---
pmid: '39880331'
title: Mitral Valve Prolapse Caused by TLL1 Gain-of-Function Mutation.
authors:
- Agam N
- Dolgin V
- Star A
- Freund O
- Jean MM
- Safran A
- Poleg T
- Zahger D
- Birk OS
journal: Can J Cardiol
year: '2025'
full_text_available: false
doi: 10.1016/j.cjca.2025.01.018
pubmed_publication_types:
- Journal Article
publication_type: PRIMARY_RESEARCH
---

# Mitral Valve Prolapse Caused by TLL1 Gain-of-Function Mutation.
**Authors:** Agam N, Dolgin V, Star A, Freund O, Jean MM, Safran A, Poleg T, Zahger D, Birk OS
**Journal:** Can J Cardiol (2025)
**DOI:** [10.1016/j.cjca.2025.01.018](https://doi.org/10.1016/j.cjca.2025.01.018)

## Abstract

1. Can J Cardiol. 2025 May;41(5):928-935. doi: 10.1016/j.cjca.2025.01.018. Epub
2025 Jan 27.

Mitral Valve Prolapse Caused by TLL1 Gain-of-Function Mutation.

Agam N(1), Dolgin V(1), Star A(2), Freund O(1), Jean MM(1), Safran A(1), Poleg
T(1), Zahger D(2), Birk OS(3).

Author information:
(1)The Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences and
National Institute of Biotechnology in the Negev, Ben Gurion University of the
Negev, Be'er Sheva, Israel.
(2)Department of Cardiology, Soroka University Medical Center, Affiliated to the
Faculty of Health Sciences, Ben Gurion University of the Negev, Be'er Sheva,
Israel.
(3)The Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences and
National Institute of Biotechnology in the Negev, Ben Gurion University of the
Negev, Be'er Sheva, Israel; Genetics Institute, Soroka University Medical
Center, Be'er Sheva, Israel; The Danek Gertner Institute of Human Genetics,
Sheba Medical Center, Ramat Gan, Israel. Electronic address: obirk@bgu.ac.il.

BACKGROUND: Mitral valve prolapse (MVP) is a common cardiac valvular anomaly
that can be caused by mutations in genes of various biologic pathways.
Individuals of 3 generations of a kindred presented with an apparently dominant
heredity of isolated MVP.
METHODS: Clinical evaluation and echocardiography were performed for all
complying members of a family (n = 13). Whole exome and genome sequencing data
of 2 affected individuals were analyzed, delineating shared heterozygous
variants, and then further tested for segregation within the kindred (Sanger
sequencing). Tolloid-like 1 (TLL1) enzymatic activity was assayed in media of
HEK293 cells transfected with wild-type vs mutant TLL1.
RESULTS: The only heterozygous variant segregating in the affected kindred as
expected for dominant heredity of MVP was p.T253A, within the catalytic domain
of TLL1. Of 8 heterozygotes, 6 had MVP and 2 had trivial mitral regurgitation.
An activity assay in the extracellular media of the HEK293-transfected cells
showed that, over time (12 hours), the enzymatic activity of the mutated TLL1
protein was 3.4-fold higher than that of the wild-type.
CONCLUSIONS: Our genetic and biochemical studies show that a TLL1
gain-of-function mutation, prolonging the half-life of TLL1 active protein in
the extracellular matrix, causes autosomal dominant MVP with variable
expressivity. TLL1 encodes an extracellular metalloprotease regulating
extracellular matrix composition and maintenance. In previous work, heterozygous
loss-of-function TLL1 mutations have been shown to cause autosomal dominant
atrial septal defects. Our findings enable novel insights into the molecular
pathways of valvular physiology and disease, the role of TLL1 in human
development, and the differing phenotypes in loss-of-function and
gain-of-function mutations of the same gene.

Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cjca.2025.01.018
PMID: 39880331 [Indexed for MEDLINE]