558631.

References

  1. 1.

    El Maghraoui A. Extra-articular manifestations of ankylosing spondylitis: prevalence, characteristics and therapeutic implications. Eur J Intern Med. 2011;22:554–60.

  2. 2.

    Stolwijk C, van Tubergen A, Castillo-Ortiz JD, Boonen A. Prevalence of extra-articular manifestations in patients with ankylosing spondylitis: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74:65–73.

  3. 3.

    Schett G. Bone formation versus bone resorption in ankylosing spondylitis: molecular mechanisms of spondyloarthropathies. Springer; New York, NY. 2009;114–21.

  4. 4.

    Robinson PC, Brown MA. Genetics of ankylosing spondylitis. Mol Immunol. 2014;57:2–11.

  5. 5.

    Maksymowych WP, Chiowchanwisawakit P, Clare T, Pedersen SJ, Østergaard M, Lambert RG. Inflammatory lesions of the spine on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis: evidence of a relationship between inflammation and new bone formation. Arthritis Rheum. 2009;60:93–102.

  6. 6.

    Cortes A, Hadler J, Pointon JP, Robinson PC, Karaderi T, Leo P, et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet. 2013;45:730.

  7. 7.

    Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011;12:745.

  8. 8.

    Brown MA, Kennedy LG, Macgregor AJ, Darke C, Duncan E, Shatford JL, et al. Susceptibility to ankylosing spondylitis in twins the role of genes, HLA, and the environment. Arthritis Rheum. 1997;40:1823–8.

  9. 9.

    Ji X, Sun K, Hu Z, Zhang Y, Ma Y, Sun Z, et al. Comparison of clinical manifestations according to HLA-B (27) genotype in ankylosing spondylitis patients: real-world evidence from smart management system for spondyloarthritis. Zhonghua nei ke za zhi. 2018;57:179–84.

  10. 10.

    Timms AE, Crane AM, Sims A-M, Cordell HJ, Bradbury LA, Abbott A, et al. The interleukin 1 gene cluster contains a major susceptibility locus for ankylosing spondylitis. Am J Hum Genet. 2004;75:587–95.

  11. 11.

    Rabbani B, Tekin M, Mahdieh N. The promise of whole-exome sequencing in medical genetics. J Hum Genet. 2014;59:5.

  12. 12.

    Robinson PC, Leo PJ, Pointon JJ, Harris J, Cremin K, Bradbury LA, et al. Exome-wide study of ankylosing spondylitis demonstrates additional shared genetic background with inflammatory bowel disease. NPJ Genom Med. 2016;1:16008.

  13. 13.

    Moll J, Wright V. New York clinical criteria for ankylosing spondylitis. A statistical evaluation. Ann Rheum Dis. 1973;32:354.

  14. 14.

    Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987;162:156–9.

  15. 15.

    Bava KA, Gromiha MM, Uedaira H, Kitajima K, Sarai A. ProTherm, version 4.0: thermodynamic database for proteins and mutants. Nucleic Acids Res. 2004;32:D120–1.

  16. 16.

    Homer N, Merriman B, Nelson SF. BFAST: an alignment tool for large scale genome resequencing. PloS one. 2009;4:e7767.

  17. 17.

    Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment/map format and SAMtools. Bioinformatics. 2009;25:2078–9.

  18. 18.

    Leinonen R, Sugawara H, Shumway M. Collaboration INSD The sequence read archive. Nucleic Acids Res. 2010;39:D19–21.

  19. 19.

    Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT. LOVD v. 2.0: the next generation in gene variant databases. Hum Mutat. 2011;32:557–63.

  20. 20.

    Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2015;44:D862–8.

  21. 21.

    Braun J, Sieper J. Ankylosing spondylitis. Lancet. 2007;369:1379–90.

  22. 22.

    O’rielly DD, Uddin M, Rahman P. Ankylosing spondylitis: beyond genome-wide association studies. Curr Opin Rheumatol. 2016;28:337–45.

  23. 23.

    Smalheiser NR, Costa E, Guidotti A, Impagnatiello F, Auta J, Lacor P, et al. Expression of reelin in adult mammalian blood, liver, pituitary pars intermedia, and adrenal chromaffin cells. Proc Natl Acad Sci. 2000;97:1281–6.

