TY - JOUR

T1 - Targeted correction of megabase-scale CNTN6 duplication in induced pluripotent stem cells and impacts on gene expression

AU - Gridina, Maria

AU - Orlova, Polina

AU - Serov, Oleg

N1 - The study was supported by the Russian Science Foundation No-21-65-00017. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2025/1/20

Y1 - 2025/1/20

N2 - Copy number variations of the human CNTN6 gene, resulting from megabase-scale microdeletions or microduplications in the 3p26.3 region, are frequently implicated in neurodevelopmental disorders such as intellectual disability and developmental delay. However, duplication of the full-length human CNTN6 gene presents with variable penetrance, resulting in phenotypes that range from neurodevelopmental disorders to no visible pathologies, even within the same family. Previously, we obtained a set of induced pluripotent stem cell lines derived from a patient with a CNTN6 gene duplication and from two healthy donors. Our findings demonstrated that CNTN6 expression in neurons carrying the duplication was significantly reduced. Additionally, the expression from the CNTN6 duplicated allele was markedly lower compared to the wild-type allele. Here, we first introduce a system for correcting megabase-scale duplications in induced pluripotent stem cells and secondly analyze the impact of this correction on CNTN6 gene expression. We showed that the deletion of one copy of the CNTN6 duplication did not affect the expression levels of the remaining allele in the neuronal cells.

AB - Copy number variations of the human CNTN6 gene, resulting from megabase-scale microdeletions or microduplications in the 3p26.3 region, are frequently implicated in neurodevelopmental disorders such as intellectual disability and developmental delay. However, duplication of the full-length human CNTN6 gene presents with variable penetrance, resulting in phenotypes that range from neurodevelopmental disorders to no visible pathologies, even within the same family. Previously, we obtained a set of induced pluripotent stem cell lines derived from a patient with a CNTN6 gene duplication and from two healthy donors. Our findings demonstrated that CNTN6 expression in neurons carrying the duplication was significantly reduced. Additionally, the expression from the CNTN6 duplicated allele was markedly lower compared to the wild-type allele. Here, we first introduce a system for correcting megabase-scale duplications in induced pluripotent stem cells and secondly analyze the impact of this correction on CNTN6 gene expression. We showed that the deletion of one copy of the CNTN6 duplication did not affect the expression levels of the remaining allele in the neuronal cells.

KW - CNTN6

KW - CRISPR/Cas9-mediated genome editing

KW - Cre/loxP system

KW - Differentiation of induced pluripotent stem cells

KW - Duplication

KW - Induced pluripotent stem cells

UR - https://www.mendeley.com/catalogue/c3ccb93f-5d68-3be3-9633-7f1135cdf5dd/

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85215664978&origin=inward&txGid=b074504fc196ed1c40ad2a31a6788dbf

U2 - 10.7717/peerj.18567

DO - 10.7717/peerj.18567

M3 - Article

C2 - 39850828

VL - 13

JO - PeerJ

JF - PeerJ

SN - 2167-8359

IS - 1

M1 - e18567

ER -