Shpitzen Shoshi, Rosen Haim, Ben-Zvi Ayal, Meir Karen, Levin Galina, Gudgold Amichay, Ben Dor Shifra, Haffner Rebecca, Zwas Donna R, Leibowitz David, Slaugenhaupt Susan A, Banin Eyal, Mizrachi Rotem, Obolensky Alexey, Levine Robert A, Gilon Dan, Leitersdorf Eran, Tessler Idit, Reshef Noga, Durst Ronen
Department of Medicine, Cardiovascular Precision Medicine Center, Hadassah Hebrew University Medical Center, P.O. Box 12000, 9112001 Jerusalem, Israel.
The Kuvin Center for the Study of Infectious and Tropical Diseases, Institute for Medical Research-Israel-Canada, Hebrew University-Hadassah Medical School, 9112001 Jerusalem, Israel.
Eur Heart J Open. 2025 Jan 3;5(1):oeae106. doi: 10.1093/ehjopen/oeae106. eCollection 2025 Jan.
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.
Exome sequencing and segregation analysis were performed on a large family with MVP. Two mouse strains were generated: a complete KO of the 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/, , and ) in valve tissues. rs117800773 V1506M mutation exhibited segregation with MVP. KO mice had a higher incidence of myxomatous changes by histology (7 of 9 of KO vs. 0 of 7 control animals, = 0.00186) and echocardiography (7 of 9 vs. 0 of 8, = 0.0011). KI mice for the human mutation showed a significantly elevated myxomatous histological phenotype (8 of 8 vs. 0 of 9, = 0.00004) as well as by echocardiography (6 of 8 vs. 0 of 9, = 0.00123). Knockout mice demonstrated an increase in the depth of the anterior chamber as well as reduced visual acuity. KO mice demonstrated overexpression of both TGF-β signalling targets and periostin ( = 0.0144 and = 0.001826, respectively).
We report a KO mouse strain with an mutation, demonstrating a valve phenotype, alongside a family with a novel mutation linked to MVP.
二尖瓣脱垂（MVP）是一种常见的瓣膜疾病，与显著的发病率和死亡率相关，具有很强的遗传基础。本研究旨在确定一个患有MVP的家族中的突变，并描述潜在转化生长因子结合蛋白2（LTBP2）基因敲除（KO）小鼠的瓣膜表型。
对一个患有MVP的大家族进行外显子组测序和分离分析。构建了两种小鼠品系：该基因的完全敲除小鼠和携带人类突变的敲入（KI）小鼠。在6个月时，使用超声心动图、组织学、眼部光学相干断层扫描以及对瓣膜组织中转化生长因子-β（TGF-β）信号靶点（骨膜蛋白/POSTN、THBS1和LTBP2）进行定量聚合酶链反应分析来进行表型分析。rs117800773 V1506M突变与MVP表现出共分离。KO小鼠通过组织学检查发现黏液瘤样改变的发生率更高（KO组9只中有7只，而对照组7只中无，P = 0.00186），超声心动图检查结果类似（9只中有7只，而8只对照组中无，P = 0.0011）。携带人类突变的KI小鼠在组织学上黏液瘤样表型显著升高（8只中有8只，而9只对照组中无，P = 0.00004），超声心动图检查结果同样如此（8只中有6只，而9只对照组中无，P = 0.00123）。敲除小鼠前房深度增加且视力下降。LTBP2基因敲除小鼠显示TGF-β信号靶点THBS1和骨膜蛋白均过表达（分别为P = 0.0144和P = 0.001826）。
我们报告了一种携带LTBP2基因突变的KO小鼠品系，其表现出瓣膜表型，同时报告了一个与MVP相关的新突变家族。
