Female X-linked Alport syndrome with somatic mosaicism

Kana Yokota, Kandai Nozu, Shogo Minamikawa, Tomohiko Yamamura, Keita Nakanishi, Hisashi Kaneda, Riku Hamada, Yoshimi Nozu, Akemi Shono, Takeshi Ninchoji, Naoya Morisada, Shingo Ishimori, Junya Fujimura, Tomoko Horinouchi, Hiroshi Kaito, Koichi Nakanishi, Ichiro Morioka, Mariko Taniguchi-Ikeda, Kazumoto Iijima

Research output: Contribution to journalArticle

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Abstract

Background: X-linked Alport syndrome (XLAS) is a progressive, hereditary nephropathy. Although males with XLAS usually develop end-stage renal disease before 30 years of age, some men show a milder phenotype and possess somatic mosaic variants of the type IV collagen α5 gene (COL4A5), with severity depending on variant frequencies. In females, somatic mosaic variants are rarely reported in XLAS, and it is not clear what determines severity. Methods: Two females with somatic mosaic mutations in COL4A5 with variant frequencies of 17.9 and 22.1% were detected using the next-generation sequencing. One patient only had hematuria. The other, however, had moderate proteinuria, which is a severe phenotype for a female XLAS patient of her age. The molecular mechanisms for the severe phenotype were investigated by examining variant frequencies in urinary sediment cells and X chromosome inactivation patterns, and by looking for modifier variants in podocyte-related genes using the next-generation sequencing. Results: The severe phenotype patient had a variant frequency of 36.6% in urinary sediment cells, which is not markedly high, nor did she show skewed X chromosome inactivation. However, she did have the heterozygous variant in COL4A3, which can affect severity. Conclusion: Factors determining severity in female XLAS patients remain unclear. One studied patient with the somatic variant in COL4A5 showed a severe phenotype without skewed X chromosome inactivation, which might be derived from digenic variants in COL4A3 and COL4A5. Further studies are required to determine molecular mechanisms behind female XLAS resulting in the severe phenotype.

Original languageEnglish
Pages (from-to)877-883
Number of pages7
JournalClinical and Experimental Nephrology
Volume21
Issue number5
DOIs
Publication statusPublished - 01-10-2017

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Hereditary Nephritis
Mosaicism
Phenotype
X Chromosome Inactivation
Collagen Type V
Podocytes
Hematuria
Proteinuria
Genes
Chronic Kidney Failure
Mutation

All Science Journal Classification (ASJC) codes

  • Physiology
  • Nephrology
  • Physiology (medical)

Cite this

Yokota, K., Nozu, K., Minamikawa, S., Yamamura, T., Nakanishi, K., Kaneda, H., ... Iijima, K. (2017). Female X-linked Alport syndrome with somatic mosaicism. Clinical and Experimental Nephrology, 21(5), 877-883. https://doi.org/10.1007/s10157-016-1352-y
Yokota, Kana ; Nozu, Kandai ; Minamikawa, Shogo ; Yamamura, Tomohiko ; Nakanishi, Keita ; Kaneda, Hisashi ; Hamada, Riku ; Nozu, Yoshimi ; Shono, Akemi ; Ninchoji, Takeshi ; Morisada, Naoya ; Ishimori, Shingo ; Fujimura, Junya ; Horinouchi, Tomoko ; Kaito, Hiroshi ; Nakanishi, Koichi ; Morioka, Ichiro ; Taniguchi-Ikeda, Mariko ; Iijima, Kazumoto. / Female X-linked Alport syndrome with somatic mosaicism. In: Clinical and Experimental Nephrology. 2017 ; Vol. 21, No. 5. pp. 877-883.
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abstract = "Background: X-linked Alport syndrome (XLAS) is a progressive, hereditary nephropathy. Although males with XLAS usually develop end-stage renal disease before 30 years of age, some men show a milder phenotype and possess somatic mosaic variants of the type IV collagen α5 gene (COL4A5), with severity depending on variant frequencies. In females, somatic mosaic variants are rarely reported in XLAS, and it is not clear what determines severity. Methods: Two females with somatic mosaic mutations in COL4A5 with variant frequencies of 17.9 and 22.1{\%} were detected using the next-generation sequencing. One patient only had hematuria. The other, however, had moderate proteinuria, which is a severe phenotype for a female XLAS patient of her age. The molecular mechanisms for the severe phenotype were investigated by examining variant frequencies in urinary sediment cells and X chromosome inactivation patterns, and by looking for modifier variants in podocyte-related genes using the next-generation sequencing. Results: The severe phenotype patient had a variant frequency of 36.6{\%} in urinary sediment cells, which is not markedly high, nor did she show skewed X chromosome inactivation. However, she did have the heterozygous variant in COL4A3, which can affect severity. Conclusion: Factors determining severity in female XLAS patients remain unclear. One studied patient with the somatic variant in COL4A5 showed a severe phenotype without skewed X chromosome inactivation, which might be derived from digenic variants in COL4A3 and COL4A5. Further studies are required to determine molecular mechanisms behind female XLAS resulting in the severe phenotype.",
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Yokota, K, Nozu, K, Minamikawa, S, Yamamura, T, Nakanishi, K, Kaneda, H, Hamada, R, Nozu, Y, Shono, A, Ninchoji, T, Morisada, N, Ishimori, S, Fujimura, J, Horinouchi, T, Kaito, H, Nakanishi, K, Morioka, I, Taniguchi-Ikeda, M & Iijima, K 2017, 'Female X-linked Alport syndrome with somatic mosaicism', Clinical and Experimental Nephrology, vol. 21, no. 5, pp. 877-883. https://doi.org/10.1007/s10157-016-1352-y

