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

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Mitral valve prolapse (MVP) is a common heart condition.
• Genetic mutations in various pathways can cause MVP.
• A family with three generations exhibiting dominant isolated MVP was studied.

Purpose of the Study:

• To identify the genetic cause of isolated mitral valve prolapse (MVP) in a multi-generational family.
• To investigate the functional consequences of identified genetic variants.
• To understand the role of TLL1 in valvular disease.

Main Methods:

• Clinical evaluation and echocardiography of 13 family members.
• Whole exome and genome sequencing to identify variants.
• Sanger sequencing for variant segregation analysis.
• Enzymatic activity assays of Tolloid-like 1 (TLL1) in transfected cells.

Main Results:

• A heterozygous p.T253A variant in the TLL1 gene segregated with MVP in the family.
• The TLL1 variant showed a 3.4-fold increase in enzymatic activity compared to wild-type.
• 6 out of 8 heterozygotes presented with MVP or trivial mitral regurgitation.

Conclusions:

• A TLL1 gain-of-function mutation causes autosomal dominant MVP with variable expressivity.
• This mutation prolongs the half-life of active TLL1 protein in the extracellular matrix.
• Findings provide novel insights into TLL1's role in valvular physiology, development, and disease.