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X-chromosome inactivation patterns in females with Fabry disease examined by both ultra-deep RNA sequencing and methylation-dependent assay

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Abstract

Background

Fabry disease is an X-linked inherited lysosomal storage disorder caused by mutations in the gene encoding α-galactosidase A. Males are usually severely affected, while females have a wide range of disease severity. This variability has been assumed to be derived from organ-dependent skewed X-chromosome inactivation (XCI) patterns in each female patient. Previous studies examined this correlation using the classical methylation-dependent method; however, conflicting results were obtained. This study was established to ascertain the existence of skewed XCI in nine females with heterozygous pathogenic variants in the GLA gene and its relationship to the phenotypes.

Methods

We present five female patients from one family and four individual female patients with Fabry disease. In all cases, heterozygous pathogenic variants in the GLA gene were detected. The X-chromosome inactivation patterns in peripheral blood leukocytes and cells of urine sediment were determined by both classical methylation-dependent HUMARA assay and ultra-deep RNA sequencing. Fabry Stabilization Index was used to determine the clinical severity.

Results

Skewed XCI resulting in predominant inactivation of the normal allele was observed only in one individual case with low ⍺-galactosidase A activity. In the remaining cases, no skewing was observed, even in the case with the highest total severity score (99.2%).

Conclusion

We conclude that skewed XCI could not explain the severity of female Fabry disease and is not the main factor in the onset of various clinical symptoms in females with Fabry disease.

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Acknowledgements

This study was supported by Grant-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (subject ID: 19K08726 to Kandai Nozu). The authors thank Edanz (https://en-author-services.edanz.com/ac) for editing the English text of a draft of this manuscript.

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Authors and Affiliations

  1. Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, Hyogo, 650-0017, Japan

    Rini Rossanti, Kandai Nozu, China Nagano, Tomoko Horinouchi, Tomohiko Yamamura, Nana Sakakibara, Shogo Minamikawa, Shinya Ishiko, Yuya Aoto, Eri Okada, Takeshi Ninchoji & Kazumoto Iijima

  2. Division of Dermatology, Kobe University Graduate School of Medicine, Kobe, Japan

    Atsushi Fukunaga

  3. Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan

    Noritoshi Kato & Shoichi Maruyama

  4. Department of Nephrology, Kobe University Graduate School of Medicine, Kobe, Japan

    Keiji Kono, Shinichi Nishi & Hideki Fujii

Authors
  1. Rini Rossanti
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  2. Kandai Nozu
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  3. Atsushi Fukunaga
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  4. China Nagano
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  15. Keiji Kono
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  17. Kazumoto Iijima
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  18. Hideki Fujii
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Corresponding author

Correspondence to Rini Rossanti.

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Conflict of interest

Kandai Nozu has received lecture fees from Sumitomo Dainippon Pharma. Atsushi Fukunaga has received lecture fees from Sumitomo Dainippon Pharma and Sanofi K.K. Kazumoto Iijima has received lecture fees from Sanofi K.K. Hideki Fujii has received lecture fees from Sumitomo Dainippon Pharma, Sanofi K.K., and Amicus Therapeutics.

Ethical approval

All procedures performed in this study were reviewed and approved by the Institutional Review Board of Kobe University Graduate School of Medicine (IRB approval number 019-301) and performed in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent for conducting this study was obtained from all participants.

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Rossanti, R., Nozu, K., Fukunaga, A. et al. X-chromosome inactivation patterns in females with Fabry disease examined by both ultra-deep RNA sequencing and methylation-dependent assay. Clin Exp Nephrol 25, 1224–1230 (2021). https://doi.org/10.1007/s10157-021-02099-4

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  • DOI: https://doi.org/10.1007/s10157-021-02099-4

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