Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Intellectual disability and abnormal cortical neuron phenotypes in patients with Bloom syndrome

Journal of Human Genetics volume 68, pages 321–327 (2023)Cite this article

Subjects

Abstract

Bloom syndrome (BS) is a rare autosomal recessive disorder characterized by genomic instability that leads to various complications, including cancer. Given the low prevalence of BS in Japan, we conducted a nationwide survey. We recruited eight patients with BS, three of whom exhibited intellectual disability. The 631delCAA mutation in the BLM gene was detected in 9 out of 16 alleles. To investigate neuronal development in patients with BS, we generated induced pluripotent stem cells derived from one of these patients (BS-iPSCs). We examined the phenotypes of the induced cortical neurons derived from the generated BS-iPSCs using a previously reported protocol; the generated BS-iPSCs showed an approximately 10-times higher frequency of sister-chromatid exchange (SCE) than the control iPSCs. Immunocytochemistry revealed shorter axons and higher proliferative potential in BS-iPSC-derived cortical neurons compared with control iPSCs. To our knowledge, our study is the first to clarify the abnormality of the cortical neuron phenotypes derived from patients with BS. Our findings may help identify the pathogenesis of neuronal differentiation in BS and aid in the development of novel therapeutic agents.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Ellis NA, Groden J, Ye TZ, Straughen J, Lennon DJ, Ciocci S, et al. The Bloom’s syndrome gene product is homologous to RecQ helicases. Cell. 1995;83:655–66.

    Article  CAS  PubMed  Google Scholar 

  2. Chaganti RS, Schonberg S, German J. A manyfold increase in sister chromatid exchanges in Bloom’s syndrome lymphocytes. Proc Natl Acad Sci USA. 1974;71:4508–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. McDaniel LD, Schultz RA. Elevated sister chromatid exchange phenotype of Bloom syndrome cells is complemented by human chromosome 15. Proc Natl Acad Sci USA. 1992;89:7968–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Raynard S, Bussen W, Sung P. A double Holliday junction dissolvasome comprising BLM, topoisomerase IIIα, and BLAP75. J Biol Chem. 2006;281:13861–4.

    Article  CAS  PubMed  Google Scholar 

  5. Yin J, Sobeck A, Xu C, Meetei AR, Hoatlin M, Li L, et al. BLAP75, an essential component of Bloom’s syndrome protein complexes that maintain genome integrity. EMBO J. 2005;24:1465i1476.

    Article  Google Scholar 

  6. Singh TR, Ali AM, Busygina V, Raynard S, Fan Q, Du CH, et al. BLAP18/RMI2, a novel OB-fold-containing protein, is an essential component of the Bloom helicase-double Holliday junction dissolvasome. Genes Dev. 2008;22:2856–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Martin CA, Sarlós K, Logan CV, Parry DA, Bizard AH, Leitch A, et al. Mutations in TOP3A cause a Bloom syndrome-like disorder. Am J Hum Genet. 2018;103:221–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hudson DF, Amor DJ, Boys A, Butler K, Williams L, Zhang T, et al. Loss of RMI2 increases genome instability and causes a Bloom-like syndrome. PLoS Genet. 2016;12:1–24.

    Article  Google Scholar 

  9. Cunniff C, Bassetti JA, Ellis NA. Bloom’s syndrome: clinical spectrum, molecular pathogenesis, and cancer predisposition. Mol Syndromol. 2017;8:4–23.

    Article  CAS  PubMed  Google Scholar 

  10. Masmoudi A, Marrakchi S, Kamoun H, Chaaben H, Salah GB, Salah RB, et al. Clinical and laboratory findings in 8 patients with Bloom’s syndrome. J Dermatol Case Rep. 2012;6:29–33.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Classen CF, Riehmer V, Landwehr C, Kosfeld A, Heilmann S, Scholz C, et al. Dissecting the genotype in syndromic intellectual disability using whole exome sequencing in addition to genome-wide copy number analysis. Hum Genet. 2013;132:825–41.

    Article  CAS  PubMed  Google Scholar 

  12. Gönenc II, Wolff A, Schmidt J, Zibat A, Müller C, Cyganek L, et al. Single-cell transcription profiles in Bloom syndrome patients link BLM deficiency with altered condensin complex expression signatures. Hum Mol Genet. 2022;31:2185–93.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Luo G, Santoro IM, McDaniel LD, Nishijima I, Mills M, Youssoufian H, et al. Cancer predisposition caused by elevated mitotic recombination in Bloom mice. Nat Genet. 2000;26:424–9.

    Article  CAS  PubMed  Google Scholar 

  14. Tereshchenko IV, Chen Y, McDaniel LD, Schultz RA, Tischfield JA, Shao C. Small scale genetic alterations contribute to increased mutability at the X-linked Hprt locus in vivo in Blm hypomorphic mice. DNA Repair (Amst). 2010;9:551–7.

    Article  CAS  PubMed  Google Scholar 

  15. Gatinois V, Desprat R, Becker F, Pichard L, Bernex F, Isidor B, et al. iPSC line derived from a Bloom syndrome patient retains an increased disease-specific sister-chromatid exchange activity. Stem Cell Res J. 2020;43:101696.

    Article  CAS  Google Scholar 

  16. Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S, et al. A more efficient method to generate integration-free human iPS cells. Nat Methods. 2011;8:409–12.