Female X-linked Alport syndrome with somatic mosaicism. / Yokota, Kana; Nozu, Kandai; Minamikawa, Shogo; Yamamura, Tomohiko; Nakanishi, Keita; Kaneda, Hisashi; Hamada, Riku; Nozu, Yoshimi; Shono, Akemi; Ninchoji, Takeshi; Morisada, Naoya; Ishimori, Shingo; Fujimura, Junya; Horinouchi, Tomoko; Kaito, Hiroshi; Nakanishi, Koichi; Morioka, Ichiro; Taniguchi-Ikeda, Mariko; Iijima, Kazumoto.

In: Clinical and Experimental Nephrology, Vol. 21, No. 5, 01.10.2017, p. 877-883.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Female X-linked Alport syndrome with somatic mosaicism

AU - Yokota, Kana

AU - Nozu, Kandai

AU - Minamikawa, Shogo

AU - Yamamura, Tomohiko

AU - Nakanishi, Keita

AU - Kaneda, Hisashi

AU - Hamada, Riku

AU - Nozu, Yoshimi

AU - Shono, Akemi

AU - Ninchoji, Takeshi

AU - Morisada, Naoya

AU - Ishimori, Shingo

AU - Fujimura, Junya

AU - Horinouchi, Tomoko

AU - Kaito, Hiroshi

AU - Nakanishi, Koichi

AU - Morioka, Ichiro

AU - Taniguchi-Ikeda, Mariko

AU - Iijima, Kazumoto

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Background: X-linked Alport syndrome (XLAS) is a progressive, hereditary nephropathy. Although males with XLAS usually develop end-stage renal disease before 30 years of age, some men show a milder phenotype and possess somatic mosaic variants of the type IV collagen α5 gene (COL4A5), with severity depending on variant frequencies. In females, somatic mosaic variants are rarely reported in XLAS, and it is not clear what determines severity. Methods: Two females with somatic mosaic mutations in COL4A5 with variant frequencies of 17.9 and 22.1% were detected using the next-generation sequencing. One patient only had hematuria. The other, however, had moderate proteinuria, which is a severe phenotype for a female XLAS patient of her age. The molecular mechanisms for the severe phenotype were investigated by examining variant frequencies in urinary sediment cells and X chromosome inactivation patterns, and by looking for modifier variants in podocyte-related genes using the next-generation sequencing. Results: The severe phenotype patient had a variant frequency of 36.6% in urinary sediment cells, which is not markedly high, nor did she show skewed X chromosome inactivation. However, she did have the heterozygous variant in COL4A3, which can affect severity. Conclusion: Factors determining severity in female XLAS patients remain unclear. One studied patient with the somatic variant in COL4A5 showed a severe phenotype without skewed X chromosome inactivation, which might be derived from digenic variants in COL4A3 and COL4A5. Further studies are required to determine molecular mechanisms behind female XLAS resulting in the severe phenotype.

AB - Background: X-linked Alport syndrome (XLAS) is a progressive, hereditary nephropathy. Although males with XLAS usually develop end-stage renal disease before 30 years of age, some men show a milder phenotype and possess somatic mosaic variants of the type IV collagen α5 gene (COL4A5), with severity depending on variant frequencies. In females, somatic mosaic variants are rarely reported in XLAS, and it is not clear what determines severity. Methods: Two females with somatic mosaic mutations in COL4A5 with variant frequencies of 17.9 and 22.1% were detected using the next-generation sequencing. One patient only had hematuria. The other, however, had moderate proteinuria, which is a severe phenotype for a female XLAS patient of her age. The molecular mechanisms for the severe phenotype were investigated by examining variant frequencies in urinary sediment cells and X chromosome inactivation patterns, and by looking for modifier variants in podocyte-related genes using the next-generation sequencing. Results: The severe phenotype patient had a variant frequency of 36.6% in urinary sediment cells, which is not markedly high, nor did she show skewed X chromosome inactivation. However, she did have the heterozygous variant in COL4A3, which can affect severity. Conclusion: Factors determining severity in female XLAS patients remain unclear. One studied patient with the somatic variant in COL4A5 showed a severe phenotype without skewed X chromosome inactivation, which might be derived from digenic variants in COL4A3 and COL4A5. Further studies are required to determine molecular mechanisms behind female XLAS resulting in the severe phenotype.

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Yokota K, Nozu K, Minamikawa S, Yamamura T, Nakanishi K, Kaneda H et al. Female X-linked Alport syndrome with somatic mosaicism. Clinical and Experimental Nephrology. 2017 Oct 1;21(5):877-883. https://doi.org/10.1007/s10157-016-1352-y