DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract

Article metrics

Abstract

Purpose

Haploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this paper is to investigate congenital anomalies of the kidney and urinary tract (CAKUT) and genital defects (GD) in patients with DYRK1A variants.

Methods

A large database of clinical exome sequencing (ES) was queried for de novo DYRK1A variants and CAKUT/GD phenotypes were characterized. Xenopus laevis (frog) was chosen as a model organism to assess Dyrk1a’s role in renal development.

Results

Phenotypic details and variants of 19 patients were compiled after an initial observation that one patient with a de novo pathogenic variant in DYRK1A had GD. CAKUT/GD data were available from 15 patients, 11 of whom presented with CAKUT/GD. Studies in Xenopus embryos demonstrated that knockdown of Dyrk1a, which is expressed in forming nephrons, disrupts the development of segments of embryonic nephrons, which ultimately give rise to the entire genitourinary (GU) tract. These defects could be rescued by coinjecting wild-type human DYRK1A RNA, but not with DYRK1AR205* or DYRK1AL245R RNA.

Conclusion

Evidence supports routine GU screening of all individuals with de novo DYRK1A pathogenic variants to ensure optimized clinical management. Collectively, the reported clinical data and loss-of-function studies in Xenopus substantiate a novel role for DYRK1A in GU development.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Aranda S, Laguna A, de la Luna S. DYRK family of protein kinases: evolutionary relationships, biochemical properties, and functional roles. FASEB J. 2011;25:449–462.

  2. 2.

    Lochhead PA, Sibbet G, Morrice N, Cleghon V. Activation-loop autophosphorylation is mediated by a novel transitional intermediate form of DYRKs. Cell. 2005;121:925–936.

  3. 3.

    Møller RS, Kübart S, Hoeltzenbein M, et al. Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly. Am J Hum Genet. 2008;82:1165–1170.

  4. 4.

    Courcet JB, Faivre L, Malzac P, et al. The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy. J Med Genet. 2012;49:731–736.

  5. 5.

    Van Bon BWM, Coe BP, Bernier R, et al. Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID. Mol Psychiatry. 2016;21:126–132.

  6. 6.

    Fitzgerald TW, Gerety SS, Jones WD, et al. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519:223–228.

  7. 7.

    Bainbridge MN, Wang M, Wu Y, et al. Targeted enrichment beyond the consensus coding DNA sequence exome reveals exons with higher variant densities. Genome Biol. 2011;12:R68.

  8. 8.

    Lupski JR, Gonzaga-Jauregui C, Yang Y. et al. Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy. Genome Med. 2013;5:57.

  9. 9.

    Bekheirnia MR, Bekheirnia N, Bainbridge MN, et al. Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene. Genet Med. 2017;19:412–420.

  10. 10.

    Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–424.

  11. 11.

    Morin RD, Chang E, Petrescu A, et al. Sequencing and analysis of 10,967 full-length cDNA clones from Xenopus laevis and Xenopus tropicalis reveals post-tetraploidization transcriptome remodeling. Genome Res. 2006;16:796–803.

  12. 12.

    Nieuwkoop PD, Faber J Normal Table of Xenopus Laevis (Daudin): A Systematical & Chronological Survey of the Development from the Fertilized Egg till the End of Metamorphosis; pp. 130–133;I-V. 1994. https://doi.org/10.1086/402265. Accessed 28 June 2019.

  13. 13.

    Sive HL, Grainger RM, Harland RM Early Development of Xenopus Laevis: A Laboratory Manual; 2000. 2012:129–32. pp. 160–260, https://doi.org/10.1101/pdb.prot067462. Accessed 28 June 2019.

  14. 14.

    DeLay BD, Krneta-Stankic V, Miller RK. Technique to target microinjection to the developing Xenopus kidney. J Vis Exp. 2016;111:e53799.

  15. 15.

    Moody SA, Kline MJ. Segregation of fate during cleavage of frog (Xenopus laevis) blastomeres. Anat Embryol (Berl). 1990;182:347–362.

  16. 16.

    Hong JY, Park J-I, Lee M, et al. Down’s-syndrome-related kinase Dyrk1A modulates the p120-catenin–Kaiso trajectory of the Wnt signaling pathway. J Cell Sci. 2012;125 Pt 3:561–569.

  17. 17.

    Davidson LA, Marsden M, Keller R, DeSimone DW. Integrin α5β1and fibronectin regulate polarized cell protrusions required for Xenopus convergence and extension. Curr Biol. 2006;16:833–844.

  18. 18.

    DeLay BD, Baldwin TA, Miller RK. Dynamin binding protein is required for Xenopus laevis kidney development. Front Physiol. 2019;10:143.

  19. 19.

    Vize PD, Jones EA, Pfister R. Development of the Xenopus pronephric system. Dev Biol. 1995;171:531–540.

  20. 20.

    Ji J, Lee H, Argiropoulos B, et al. DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies. Eur J Hum Genet. 2015;23:1473–1481.

  21. 21.

    Lek M, Karczewski KJ, Minikel EV, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–291.

  22. 22.

    Evers JMG, Laskowski RA, Bertolli M, et al. Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders. Hum Mol Genet. 2017;26:519–526.

  23. 23.

    Widowati EW, Ernst S, Hausmann R, Müller-Newen G, Becker W. Functional characterization of DYRK1A missense variants associated with a syndromic form of intellectual deficiency and autism. Biol Open. 2018;7:bio032862.

  24. 24.

    Arranz J, Balducci E, Arató K, et al. Impaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome. Neurobiol Dis. 2019;127:210–222.

  25. 25.

    Vize PD, Carroll TJ, Wallingford JB. Induction, development, and physiology of the pronephric tubules. In: Vize PD, Woolf AS, Bard JBL, (eds.) The kidney: from normal development to congenital disease. San Diego, CA: Academic Press; 2003. p. 19–50.

