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A Latent Tgf-β binding Protein 2 Mutation Segregates With Mitral Valve Prolapse In A Large Pedigree

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A Latent TGF-β protein 2 mutation segregates with mitral valve prolapse in a large pedigree
Amichai Gutgold1. Shoshi Shpitzen2, Dona Zfat3, David Leibowitz4, Eran Leitersdorf2, Ronen Beeri3, Chaim Lotan3*, Dan Gilon3, Ronen Durst2,3*
1Medicin, Hadassah Mount Scoups, Jerusalem; 2Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah Ein-Kerem, Jerusalem; 3Cardiology, Hadassah Ein-Kerem, Jerusalem; 4Cardiology, Hadassah Mount Scoups, Jerusalem.

Objective: Mitral Valve Prolapse (MVP) is a prevalent valve defect, but the pathophysiolical mechanisms leading to the development of the disease are not well known. As MVP has a familial association, we aimed to find a gene linked to MVP phenotype in a family with a presumed autosomal-dominant inheritance.

Methods: In a 3 generations Ashkenazi-Jewish  family, 6 out of 25 examined family members had echocardiographic criteria for MVP, and 2 others had a 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

Results: 300 mutations shared by all 4 affected were identified. Of these, 11 most probable mutations, based upon the type of mutation, predicted pathogenicity and  frequencty in dbSNP were sequenced for all family members. 9 mutations didn't show segregation, and one more seemed improbable because the mutation was found in all the tested DNA samples. A single C to T nucleotide substitution mutation in LTBP2 (Latent TGF-β binding protein 2) gene, located in chromosome 14, was identified as a probable and suitable gene in linkage analysis tests.

Conclusion: We found that a mutation in LTBP2 gene may be responsible for a non-syndromic MVP in an Ashkenazi-Jewish family. LTBP2 is a protein similar to the Fibrillin1 protein, which was identified to be the defective protein in Marphan syndrome. The LTBP2 protein is assumed to have mainly structural properties, along with TGF-β regulation activity. A defect in both of these functions, might lead to a defect in connective tissue development and regeneration, underlying the basic pathology of MVP. Further research of prevalence of this mutation in familial MVP, and the functional significance of the identified mutation must be carried out in order to understand its exact role.

Mitral Valve Prolapse has a familial, syndromatic and non-syndromatic association, the later constitutes 5% of the cases. In most cases there is an autosomal-dominant  inheritance with partial penetrance.

Several mutation causing MVP non syndromic MVP were identified so far

1.A mutation in filamin A, and X linked gene, has been associated with valvular dystrophy
2.Two other loci (MMVP2 and MMVP3 were identified)
3. A mutation in DCHS1, a gene within MMVP2 loci was recently described.

These explain only a part of familial MVP type. The purpose of the current study is to identify MVP causing mutation in an Ashkenazi Jewish mutation

23 family members of a large, Ashkenazy-Jewish family with an autosomal-dominant MVP,  were screened for MVP. 6 were found  to fit the  echocardiographic diagnostic criteria (black), and 2 others had a thickened leaflets but didn’t fulfilled the criteria (gray).

Aim of study 

To identify a gene mutation, responsible for a familial MVP, in order to promote our understanding of molecular pathogenesis.

•300 gene mutations, compatible with AD mutations and common to all 4 
•Cross-matching of exom sequencing results from 4 family members DNA
•11 genes were selected for highest probability to have phenotypic influence
•Filtering results according to type of mutation and known clinical association
•2 mutations: in ATN1 and  LTBP2 genes, demonstrated genotype- phenotype segregation.
•First generation sequencing was done to all family members, searching for these 11 gene mutations and determining segregation for each gene mutation
• mutation
•ATN1 mutation has several characteristics making it much less probable to be a disease causing mutation

Latent TGF-β binding protein-2 (LTBP2) gene, on chromosome 14, encodes to LTBP2 protein, is one of four identified LTBP proteins.

LTBP family has structural similarity to the fibrillin protein family, and share its double function, as an ECM structural gene, with a regulatory function. Most LTBP family proteins regulates TGF-β function and tissue availability, and by that, influence remodeling of the ECM.

LTBP2 apparently has more structural role and less impact over TGF-β function, but it may influence other ECM components, as Fibulin-5, and probably effects the elastic components of the tissue


1.We describe a family with non syndromic MVP
2.Linkage with a mutation in LTBP2 was identified.

Further validation studies are needed to prove causality


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