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Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder

Pathogenic hemizygous or heterozygous mutations in the IQSEC2 gene cause X-linked intellectual developmental disorder-1 (XLID1), characterized by a variable phenotype including developmental delay, intellectual disability, epilepsy, hypotonia, autism, microcephaly and stereotypies. It affects both m...

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Autores principales: Baladron, Beatriz, Mielu, Lidia M., López-Martín, Estrella, Barrero, Maria J., Lopez, Lidia, Alvarado, Jose I., Monzón, Sara, Varona, Sarai, Cuesta, Isabel, Cazorla, Rosario, Lara, Julián, Iglesias, Gemma, Román, Enriqueta, Ros, Purificación, Gomez-Mariano, Gema, Cubillo, Isabel, Miguel, Esther Hernandez-San, Rivera, Daniel, Alonso, Javier, Bermejo-Sánchez, Eva, Posada, Manuel, Martínez-Delgado, Beatriz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409358/
https://www.ncbi.nlm.nih.gov/pubmed/36012761
http://dx.doi.org/10.3390/ijms23169480
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author Baladron, Beatriz
Mielu, Lidia M.
López-Martín, Estrella
Barrero, Maria J.
Lopez, Lidia
Alvarado, Jose I.
Monzón, Sara
Varona, Sarai
Cuesta, Isabel
Cazorla, Rosario
Lara, Julián
Iglesias, Gemma
Román, Enriqueta
Ros, Purificación
Gomez-Mariano, Gema
Cubillo, Isabel
Miguel, Esther Hernandez-San
Rivera, Daniel
Alonso, Javier
Bermejo-Sánchez, Eva
Posada, Manuel
Martínez-Delgado, Beatriz
author_facet Baladron, Beatriz
Mielu, Lidia M.
López-Martín, Estrella
Barrero, Maria J.
Lopez, Lidia
Alvarado, Jose I.
Monzón, Sara
Varona, Sarai
Cuesta, Isabel
Cazorla, Rosario
Lara, Julián
Iglesias, Gemma
Román, Enriqueta
Ros, Purificación
Gomez-Mariano, Gema
Cubillo, Isabel
Miguel, Esther Hernandez-San
Rivera, Daniel
Alonso, Javier
Bermejo-Sánchez, Eva
Posada, Manuel
Martínez-Delgado, Beatriz
author_sort Baladron, Beatriz
collection PubMed
description Pathogenic hemizygous or heterozygous mutations in the IQSEC2 gene cause X-linked intellectual developmental disorder-1 (XLID1), characterized by a variable phenotype including developmental delay, intellectual disability, epilepsy, hypotonia, autism, microcephaly and stereotypies. It affects both males and females typically through loss of function in males and haploinsufficiency in heterozygous females. Females are generally less affected than males. Two novel unrelated cases, one male and one female, with de novo IQSEC2 variants were detected by trio-based whole exome sequencing. The female case had a previously undescribed frameshift mutation (NM_001111125:c.3300dup; p.Met1101Tyrfs*5), and the male showed an intronic variant in intron 6, with a previously unknown effect (NM_001111125:c.2459+21C>T). IQSEC2 gene expression study revealed that this intronic variant created an alternative donor splicing site and an aberrant product, with the inclusion of 19bp, confirming the pathogenic effect of the intron variant. Moreover, a strong reduction in the expression of the long, but also the short IQSEC2 isoforms, was detected in the male correlating with a more severe phenotype, while the female case showed no decreased expression of the short isoform, and milder effects of the disease. This suggests that the abnormal expression levels of the different IQSEC2 transcripts could be implicated in the severity of disease manifestations.
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spelling pubmed-94093582022-08-26 Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder Baladron, Beatriz Mielu, Lidia M. López-Martín, Estrella Barrero, Maria J. Lopez, Lidia Alvarado, Jose I. Monzón, Sara Varona, Sarai Cuesta, Isabel Cazorla, Rosario Lara, Julián Iglesias, Gemma Román, Enriqueta Ros, Purificación Gomez-Mariano, Gema Cubillo, Isabel Miguel, Esther Hernandez-San Rivera, Daniel Alonso, Javier Bermejo-Sánchez, Eva Posada, Manuel Martínez-Delgado, Beatriz Int J Mol Sci Article Pathogenic hemizygous or heterozygous mutations in the IQSEC2 gene cause X-linked intellectual developmental disorder-1 (XLID1), characterized by a variable phenotype including developmental delay, intellectual disability, epilepsy, hypotonia, autism, microcephaly and stereotypies. It affects both males and females typically through loss of function in males and haploinsufficiency in heterozygous females. Females are generally less affected than males. Two novel unrelated cases, one male and one female, with de novo IQSEC2 variants were detected by trio-based whole exome sequencing. The female case had a previously undescribed frameshift mutation (NM_001111125:c.3300dup; p.Met1101Tyrfs*5), and the male showed an intronic variant in intron 6, with a previously unknown effect (NM_001111125:c.2459+21C>T). IQSEC2 gene expression study revealed that this intronic variant created an alternative donor splicing site and an aberrant product, with the inclusion of 19bp, confirming the pathogenic effect of the intron variant. Moreover, a strong reduction in the expression of the long, but also the short IQSEC2 isoforms, was detected in the male correlating with a more severe phenotype, while the female case showed no decreased expression of the short isoform, and milder effects of the disease. This suggests that the abnormal expression levels of the different IQSEC2 transcripts could be implicated in the severity of disease manifestations. MDPI 2022-08-22 /pmc/articles/PMC9409358/ /pubmed/36012761 http://dx.doi.org/10.3390/ijms23169480 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Baladron, Beatriz
Mielu, Lidia M.
López-Martín, Estrella
Barrero, Maria J.
Lopez, Lidia
Alvarado, Jose I.
Monzón, Sara
Varona, Sarai
Cuesta, Isabel
Cazorla, Rosario
Lara, Julián
Iglesias, Gemma
Román, Enriqueta
Ros, Purificación
Gomez-Mariano, Gema
Cubillo, Isabel
Miguel, Esther Hernandez-San
Rivera, Daniel
Alonso, Javier
Bermejo-Sánchez, Eva
Posada, Manuel
Martínez-Delgado, Beatriz
Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder
title Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder
title_full Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder
title_fullStr Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder
title_full_unstemmed Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder
title_short Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder
title_sort differences in expression of iqsec2 transcript isoforms in male and female cases with loss of function variants and neurodevelopmental disorder
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409358/
https://www.ncbi.nlm.nih.gov/pubmed/36012761
http://dx.doi.org/10.3390/ijms23169480
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