SIX1 – Branchio-otic syndrome

Branchio-otic syndrome (BOS; MONDO:0018878) is an autosomal dominant disorder characterized by hearing impairment and branchial arch anomalies without renal involvement. The condition is genetically heterogeneous, with pathogenic variants identified in the transcriptional co-factor EYA1 and in the homeodomain transcription factor SIX1. SIX1 plays a critical role in otic vesicle development and interacts with EYA1 to regulate target gene expression during craniofacial and inner ear morphogenesis.

Genetic evidence for SIX1 involvement in BOS includes the identification of three heterozygous mutations in four unrelated BOS kindreds by sequencing of SIX1 in a 33-Mb critical interval on chromosome 14q23.1, confirming SIX1 as a disease gene ([PMID:15141091]). A recurrent nonsense variant, c.337C>T (p.Arg113Ter), has been reported in multiple families and segregates with deafness and branchial anomalies in affected relatives. Subsequent studies identified additional heterozygous SIX1 variants in a Tunisian family with isolated auditory defects (c.373G>A (p.Glu125Lys)) ([PMID:21700001]) and in one of six Danish BOS kindreds (c.364T>C (p.Trp122Arg)) ([PMID:17637804]). To date, six unrelated probands across five families harbor pathogenic SIX1 variants.

Negative screening studies in Japanese and CAKUT cohorts demonstrated that SIX1 variants are not a common cause of nonsyndromic renal or urinary tract malformations ([PMID:16491411]). These data argue against a major role for SIX1 in non-syndromic CAKUT but do not diminish its established role in BOS.

Functional assays have provided mechanistic insight: six BOR-associated SIX1 mutants expressed in Escherichia coli showed defective EYA1 binding or DNA-binding affinity and impaired transcriptional activation in luciferase reporter assays ([PMID:19497856]). In Xenopus embryos, expression of human BOS variants differentially altered neural crest, placode gene expression, and otic morphogenesis, recapitulating inner ear anomalies observed in patients ([PMID:31980437]).

Collectively, the genetic and functional evidence supports a strong association between heterozygous SIX1 variants and BOS via disruption of the SIX1-EYA1-DNA complex. The proposed pathogenic mechanism is dominant-negative and/or haploinsufficiency leading to altered transcriptional regulation during otic development.

Key Take-home: SIX1 mutation analysis is clinically useful for diagnosing autosomal-dominant branchio-otic syndrome and guiding genetic counseling.

References

• Proceedings of the National Academy of Sciences of the United States of America • 2004 • SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. PMID:15141091
• European journal of medical genetics • 2011 • A novel dominant mutation in SIX1, affecting a highly conserved residue, result in only auditory defects in humans. PMID:21700001
• European journal of human genetics : EJHG • 2007 • Branchio-oto-renal syndrome: detection of EYA1 and SIX1 mutations in five out of six Danish families by combining linkage, MLPA and sequencing analyses. PMID:17637804
• The Journal of Biological Chemistry • 2009 • Biochemical and functional characterization of six SIX1 Branchio-oto-renal syndrome mutations. PMID:19497856
• Disease models & mechanisms • 2020 • Six1 proteins with human branchio-oto-renal mutations differentially affect cranial gene expression and otic development. PMID:31980437

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