Taken together, our experiments demonstrate that the SIX1BOR mutations contribute to the pathology of the disease through at least two different mechanisms that involve: 1) abolishing the formation of the SIX1-EYA complex or 2) diminishing the ability of SIX1 to bind DNA.
Further evaluation of SIX1 and its related target genes may provide a better understanding of the pathophysiology of BOR syndrome and offer greater clues to the disease mechanisms.
Gene mutations that have dominant inheritance and cause RHD, urinary tract anomalies, and defined extrarenal symptoms have been identified in TCF2 (renal cysts and diabetes syndrome), PAX2 (renal-coloboma syndrome), EYA1 and SIX1 (branchio-oto-renal syndrome), and SALL1 (Townes-Brocks syndrome).
We examined six Danish families with BOR syndrome by assessing linkage to BOR loci, by performing EYA1 multiplex ligation-dependent probe amplification (MLPA) analysis for deletions and duplications and by sequencing of EYA1, SIX1 and SIX5.