Hydrops fetalis due to loss of function of hNav1.4 channel via compound heterozygous variants

Kubota, Tomoya; Nagata, Miho; Takagi, Kazuko; Ishihara, Yasuki; Kojima, Kurumi; Uchikura, Yuka; Yamamoto, Reina; Yonei, Ayumi; Ozaki, Erina; Kira, Natsuki; Takahashi, Satoe; Homma, Kazuaki; Miyashita, Yohei; Eguchi-Ishimae, Minenori; Sakai, Norio; Asano, Yoshihiro; Sakata, Yasushi; Ozono, Keiichi; Eguchi, Mariko; Takahashi, Masanori P.

doi:https://doi.org/10.1038/s10038-024-01284-z

Hydrops fetalis due to loss of function of hNav1.4 channel via compound heterozygous variants

Kubota, Tomoya; Nagata, Miho; Takagi, Kazuko et al.

Journal of Human Genetics, 2024

Number of Access:102（2025-04-30 13:09 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/98112

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Title	Hydrops fetalis due to loss of function of hNav1.4 channel via compound heterozygous variants
Creator	NRID 1000020573231 1000020573231 ORCID 0000-0003-1004-8537 0000-0003-1004-8537 researchmap permalink n-phys n-phys Scopus Author ID 26633163700 26633163700 CreatorName Kubota, Tomoya
	CreatorName Nagata, Miho
	NRID 1000080648626 1000080648626 CreatorName Takagi, Kazuko
	NRID 1000000886525 1000000886525 ORCID 0000-0002-0307-238X 0000-0002-0307-238X researchmap permalink yskishr yskishr CreatorName Ishihara, Yasuki
	CreatorName Kojima, Kurumi
	NRID 1000050648623 1000050648623 CreatorName Uchikura, Yuka
	CreatorName Yamamoto, Reina
	CreatorName Yonei, Ayumi
	CreatorName Ozaki, Erina
	CreatorName Kira, Natsuki
	CreatorName Takahashi, Satoe
	CreatorName Homma, Kazuaki
	NRID 1000060816312 1000060816312 ORCID 0000-0002-1739-4734 0000-0002-1739-4734 researchmap permalink y-miyashita y-miyashita Scopus Author ID 57208672131 57208672131 CreatorName Miyashita, Yohei
	NRID 1000050420782 1000050420782 CreatorName Eguchi-Ishimae, Minenori
	NRID 1000030314313 1000030314313 researchmap permalink norio_sakai1121 norio_sakai1121 CreatorName Sakai, Norio
	NRID 1000060527670 1000060527670 researchmap permalink osaka-med-yasano osaka-med-yasano Scopus Author ID 7401729290 7401729290 CreatorName Asano, Yoshihiro
	NRID 1000000397671 1000000397671 ORCID 0000-0002-5618-4721 0000-0002-5618-4721 researchmap permalink C4589 C4589 Scopus Author ID 35395964700 35395964700 CreatorName Sakata, Yasushi
	NRID 1000020270770 1000020270770 researchmap permalink read0092357 read0092357 Scopus Author ID 55545335700 55545335700 CreatorName Ozono, Keiichi
	NRID 1000040420781 1000040420781 CreatorName Eguchi, Mariko
	NRID 1000020359847 1000020359847 researchmap permalink mtakahas mtakahas Scopus Author ID 15038719500 15038719500 CreatorName Takahashi, Masanori P.
Description	Kubota T., Nagata M., Takagi K., et al. Hydrops fetalis due to loss of function of hNav1.4 channel via compound heterozygous variants. Journal of Human Genetics, (2024); https://doi.org/10.1038/s10038-024-01284-z.
Abstract	Hydrops fetalis, characterized by abnormal fluid accumulation in fetuses, presents a significant risk of stillbirth and neonatal mortality. Although the etiology of nonimmune hydrops fetalis (NIHF) is multifaceted, recent studies have highlighted genetic factors as crucial determinants. This study focused on a family with three consecutive stillbirths, each with pronounced hydrops fetalis. Using whole-exome sequencing (WES), we identified compound heterozygous variants of the SCN4A gene encoding the voltage-gated sodium channel of the skeletal muscle (hNav1.4), c.2429T>A p.L810Q and c.4556T>C p.F1519S, in all three deceased infants. A functional analysis conducted using the whole-cell patch-clamp technique revealed loss-of-function defects in both variant channels, with F1519S exhibiting a complete loss of ionic current and L810Q showing a reduced channel opening. These findings support the pathogenicity of SCN4A variants in NIHF and underscore the significance of functional studies in elucidating genotype-phenotype correlations. Furthermore, our study emphasizes the diagnostic value of WES in cases of NIHF in where standard genetic testing fails to identify causative variants.
