LTBP2 mutation cuases familial type of myxomatous degeneration

Background: Familial studies of idiopathic or non-syndromic MVP suggest an autosomal dominant mode of inheritance with incomplete penetrance. Recent genetic studies utilizing improved diagnostic methods support autosomal dominant inheritance with age-dependent penetrance . We sought to define MVP causing mutation in a family segregating MVP

Methods and results: we recruited a 3 generations Ashkenazi-Jewish family segregating MVP. 6 out of 25 examined family members had echocardiographic criteria for MVP, and 2 others had thickened leaflets that do not fulfill diagnostic criteria. Next-generation sequencing was done on 4 affected family members. Coding sequence variations shared by all were tested for segregation in the rest of the family. Three hundred alterations shared by all 4 affected were identified. Of these, 11 most probable mutations, based upon predicted pathogenicity and low frequency in dbSNP were sequenced for all family members. A single C to T nucleotide substitution mutation in LTBP2 gene on chromosome 14 resulting in a Val1506Met mutation segregating with the trait

Animal data: Two mice strains were generated using CRIPR CAS technology. A complete knockout (deletion of the first exon) and a knock in mouse. Nineteen 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).

Discussion: We identified an MVP family with an LTBP-2 Val1506Met mutation segregating with the trait. This family has severe form of the disease evident by substantial amount of individuals needing valve repair surgery and with high degree penetrance. Mice model of LTBP cknockout demonstrates valvular myxomatous degeneration proving relation between the gene and the trait.