Our objectives were to identify MVP causative genes using familial approach, to assess MVP phenotype and to determine the molecular and cellular mechanisms involved in the pathology. The family was identified after one member underwent valve surgery for Barlow-type MVP. Exome sequencing in 3 affected coupled to IBD analysis identified a rare variant (MAF<0,001) (chr1(GRCh37): g.44044896C>G (p.Ile328Met) in PTPRF gene. Out of 16 mutated patients, 12 (75%) had a MVP (7 bileaflet and 5 posterior leaflet MVP) and 3 (19%) abnormal anterior coaptation. Phenotype assessed by echocardiography showed elongated and significantly thickened mitral leaflets. PTPRF alternative splicing gives rise to several isoforms in humans. The longest isoform encodes the LAR receptor involved in neuronal development and axon guidance. LAR is a repressor of cell migration and proliferation, participates in adherens junctions, modulates small GTPases activity by interacting with the Rho/Rac regulator Trio and inhibits EGF/FGF signaling. It also interacts with Heparan Sulfates Proteoglycans (HSPGs) involved in cell-cell and cell-matrix adhesion. PTPRF thus appeared as a good MVP causing candidate gene. However, the identified mutation (I328M) only targets the short isoform (sPTPRF) whose structure, expression profile and functions remain unknown. We showed here by RT-PCR in mitral valve tissue that sPTPRF is expressed in human mitral valve together with the longest PTPRF isoform encoding LAR. Re-expression study in Hek293 cells revealed the sPTPRF isoform interacts with HSPGs. PTPRF protein stability experiments evaluated by western blotting after cycloheximide treatment showed that the I328M mutation decreases the protein stability.Our results suggest a potential loss of function mutation in PTPRF-short isoform in autosomal dominant Barlow's disease. The precise role of the mutation on cell proliferation, cytokine (EGF-TGFβ) signaling and cell matrix interaction remains to be elucidated.

The author hereby declares no conflict of interest