Ubiquitin fusion degradation 1–like gene dysregulation in bicuspid aortic valve

Objective

Bicuspid aortic valve, the most common congenital cardiac malformation, is caused by fusion of valve cushions at the onset of valvulogenesis. Although its exact pathogenesis is still unclear, a genetic basis is appearing more and more likely. Search for a potential candidate gene by reviewing semilunar valve morphogenesis led us to the ubiquitin fusion degradation 1–like gene (UFD1L), which is highly expressed in the cardiac outflow tract during embryogenesis.

Methods

Aortic valves were collected during surgery from 39 patients with bicuspid aortic valve (mean age 56.8 ± 18.1 years) and from 38 patients with tricuspid aortic valve (mean age 61.7 ± 16.1 years). Fluorescence in situ hybridization was performed for detection of microdeletion, quantitative reverse transcriptase–polymerase chain reaction to measure gene expression, and Western blotting to analyze the amount of UFD1L gene product.

Results

No microdeletion was found in either group in the critical region of chromosome 22 containing the UFD1L gene. UFD1L gene expression, however, was significantly reduced in bicuspid aortic valve samples (median 787-fold) relative to tricuspid aortic valve samples (median 10,887-fold, P = .001). The amount of UFD1L gene product was also significantly diminished in bicuspid aortic valve samples (3.9 ± 2.6 vs 8.4 ± 4.8 optical density units, P < .05).

Conclusion

Bicuspid aortic valve was associated with downregulation of UFD1L gene expression, supporting the hypothesis that bicuspid aortic valve is a genetic disorder, with the UFD1L gene as a potential candidate gene.

Abbreviations and Acronyms:  AP-2, activating enhancer-binding protein 2, BAV, bicuspid aortic valve, CATCH, cardiac defect, abnormal facies, thymic hypoplasia or aplasia and T-cell deficiency, cleft palate, hypoparathyroidism, and hypocalcemia, dHAND, deciduum, heart, autonomic nervous system, neural crest-derived, GAPDH, reduced glyceraldehyde-phosphate dehydrogenase gene, NF-ATc, nuclear factor of activated T cells, SRY, sex determining region Y–box 4 (SOX4), TAV, tricuspid aortic valve, TBX1, T-box 1 gene, UFD1L, ubiquitin fusion degradation 1–like gene

CTSNet classification:  23, 29, 35