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Six1 proteins with human branchio-oto-renal mutations differentially affect cranial gene expression and otic development
Single-nucleotide mutations in human SIX1 result in amino acid substitutions in either the protein-protein interaction domain or the homeodomain, and cause ∼4% of branchio-otic (BOS) and branchio-oto-renal (BOR) cases. The phenotypic variation between patients with the same mutation, even within aff...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Company of Biologists Ltd
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063838/ https://www.ncbi.nlm.nih.gov/pubmed/31980437 http://dx.doi.org/10.1242/dmm.043489 |
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author | Shah, Ankita M. Krohn, Patrick Baxi, Aparna B. Tavares, Andre L. P. Sullivan, Charles H. Chillakuru, Yeshwant R. Majumdar, Himani D. Neilson, Karen M. Moody, Sally A. |
author_facet | Shah, Ankita M. Krohn, Patrick Baxi, Aparna B. Tavares, Andre L. P. Sullivan, Charles H. Chillakuru, Yeshwant R. Majumdar, Himani D. Neilson, Karen M. Moody, Sally A. |
author_sort | Shah, Ankita M. |
collection | PubMed |
description | Single-nucleotide mutations in human SIX1 result in amino acid substitutions in either the protein-protein interaction domain or the homeodomain, and cause ∼4% of branchio-otic (BOS) and branchio-oto-renal (BOR) cases. The phenotypic variation between patients with the same mutation, even within affected members of the same family, make it difficult to functionally distinguish between the different SIX1 mutations. We made four of the BOS/BOR substitutions in the Xenopus Six1 protein (V17E, R110W, W122R, Y129C), which is 100% identical to human in both the protein-protein interaction domain and the homeodomain, and expressed them in embryos to determine whether they cause differential changes in early craniofacial gene expression, otic gene expression or otic morphology. We confirmed that, similar to the human mutants, all four mutant Xenopus Six1 proteins access the nucleus but are transcriptionally deficient. Analysis of craniofacial gene expression showed that each mutant causes specific, often different and highly variable disruptions in the size of the domains of neural border zone, neural crest and pre-placodal ectoderm genes. Each mutant also had differential effects on genes that pattern the otic vesicle. Assessment of the tadpole inner ear demonstrated that while the auditory and vestibular structures formed, the volume of the otic cartilaginous capsule, otoliths, lumen and a subset of the hair cell-containing sensory patches were reduced. This detailed description of the effects of BOS/BOR-associated SIX1 mutations in the embryo indicates that each causes subtle changes in gene expression in the embryonic ectoderm and otocyst, leading to inner ear morphological anomalies. |
format | Online Article Text |
id | pubmed-7063838 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | The Company of Biologists Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-70638382020-03-12 Six1 proteins with human branchio-oto-renal mutations differentially affect cranial gene expression and otic development Shah, Ankita M. Krohn, Patrick Baxi, Aparna B. Tavares, Andre L. P. Sullivan, Charles H. Chillakuru, Yeshwant R. Majumdar, Himani D. Neilson, Karen M. Moody, Sally A. Dis Model Mech Research Article Single-nucleotide mutations in human SIX1 result in amino acid substitutions in either the protein-protein interaction domain or the homeodomain, and cause ∼4% of branchio-otic (BOS) and branchio-oto-renal (BOR) cases. The phenotypic variation between patients with the same mutation, even within affected members of the same family, make it difficult to functionally distinguish between the different SIX1 mutations. We made four of the BOS/BOR substitutions in the Xenopus Six1 protein (V17E, R110W, W122R, Y129C), which is 100% identical to human in both the protein-protein interaction domain and the homeodomain, and expressed them in embryos to determine whether they cause differential changes in early craniofacial gene expression, otic gene expression or otic morphology. We confirmed that, similar to the human mutants, all four mutant Xenopus Six1 proteins access the nucleus but are transcriptionally deficient. Analysis of craniofacial gene expression showed that each mutant causes specific, often different and highly variable disruptions in the size of the domains of neural border zone, neural crest and pre-placodal ectoderm genes. Each mutant also had differential effects on genes that pattern the otic vesicle. Assessment of the tadpole inner ear demonstrated that while the auditory and vestibular structures formed, the volume of the otic cartilaginous capsule, otoliths, lumen and a subset of the hair cell-containing sensory patches were reduced. This detailed description of the effects of BOS/BOR-associated SIX1 mutations in the embryo indicates that each causes subtle changes in gene expression in the embryonic ectoderm and otocyst, leading to inner ear morphological anomalies. The Company of Biologists Ltd 2020-03-03 /pmc/articles/PMC7063838/ /pubmed/31980437 http://dx.doi.org/10.1242/dmm.043489 Text en © 2020. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/4.0This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Article Shah, Ankita M. Krohn, Patrick Baxi, Aparna B. Tavares, Andre L. P. Sullivan, Charles H. Chillakuru, Yeshwant R. Majumdar, Himani D. Neilson, Karen M. Moody, Sally A. Six1 proteins with human branchio-oto-renal mutations differentially affect cranial gene expression and otic development |
title | Six1 proteins with human branchio-oto-renal mutations differentially affect cranial gene expression and otic development |
title_full | Six1 proteins with human branchio-oto-renal mutations differentially affect cranial gene expression and otic development |
title_fullStr | Six1 proteins with human branchio-oto-renal mutations differentially affect cranial gene expression and otic development |
title_full_unstemmed | Six1 proteins with human branchio-oto-renal mutations differentially affect cranial gene expression and otic development |
title_short | Six1 proteins with human branchio-oto-renal mutations differentially affect cranial gene expression and otic development |
title_sort | six1 proteins with human branchio-oto-renal mutations differentially affect cranial gene expression and otic development |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063838/ https://www.ncbi.nlm.nih.gov/pubmed/31980437 http://dx.doi.org/10.1242/dmm.043489 |
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