Publisher	Springer Nature
Source Title	Journal of Human Genetics
Date of Issued	2024-08-21
Language	English
Handle URL	https://hdl.handle.net/11094/98112
PISSN	14345161
eISSN	1435232X
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1038/s10038-024-01284-z
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCTERMS.bibliographicCitation	Journal of Human Genetics. 2024
DC.title	Hydrops fetalis due to loss of function of hNav1.4 channel via compound heterozygous variants
DC.creator	Kubota, Tomoya
	Nagata, Miho
	Takagi, Kazuko
	Ishihara, Yasuki
	Kojima, Kurumi
	Uchikura, Yuka
	Yamamoto, Reina
	Yonei, Ayumi
	Ozaki, Erina
	Kira, Natsuki
	Takahashi, Satoe
	Homma, Kazuaki
	Miyashita, Yohei
	Eguchi-Ishimae, Minenori
	Sakai, Norio
	Asano, Yoshihiro
	Sakata, Yasushi
	Ozono, Keiichi
	Eguchi, Mariko
	Takahashi, Masanori P.
DC.publisher	Springer Nature
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-08-21
DC.identifier	https://doi.org/10.1038/s10038-024-01284-z
DC.description	Kubota T., Nagata M., Takagi K., et al. Hydrops fetalis due to loss of function of hNav1.4 channel via compound heterozygous variants. Journal of Human Genetics, (2024); https://doi.org/10.1038/s10038-024-01284-z.
DCTERMS.abstract	Hydrops fetalis, characterized by abnormal fluid accumulation in fetuses, presents a significant risk of stillbirth and neonatal mortality. Although the etiology of nonimmune hydrops fetalis (NIHF) is multifaceted, recent studies have highlighted genetic factors as crucial determinants. This study focused on a family with three consecutive stillbirths, each with pronounced hydrops fetalis. Using whole-exome sequencing (WES), we identified compound heterozygous variants of the SCN4A gene encoding the voltage-gated sodium channel of the skeletal muscle (hNav1.4), c.2429T>A p.L810Q and c.4556T>C p.F1519S, in all three deceased infants. A functional analysis conducted using the whole-cell patch-clamp technique revealed loss-of-function defects in both variant channels, with F1519S exhibiting a complete loss of ionic current and L810Q showing a reduced channel opening. These findings support the pathogenicity of SCN4A variants in NIHF and underscore the significance of functional studies in elucidating genotype-phenotype correlations. Furthermore, our study emphasizes the diagnostic value of WES in cases of NIHF in where standard genetic testing fails to identify causative variants.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	98112
citation_title	Hydrops fetalis due to loss of function of hNav1.4 channel via compound heterozygous variants
citation_author	Kubota, Tomoya
	Nagata, Miho
	Takagi, Kazuko
	Ishihara, Yasuki
	Kojima, Kurumi
	Uchikura, Yuka
	Yamamoto, Reina
	Yonei, Ayumi
	Ozaki, Erina
	Kira, Natsuki
	Takahashi, Satoe
	Homma, Kazuaki
	Miyashita, Yohei
	Eguchi-Ishimae, Minenori
	Sakai, Norio
	Asano, Yoshihiro
	Sakata, Yasushi
	Ozono, Keiichi
	Eguchi, Mariko
	Takahashi, Masanori P.
citation_publisher	Springer Nature
citation_language	English
citation_date	2024-08-21
citation_journal_title	Journal of Human Genetics
citation_doi	https://doi.org/10.1038/s10038-024-01284-z
citation_public_url	https://hdl.handle.net/11094/98112

Hydrops fetalis due to loss of function of hNav1.4 channel via compound heterozygous variants

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