  24. 24.

    D'Arcangelo G, Miao GG, Chen S-C, Scares HD, Morgan JI, Curran T: A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature. 1995;374:719–23.

  25. 25.

    D’Arcangelo G, Nakajima K, Miyata T, Ogawa M, Mikoshiba K, Curran T. Reelin is a secreted glycoprotein recognized by the CR-50 monoclonal antibody. J Neurosci. 1997;17:23–31.

  26. 26.

    Ranaivoson FM, von Daake S, Comoletti D. Structural insights into reelin function: present and future. Front Cell Neurosci. 2016;10:137.

  27. 27.

    Esmaeilzadeh-Gharehdaghi E, Razmara E, Bitaraf A, Mahmoudi M, Garshasbi M. S3440P substitution in C-terminal region of human reelin dramatically impairs secretion of reelin from HEK 293T cells. Cell Mol Biol. 2019;65:12–6.

  28. 28.

    Hong SE, Shugart YY, Huang DT, Al Shahwan S, Grant PE, Hourihane JOB, et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet. 2000;26:93.

  29. 29.

    Nishibe M, Katsuyama Y, Yamashita T. Developmental abnormality contributes to cortex-dependent motor impairments and higher intracortical current requirement in the reeler homozygous mutants. Brain Struct Funct. 2018;1–13.

  30. 30.

    Seripa D, Matera MG, Franceschi M, Daniele A, Bizzarro A, Rinaldi M, et al. The RELN locus in Alzheimer’s disease. J Alzheimers Dis. 2008;14:335–44.

  31. 31.

    Lammert DB, Howell BW. RELN mutations in autism spectrum disorder. Front Cell Neurosci. 2016;10:84.

  32. 32.

    Guidotti A, Grayson DR, Caruncho HJ. Epigenetic RELN dysfunction in schizophrenia and related neuropsychiatric disorders. Front Cell Neurosci. 2016;10:89.

  33. 33.

    Capriotti E, Fariselli P, Casadio R. I-Mutant2. 0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res. 2005;33:W306–10.

  34. 34.

    Arnaud L, Ballif BA, Förster E, Cooper JA. Fyn tyrosine kinase is a critical regulator of disabled-1 during brain development. Curr Biol. 2003;13:9–17.

  35. 35.

    Suetsugu S, Tezuka T, Morimura T, Hattori M, Mikoshiba K, Yamamoto T, et al. Regulation of actin cytoskeleton by mDab1 through N-WASP and ubiquitination of mDab1. Biochem J. 2004;384:1–8.

  36. 36.

    Du Y, Yang M, Wei W, Huynh H, Herz J, Saghatelian A, et al. Macrophage VLDL receptor promotes PAFAH secretion in mother’s milk and suppresses systemic inflammation in nursing neonates. Nat Commun. 2012;3:1008.

  37. 37.

    Magnani A, Pattacini L, Boiardi L, Casali B, Salvarani C. Reelin levels are increased in synovial fluid of patients with rheumatoid arthritis. Clin Exp Rheumatol. 2010;28:546–8.

  38. 38.

    You S, Cho C-S, Lee I, Hood L, Hwang D, Kim W-U. A systems approach to rheumatoid arthritis. PLoS One 2012;7:e51508.

  39. 39.

    Inman R, El-Gabalawy H. The immunology of ankylosing spondylitis and rheumatoid arthritis: a tale of similarities and dissimilarities. Clin Exp Rheumatol. 2009;27:S26.

  40. 40.

    Greenjohnson J, Zalcman S, Vriend C, Nance D, Greenberg A. Suppressed T cell and macrophage function in the” reeler”(rl/rl) mutant, a murine strain with elevated cerebellar norepinephrine concentration. Brain Behav Immun. 1995;9:47–60.

  41. 41.

    Smith JA, Barnes MD, Hong D, DeLay ML, Inman RD, Colbert RA. Gene expression analysis of macrophages derived from ankylosing spondylitis patients reveals interferon-gamma dysregulation. Arthritis Rheum. 2008;58:1640–9.

