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XB-ART-56645
Dis Model Mech January 1, 2020; 13 (3):

Six1 proteins with human branchio-oto-renal mutations differentially affect cranial gene expression and otic development.

Shah AM , Krohn P , Baxi AB , Tavares ALP , Sullivan CH , Chillakuru YR , Majumdar HD , Neilson KM , Moody SA .


Abstract
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.

PubMed ID: 31980437
PMC ID: PMC7063838
Article link: Dis Model Mech
Grant support: [+]
Genes referenced: ctrl dlx5 eya1 foxd3 irx1 msx1 myc otx2 pax2 six1 sox11 sox9 tbx1 zic2
GO keywords: neural crest cell development [+]
Antibodies: Actb Ab6 Myc Ab16 Myc Ab17 Six1 Ab1

Disease Ontology terms: branchiootic syndrome [+]

Article Images: [+] show captions


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