Phenotypic and molecular basis of SIX1 variants linked to non-syndromic deafness and atypical branchio-otic syndrome in South Korea
Branchio-oto-renal (BOR)/branchio-otic (BO) syndrome is a rare disorder and exhibits clinically heterogenous phenotypes, marked by abnormalities in the ear, branchial arch, and renal system. Sporadic cases of atypical BOR/BO syndrome have been recently reported; however, evidence on genotype–phenoty...
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Veröffentlicht in: | Scientific reports 2023-07, Vol.13 (1), p.11776-11776, Article 11776 |
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Sprache: | eng |
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Zusammenfassung: | Branchio-oto-renal (BOR)/branchio-otic (BO) syndrome is a rare disorder and exhibits clinically heterogenous phenotypes, marked by abnormalities in the ear, branchial arch, and renal system. Sporadic cases of atypical BOR/BO syndrome have been recently reported; however, evidence on genotype–phenotype correlations and molecular mechanisms of those cases is lacking. We herein identified five
SIX1
heterozygous variants (c.307dupC:p.Leu103Profs*51, c.373G>A:p.Glu125Lys, c.386_391del:p.Tyr129_Cys130del, c.397_399del:p.Glu133del, and c.501G>C:p.Gln167His), including three novel variants, through whole-exome sequencing in five unrelated Korean families. All eight affected individuals with
SIX1
variants displayed non-syndromic hearing loss (DFNA23) or atypical BO syndrome. The prevalence of major and minor criteria for BOR/BO syndrome was significantly reduced among individuals with
SIX1
variants, compared to 15 BOR/BO syndrome families with
EYA1
variants. All
SIX1
variants interacted with the EYA1 wild-type; their complexes were localized in the nucleus except for the p.Leu103Profs*51 variant. All mutants also showed obvious but varying degrees of reduction in DNA binding affinity, leading to a significant decrease in transcriptional activity. This study presents the first report of
SIX1
variants in South Korea, expanding the genotypic and phenotypic spectrum of
SIX1
variants, characterized by DFNA23 or atypical BO syndrome, and refines the diverse molecular aspects of
SIX1
variants according to the EYA1–SIX1–DNA complex theory. |
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ISSN: | 2045-2322 2045-2322 |
DOI: | 10.1038/s41598-023-38909-w |