GJB2 c.35del variant up-regulates GJA1 gene expression and affects differentiation of human stem cells

IF 16.4 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Accounts of Chemical Research Pub Date : 2024-04-15 DOI:10.1590/1678-4685-GMB-2023-0170

A. C. Batissoco, Dayane Bernardino Cruz, Thiago Geronimo Pires Alegria, Gerson Kobayashi, J. Oiticica, Luís Eduardo Soares Netto, M. Passos-Bueno, L. A. Haddad, R. C. Mingroni Netto

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Abstract

Abstract Pathogenic DNA alterations in GJB2 are present in nearly half of non-syndromic hearing loss cases with autosomal recessive inheritance. The most frequent variant in GJB2 causing non-syndromic hearing loss is the frameshifting c.35del. GJB2 encodes Cx26, a protein of the connexin family that assembles hemichannels and gap junctions. The expression of paralogous proteins is believed to compensate for the loss of function of specific connexins. As Cx26 has been involved in cell differentiation in distinct tissues, we employed stem cells derived from human exfoliated deciduous teeth (SHEDs), homozygous for the c.35del variant, to assess GJB2 roles in stem cell differentiation and the relationship between its loss of function and the expression of paralogous genes. Primary SHED cultures from patients and control individuals were compared. SHEDs from patients had significantly less GJB2 mRNA and increased amount of GJA1 (Cx43), but not GJB6 (Cx30) or GJB3 (Cx31) mRNA. In addition, they presented higher induced differentiation to adipocytes and osteocytes but lower chondrocyte differentiation. Our results suggest that GJA1 increased expression may be involved in functional compensation for GJB2 loss of function in human stem cells, and it may explain changes in differentiation properties observed in SHEDs with and without the c.35del variant.

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GJB2 c.35del 变异可上调 GJA1 基因的表达并影响人类干细胞的分化

摘要在常染色体隐性遗传的非综合征听力损失病例中，近一半存在 GJB2 的致病性 DNA 改变。导致非综合征性听力损失的 GJB2 最常见变异是框架转换 c.35del。GJB2 编码 Cx26，Cx26 是连接蛋白家族的一种蛋白质，可组装半通道和间隙连接。旁系亲属蛋白的表达被认为可以弥补特定连接蛋白功能的缺失。由于Cx26参与了不同组织的细胞分化，我们采用了来自人类脱落牙齿（SHEDs）的干细胞（c.35del变体同源），以评估GJB2在干细胞分化中的作用及其功能缺失与旁系基因表达之间的关系。研究人员比较了患者和对照组的原始SHED培养物。患者的SHED的GJB2 mRNA明显减少，GJA1（Cx43）的含量增加，但GJB6（Cx30）或GJB3（Cx31）的mRNA没有增加。此外，它们向脂肪细胞和骨细胞的诱导分化较高，但软骨细胞分化较低。我们的研究结果表明，GJA1表达的增加可能参与了人类干细胞GJB2功能缺失的功能补偿，这可能解释了在有c.35del变异和无c.35del变异的SHEDs中观察到的分化特性变化。

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来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.