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.

  • Brief Communication
  • Published:

CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy

Journal of Human Genetics volume 69, pages 159–162 (2024)Cite this article

Subjects

Abstract

Missense mutations in the alpha-B crystallin gene (CRYAB) have been reported in desmin-related myopathies with or without cardiomyopathy and have also been reported in families with only a cataract phenotype. Dilated cardiomyopathy (DCM) is a disorder with a highly heterogeneous genetic etiology involving more than 60 causative genes, hindering genetic diagnosis. In this study, we performed whole genome sequencing on 159 unrelated patients with DCM and identified an unusual stop-loss pathogenic variant in NM_001289808.2:c.527A>G of CRYAB in one patient. The mutant alpha-B crystallin protein is predicted to have an extended strand with addition of 19 amino acid residues, p.(Ter176TrpextTer19), which may contribute to aggregation and increased hydrophobicity of alpha-B crystallin. The proband, diagnosed with DCM at age 32, had a history of bilateral congenital cataracts but had no evidence of myopathy or associated symptoms. He also has a 10-year-old child diagnosed with bilateral congenital cataracts with the same CRYAB variant. This study expands the mutational spectrum of CRYAB and deepens our understanding of the complex phenotypes of alpha-B crystallinopathies.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1
Fig. 2

References

  1. Partan ES. CRYSTALLIN, ALPHA-B; CRYAB. https://www.omim.org/entry/123590?search=cryab&highlight=cryab. Updated January 58, 2021.

  2. Del Bigio MR, Chudley AE, Sarnat HB, Campbell C, Goobie S, Chodirker BN, et al. Infantile muscular dystrophy in Canadian aboriginals is an αB-crystallinopathy. Ann Neurol. 2011;69:866–71.

    Article  PubMed  PubMed Central  Google Scholar 

  3. McKenna WJ, Judge DP. Epidemiology of the inherited cardiomyopathies. Nat Rev Cardiol. 2021;18:22–36.

    Article  PubMed  Google Scholar 

  4. Zhong Y, Xu F, Wu J, Schubert J, Li MM. Application of next generation sequencing in laboratory medicine. Ann Lab Med. 2021;41:25–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales-Villa R, Basso C, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023. https://doi.org/10.1093/eurheartj/ehad194.

  6. Charron P, Arad M, Arbustini E, Basso C, Bilinska Z, Elliott P, et al. Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2010;31:2715–26.

    Article  PubMed  Google Scholar 

  7. Berezin AE, Berezin AA. Biomarkers in heart failure: from research to clinical practice. Ann Lab Med. 2023;43:225–36.

    Article  CAS  PubMed  Google Scholar 

  8. Pugh TJ, Kelly MA, Gowrisankar S, Hynes E, Seidman MA, Baxter SM, et al. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. Genet Med. 2014;16:601–8.

    Article  CAS  PubMed  Google Scholar 

  9. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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;17:405–24.

    Article  PubMed  PubMed Central  Google Scholar 

  10. van der Smagt JJ, Vink A, Kirkels JH, Nelen M, ter Heide H, Molenschot MM, et al. Congenital posterior pole cataract and adult onset dilating cardiomyopathy: expanding the phenotype of αB-crystallinopathies. Clin Genet. 2014;85:381–5.

    Article  PubMed  Google Scholar 

  11. Yu Y, Xu J, Qiao Y, Li J, Yao K. A new heterozygous mutation in the stop codon of CRYAB (p.X176Y) is liable for congenital posterior pole cataract in a Chinese family. Ophthalmic Genet. 2021;42:139–43.

    Article  CAS  PubMed  Google Scholar 

  12. Yamamoto S, Yamashita A, Arakaki N, Nemoto H, Yamazaki T. Prevention of aberrant protein aggregation by anchoring the molecular chaperone αB-crystallin to the endoplasmic reticulum. Biochem Biophys Res Commun. 2014;455:241–5.

    Article  CAS  PubMed  Google Scholar 

  13. Bloemendal H, de Jong W, Jaenicke R, Lubsen NH, Slingsby C, Tardieu A. Ageing and vision: structure, stability and function of lens crystallins. Prog Biophys Mol Biol. 2004;86:407–85.

    Article  CAS  PubMed  Google Scholar 

  14. Berry V, Francis P, Reddy MA, Collyer D, Vithana E, MacKay I, et al. Alpha-B crystallin gene (CRYAB) mutation causes dominant congenital posterior polar cataract in humans. Am J Hum Genet. 2001;69:1141–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Forrest KM, Al-Sarraj S, Sewry C, Buk S, Tan SV, Pitt M, et al. Infantile onset myofibrillar myopathy due to recessive CRYAB mutations. Neuromuscul Disord. 2011;21:37–40.

    Article  PubMed  Google Scholar 

  16. Marcos AT, Amorós D, Muñoz-Cabello B, Galán F, Rivas Infante E, Alcaraz-Mas L, et al. A novel dominant mutation in CRYAB gene leading to a severe phenotype with childhood onset. Mol Genet Genom Med. 2020;8:e1290.

    Article  CAS  Google Scholar 

  17. Selcen D, Engel AG. Myofibrillar myopathy caused by novel dominant negative alpha B-crystallin mutations. Ann Neurol. 2003;54:804–10.

    Article  CAS  PubMed  Google Scholar 

  18. Davies MJ. Protein oxidation and peroxidation. Biochem J. 2016;473:805–25.

    Article  CAS  PubMed  Google Scholar 

  19. Leinisch F, Mariotti M, Rykaer M, Lopez-Alarcon C, Hägglund P, Davies MJ. Peroxyl radical- and photo-oxidation of glucose 6-phosphate dehydrogenase generates cross-links and functional changes via oxidation of tyrosine and tryptophan residues. Free Radic Biol Med. 2017;112:240–52.

    Article  CAS  PubMed  Google Scholar 

  20. Kim N, Kong SY, Yoo J, Kim DH, Seo SH, Kim J. Current issues, challenges, and future perspectives of genetic counseling in Korea. Ann Lab Med. 2022;42:314–20.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was performed as part of the National Project of Bio Big Data. We thank the patient and his family for participating to this study.

Author information

Authors and Affiliations

  1. Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea

    Changhee Ha, Young-gon Kim, Ja-Hyun Jang, Jong-Won Kim & Mi-Ae Jang

  2. Division of Cardiology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea

    Darae Kim, Minjung Bak & Jin-Oh Choi

  3. Clinical Genome Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea

    Jong-Ho Park & Jong-Won Kim

Authors
  1. Changhee Ha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Darae Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Minjung Bak
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jong-Ho Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Young-gon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ja-Hyun Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jong-Won Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jin-Oh Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mi-Ae Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jin-Oh Choi or Mi-Ae Jang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the Institutional Review Board of Samsung Medical Center (IRB No.: SMC 2020-10-042).

Additional information

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ha, C., Kim, D., Bak, M. et al. CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy. J Hum Genet 69, 159–162 (2024). https://doi.org/10.1038/s10038-023-01218-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s10038-023-01218-1

Search

Advanced search

Quick links