  26. 26.

    Zhou X, Vize PD. Proximo-distal specialization of epithelial transport processes within the Xenopus pronephric kidney tubules. Dev Biol. 2004;271:322–338.

  27. 27.

    Raciti D, Reggiani L, Geffers L, et al. Organization of the pronephric kidney revealed by large-scale gene expression mapping. Genome Biol. 2008;9:R84.

  28. 28.

    Blackburn ATM, Miller RK. Modeling congenital kidney diseases in Xenopus laevis. Dis Model Mech. 2019;12:dmm038604.

  29. 29.

    Romagnani P, Lasagni L, Remuzzi G. Renal progenitors: an evolutionary conserved strategy for kidney regeneration. Nat Rev Nephrol. 2013;9:137–146.

  30. 30.

    Kobayashi A. Distinct and sequential tissue-specific activities of the LIM-class homeobox gene Lim1 for tubular morphogenesis during kidney development. Development. 2005;132:2809–2823.

  31. 31.

    Gruenwald P. The relation of the growing müllerian duct to the wolffian duct and its importance for the genesis of malformations. Anat Rec. 1941;81:1–19.

  32. 32.

    Jansson E, Mattsson A, Goldstone J, Berg C. Sex-dependent expression of anti-Müllerian hormone (amh) and amh receptor 2 during sex organ differentiation and characterization of the Müllerian duct development in Xenopus tropicalis. Gen Comp Endocrinol. 2016;229:132–144.

  33. 33.

    Piprek RP, Pecio A, Kloc M, Kubiak JZ, Szymura JM. Evolutionary trend for metamery reduction and gonad shortening in anurans revealed by comparison of gonad development. Int J Dev Biol. 2014;58:929–934.

  34. 34.

    Nestor JG, Groopman EE, Gharavi AG. Towards precision nephrology: the opportunities and challenges of genomic medicine. J Nephrol. 2018;31:47–60.

  35. 35.

    van der Ven AT, Connaughton DM, Ityel H, et al. Whole-exome sequencing identifies causative mutations in families with congenital anomalies of the kidney and urinary tract. J Am Soc Nephrol. 2018;29:2348–2361.

  36. 36.

    Woolf AS. A molecular and genetic view of human renal and urinary tract malformations. Kidney Int. 2000;58:500–512.

  37. 37.

    Gbadegesin Ra, Brophy PD, Adeyemo A, et al. TNXB mutations can cause vesicoureteral reflux. J Am Soc Nephrol. 2013;24:1313–1322.

  38. 38.

    Chatterjee R, Ramos E, Hoffman M, et al. Traditional and targeted exome sequencing reveals common, rare and novel functional deleterious variants in RET-signaling complex in a cohort of living US patients with urinary tract malformations. Hum Genet. 2012;131:1725–1738.

  39. 39.

    Sanna-Cherchi S, Sampogna RV, Papeta N, et al. Mutations in DSTYK and dominant urinary tract malformations. N Engl J Med. 2013;369:621–629.

Download references

Acknowledgements

We express our sincere gratitude to the patients and their families for their participation in this study. The human studies were supported in part by K12 DK0083014 Multidisciplinary K12 Urologic Research Career Development Program, R01DK078121 from the National Institute of Diabetes and Digestive and Kidney Diseases awarded to D.J.L., startup funding from the Department of Pediatrics (Renal Section to M.R.B.), and the Wood Family Foundation. We appreciate all the efforts by BG diagnostic laboratory faculty and staff. Xenopus studies were supported by National Institute of Diabetes and Digestive and Kidney Diseases grants (K01DK092320, R03DK118771 and R01 DK115655 to R.K.M.) and startup funding from the Department of Pediatrics, Pediatric Research Center at the McGovern Medical School (to R.K.M.). Xenopus gene expression studies were also generously supported by Matthew W. State (University of California–San Francisco [UCSF]) and Richard M. Harland (UC Berkeley) and through National Institute of Mental Health grants (U01 MH115747-01A1 to M.W.S. and 1R21MH112158-01 to R.M.H.). We thank the instructors and teaching assistants of the 2017 Cold Spring Harbor Laboratory Xenopus course, in particular K.J. Liu and M.K. Khokha. We are grateful to the members of the laboratories of R.K. Miller and P.D. McCrea, as well as to M. Kloc, for their helpful suggestions and advice throughout this project. In particular, we thank H. Ji and P.D. McCrea for valuable constructs. J.C. Whitney and T.H. Gomez who took care of the animals, even during Hurricane Harvey. We are grateful to the UTHealth Office of the Executive Vice President and Chief Academic Officer and the Department of Pediatrics Microscopy Core for funding the Zeiss LSM800 confocal microscope used in this work. Research reported in this publication was partially supported by the National Institute of Neurological Disorders and Stroke (NINDS) under award number K08NS092898 and Jordan’s Guardian Angels (to G.M.M.).

Author information

Correspondence to Rachel K. Miller PhD or Mir Reza Bekheirnia MD.

Ethics declarations

Disclosure

The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from clinical exome sequencing offered by the Baylor Genetics Laboratories. Authors who are faculty members in the Department of Molecular and Human Genetics at Baylor College of Medicine are identified as such in the affiliation section. M.N.B. is the founder of Codified Genomics LLC, a genomic interpretation company. The other authors declare no conflicts of interest.

Additional information

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

Supplementary information

Supplementary Figure 1

Supplementary Figure 2

Supplementary Figure 3

Supplementary Figure 4

Supp Tables1 2 and 3

supplemental figure legends

supplemental methods

author contributions

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Keywords

  • CAKUT
  • kidney
  • exome sequencing
  • DYRK1A
  • Xenopus