  42. 42.

    Sabzevary-Ghahfarokhi M, Shohan M, Shirzad H, Rahimian G, Bagheri N, Soltani A, et al. The expression analysis of Fra-1 gene and IL-11 protein in Iranian patients with ulcerative colitis. BMC Immunol. 2018;19:17.

  43. 43.

    van den Berg R, Jongbloed EM, de Schepper EIT, Bierma-Zeinstra SMA, Koes BW, Luijsterburg PAJ. The association between pro-inflammatory biomarkers and nonspecific low back pain: a systematic review. Spine J. 2018.

  44. 44.

    Dougados M, Béhier JM, Jolchine I, Calin A, van der Heijde D, Olivieri I, et al. Efficacy of celecoxib, a cyclooxygenase 2–specific inhibitor, in the treatment of ankylosing spondylitis: A six‐week controlled study with comparison against placebo and against a conventional nonsteroidal antiinflammatory drug. Arthritis Rheum. 2001;44:180–5.

  45. 45.

    Carvajal AE, Vázquez-Carretero MD, García-Miranda P, Peral MJ, Calonge ML, Ilundain AA. Reelin expression is up-regulated in mice colon in response to acute colitis and provides resistance against colitis. Biochim Biophys Acta. 2017;1863:462–73.

  46. 46.

    Ding Y, Huang L, Xian X, Yuhanna IS, Wasser CR, Frotscher M, et al. Loss of Reelin protects against atherosclerosis by reducing leukocyte–endothelial cell adhesion and lesion macrophage accumulation. Sci Signal. 2016;9:ra29.

  47. 47.

    Lories RJ, Luyten FP, De Vlam K. Progress in spondylarthritis. Mechanisms of new bone formation in spondyloarthritis. Arthritis Res Ther. 2009;11:221.

  48. 48.

    Lee GH, D’Arcangelo G. New insights into reelin-mediated signaling pathways. Front Cell Neurosci. 2016;10:122.

  49. 49.

    D’Arcangelo G, Homayouni R, Keshvara L, Rice DS, Sheldon M, Curran T. Reelin is a ligand for lipoprotein receptors. Neuron. 1999;24:471–9.

  50. 50.

    Bock HH, Jossin Y, Liu P, Förster E, May P, Goffinet AM, et al. Phosphatidylinositol 3-kinase interacts with the adaptor protein Dab1 in response to Reelin signaling and is required for normal cortical lamination. J Biol Chem. 2003;278:38772–9.

  51. 51.

    Day TF, Guo X, Garrett-Beal L, Yang Y. Wnt/β-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell. 2005;8:739–50.

  52. 52.

    Zhang J, Zhang X, Zhang L, Zhou F, van Dinther M, ten Dijke P. LRP8 mediates Wnt/β‐catenin signaling and controls osteoblast differentiation. J Bone Min Res. 2012;27:2065–74.

Download references

Acknowledgements

We thank the family for their valuable contributions. We are also grateful for Corinna Jensen, Helmholtz-Zentrum Geesthacht, University of Hamburg, and Christian Sperling for their excellent technical help and Robert Weissmann and Dr Farveh Ehya for their supports in bioinformatics analysis.

Author information

Affiliations

Authors

Contributions

Conceived and designed the experiments: MM, ARJ, and MG. Conducted the experiments: MG, EEGH, ER, EF, ARB, SA, SHP, SMA, and LRJ. Analyzed and interpreted the data: MG, LRJ, EEGH, and ER. Contributed reagents/materials/analysis tools: MM, MG, MV, AWK. Wrote the paper: MG, ARB, EEGH, and ER. All authors read and approved the final paper.

Corresponding authors

Correspondence to Mahdi Mahmoudi or Ahmadreza Jamshidi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Garshasbi, M., Mahmoudi, M., Razmara, E. et al. Identification of RELN variant p.(Ser2486Gly) in an Iranian family with ankylosing spondylitis; the first association of RELN and AS. Eur J Hum Genet (2020). https://doi.org/10.1038/s41431-020-0573-4

Download citation