Characterization of LTBP2 mutation in causing Mitral Valve Prolapse

Haim Rosen ³ Ayal Ben Zvi ⁴ Eran Leitersdorf ¹ Idit Tesler ¹ Dan Gilon ² Karen Meir ⁵ Galina Levin ² Shifra Ben Dor ⁶ David Leibowitz ² Donna Zwas ² Amichay Gudgold ¹ Rebeca Haffner ⁶ Noga Reshef ¹ Ronen Durst ^1,2 Shoshi Shpitzen

¹Cardiovascular Precision Medicine Center, Hadassah Medical Center, Israel
²Cardiology department Hadassah Hebrew University Medical Center, Hadassah Medical Center, Israel
³The Department of Microbiology and Molecular Genetics Hebrew University, Hebrew University, Israel
⁴Developmental Biology and Cancer Research Hebrew University, Hebrew University, Israel
⁵Phatological department Hadassah Hebrew University Medical Center, Hadassah Medical Center, Israel
⁶Bioinformatics and Biological Computing Unit Weizmann institute of science, Weizmann Institute of Science, Israel

Background: Mitral Valve Prolapse (MIM 157700) is a very common cardiac disorder occurring in 2.4% of the general population. MVP is characterized by myxomatous degeneration resulting in valve thickening, prolapsing and regurgitation. MVP results in, arrhythmias, bacterial endocarditis, congestive heart failure and sudden death. Familial studies of MVP suggest an autosomal dominant model of inheritance with incomplete penetrance.
Methods and results: We identified an MVP family with an LTBP-2 Val1506Met rare mutation (minor allele frequency of 0.0001) segregating with the MVP (LOD score of 1.5 out of a maximal potential of 2.6). LTBP2 is an excellent candidate gene for MVP because it might regulates TGFβ signaling activity, shown to be disrupted in Marfan’s syndrome mitral valvulopathy. High prevalence of MVP was reported in relatives of patients with Weill Marchesani syndrome, caused by LTBP2 mutations.
We generated two strains of mice using CRISPR technology. A complete knockout and a knock in mouse. 19 mice were dissected so far. None of the wt mice (n=8) demonstrated myxomatous degeneration. Of the 11 mice with mutation, 8 homozygote for deletion and 3 homozygote for the human mutation, 8 demostrated myxomatous Degeneration by histology (1 knockin mouse ~ 70% pentrance in male mice, p=0.001, Fisher exact test). The pathologist that read the studies was blinded to the genotype. Echocardiography of theses mice demonstrated findings consistant with MVP in 50%of affected mice and not in controls
Conclusion: We demonstrated that Both our human and animal model data suggest a role for LTBP2 mutations in MVP development.