    Article  CAS  PubMed  Google Scholar 

  17. Ohuchi K, Funato M, Kato Z, Seki J, Kawase C, Tamai Y, et al. Established stem cell model of spinal muscular atrophy is applicable in the evaluation of the efficacy of thyrotropin-releasing hormone analog. Stem Cells Transl Med. 2016;5:152–63.

    Article  CAS  PubMed  Google Scholar 

  18. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.

    Article  CAS  PubMed  Google Scholar 

  19. Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, et al. Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. Cell Stem Cell. 2013;12:487–96.

    Article  CAS  PubMed  Google Scholar 

  20. Schoenaker MHD, Henriet SS, Zonderland J, van Deuren M, Pan-Hammarström Q, Posthumus-van Sluijs SJ, et al. Immunodeficiency in Bloom’s syndrome. J Clin Immunol. 2018;38:35–44.

    Article  CAS  PubMed  Google Scholar 

  21. Kaneko H, Isogai K, Fukao T, Matsui E, Kasahara K, Yachie A, et al. Relatively common mutations of the Bloom syndrome gene in the Japanese population. Int J Mol Med. 2004;14:439–42.

    CAS  PubMed  Google Scholar 

  22. Oka Y, Hamada M, Nakazawa Y, Muramatsu H, Okuno Y, Higasa K, et al. Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome. Sci Adv. 2020;18:6.

    Google Scholar 

  23. Bouman A, van Koningsbruggen S, Karakullukcu MB, Schreuder WH, Lakeman P. Bloom syndrome does not always present with sun-sensitive facial erythema. Eur J Med Genet. 2018 ;61:94–7.

    Article  PubMed  Google Scholar 

  24. Bulfone A, Smiga SM, Shimamura K, Peterson A, Puelles L, Rubenstein JL. T-brain-1: a homolog of Brachyury whose expression defines molecularly distinct domains within the cerebral cortex. Neuron. 1995;15:63–78.

    Article  CAS  PubMed  Google Scholar 

  25. Bulfone A, Wang F, Hevner R, Anderson S, Cutforth T, Chen S, et al. An olfactory sensory map develops in the absence of normal projection neurons or GABAergic interneurons. Neuron. 1998;21:1273–82.

    Article  CAS  PubMed  Google Scholar 

  26. Medina L, Legaz I, Gonzalez G, De Castro F, Rubenstein JL, Puelles L. Expression of Dbx1, Neurogenin 2, Semaphorin 5A, Cadherin 8, and Emx1 distinguish ventral and lateral pallial histogenetic divisions in the developing mouse claustroamygdaloid complex. J Comp Neurol. 2004;474:504–23.

    Article  PubMed  Google Scholar 

  27. Remedios R, Huilgol D, Saha B, Hari P, Bhatnagar L, Kowalczyk T, et al. A stream of cells migrating from the caudal telencephalon reveals a link between the amygdala and neocortex. Nat Neurosci. 2007;10:1141–50.

    Article  CAS  PubMed  Google Scholar 

  28. Hachiya Y, Motonaga K, Itoh M, Masuko T, Enomoto T, Sonobe H, et al. Immunohistochemical expression and pathogenesis of BLM in the human brain and visceral organs. Neuropathology. 2001;21:123–8.

    Article  CAS  PubMed  Google Scholar 

  29. Toba T, Nishimuta T, Funabashi S, Adachi M. Serum protein levels in healthy Japanese children, with special regard to 5 classes of immunoglobulin (author’s transl)]. Rinsho Byori. 1975;23:763–9.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the patients who participated in this study as well as their families. We would also like to thank Dr. K. Osafune (Kyoto University) for providing the human iPSC line 201B7.

Funding

This study was supported in part by the Health and Labor Sciences Research Grants for Research on Measures for Intractable Diseases of the Ministry of Health, Labour and Welfare.

Author information

Authors and Affiliations

  1. Department of Pediatric Medical Care, Gifu Prefectural General Medical Center, Gifu, Japan

    Hideo Kaneko

  2. Department of Clinical Research, National Hospital Organization, Nagara Medical Center, Gifu, Japan

    Hideo Kaneko, Chizuru Kawase, Junko Seki & Michinori Funato

  3. Department of Pediatrics, School of Medicine Institute of Medical Pharmaceutical and Health Science, Kanazawa University, Kanazawa, Japan

    Yasuhiro Ikawa

  4. Division of Medical Safety, Kanazawa University Hospital, Kanazawa, Japan

    Akihiro Yachie

Authors
  1. Hideo Kaneko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chizuru Kawase
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junko Seki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasuhiro Ikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Akihiro Yachie
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michinori Funato
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Research design: MF, CK, YI, AY, and HK. Experiments, data acquisition, and data analysis: CK and HK. Manuscript writing: HK.

Corresponding author

Correspondence to Hideo Kaneko.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

The generation and pathological analysis (including human gene analysis) of patient-derived iPSCs in this study were approved by the Ethical Review Committee of the National Hospital Organization, Nagara Medical Center (approval no. 26-15). Established human stem cells were handled according to revisions of the guidelines for clinical research using human stem cells by the Ministry of Health, Labour and Welfare of Japan. Written informed consent was obtained from the Bloom syndrome patient for the publication of this report. The 201B7 line was provided by Dr. K. Osafune (Kyoto University).

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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kaneko, H., Kawase, C., Seki, J. et al. Intellectual disability and abnormal cortical neuron phenotypes in patients with Bloom syndrome. J Hum Genet 68, 321–327 (2023). https://doi.org/10.1038/s10038-023-01121-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s10038-023-01121-9

Search

Advanced search

Quick links