Characterization of LTBP2 mutation causing mitral valve prolapse

Aims: Mitral valve prolapse (MVP) is a common valvular disorder associated with significant morbidity and mortality, with a strong genetic basis. This study aimed to identify a mutation in a family with MVP and to characterize the valve phenotype in LTBP2 knockout (KO) mice. Methods and results: Exome sequencing and segregation analysis were performed on a large family with MVP. Two mouse strains were generated: a complete KO of the LTBP2 gene and a knockin (KI) of the human mutation. At 6 months, phenotyping was conducted using echocardiography, histology, eye optical coherence tomography, and quantitative polymerase chain reaction analysis for TGF-β signalling targets (periostin/POSTN, RUNX2, and CTGF) in valve tissues. LTBP2 rs117800773 V1506M mutation exhibited segregation with MVP. LTBP2 KO mice had a higher incidence of myxomatous changes by histology (7 of 9 of KO vs. 0 of 7 control animals, P = 0.00186) and echocardiography (7 of 9 vs. 0 of 8, P = 0.0011). LTBP2 KI mice for the human mutation showed a significantly elevated myxomatous histological phenotype (8 of 8 vs. 0 of 9, P = 0.00004) as well as by echocardiography (6 of 8 vs. 0 of 9, P = 0.00123). Knockout mice demonstrated an increase in the depth of the anterior chamber as well as reduced visual acuity. LTBP2 KO mice demonstrated overexpression of both TGF-β signalling targets RUNX2 and periostin (P = 0.0144 and P = 0.001826, respectively). Conclusion: We report a KO mouse strain with an LTBP2 mutation, demonstrating a valve phenotype, alongside a family with a novel mutation linked to MVP.