Abstract Background and 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 mice. Methods Exome sequencing and segregation analysis were performed on a large family with MVP. Two mouse strains were generated: a complete knockout (KO) of the LTBP2 gene and a knock-in (KI) of the human mutation. At 6 months, phenotyping was conducted using echocardiography, histology, eye optical coherence tomography, and qPCR analysis for TGFβ signaling targets (periostin/POSTN, RUNX2, and CTGF) in valve tissues. Results LTBP2 rs117800773 V1506M mutation exhibited segregation with MVP. LTBP2 KO mice had 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 Knock-in 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). KO mice demonstrated an increase in the depth of the anterior chamber as well as reduced visual acuity. LTBP2 KO mice demonstrated overexpression of both TGFβ signaling targets RUNX2 and periostin (P=0.0144 and P=0.001826, respectively). Conclusions We report a knockout mouse strain with an LTBP2 mutation, demonstrating a valve phenotype, alongside a family with a novel mutation linked to MVP

Characterization of LTBP2 mutation causing Mitral Valve Prolapse