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

Autor(es)

Ana Carla Batissoco ; Dayane Bernardino Cruz ^[2] ; Thiago Geronimo Pires Alegria ^[3] ; Gerson Kobayashi ^[4] ; Jeanne Oiticica ; Luis Eduardo Soares Netto ^[6] ; Maria Rita Passos-Bueno ^[7] ; Luciana Amaral Haddad ^[8] ; Regina Célia Mingroni Netto ^[9]

• Tipo de documento: Artigo Científico
• Fonte: GENETICS AND MOLECULAR BIOLOGY; v. 47, n. 2 2024-04-15.

Resumo

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. (AU)

• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs