# Dchs1 and the Septin Cytoskeleton: a Molecular and Developmental Etiology Underlying Mitral Valve Prolapse

> **NIH NIH F31** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2021 · $13,340

## Abstract

ABSTRACT
Mitral valve prolapse (MVP) is one of the most common forms of cardiac valve disease and affects ~2-3% of the
human population. There are no effective nonsurgical treatments for MVP and therapeutic efforts have been
hindered by an incomplete understanding of its fundamental causes. However, we now have compelling genetic
and functional evidence that significantly advances our understanding of MVP pathogenesis. Our group was the
first to identify a genetic cause for MVP through identification of mutations in the atypical cadherin gene, DCHS1,
in multiple families with non-syndromic MVP and have traced the origin of disease back to defects in fetal valve
morphogenesis. The distinct functional and molecular consequences of DCHS1 deficiency are not currently
known, but recent two-hybrid studies have revealed a novel protein complex between DCHS1, Lix-1 like (LIX1L),
and Septin-9 (SEPT9) (DLS). Preliminary evidence supports a mechanism in which this complex links DCHS1-
based cell adhesions to the actin cytoskeleton through its interactions with cytoplasmic LIX1L and SEPT9. Thus,
we hypothesize that valve remodeling occurs through a DCHS1-LIX1L-SEPT9-actin mechanism, which may
provide a molecular and cellular origin for MVP. This hypothesis will be tested by defining mechanisms by which
the DLS complex regulates actin organization (Aim 1), directs proper valve remodeling ex vivo (Aim 2) and
genetically interacts within the same pathway to regulate proper valve geometry and ECM organization (Aim 3).
Aim 1 of this proposal involves an in vitro approach to define the effect of DLS on actin filament organization by
quantifying septin-actin network formation and the resulting intracellular tension in genetically modified mouse
cardiac fibroblasts. The functional consequences of DLS interactions with the actin cytoskeleton and its role in
valve remodeling will be measured through application of a novel ex vivo approach in Aim 2. Here, valve
interstitial cells (VICs) will be isolated from control and global Dchs1 and/or LIX1L heterozygote mouse hearts
and seeded into a 3D bioengineered valve construct that recapitulates the native valve environment. Readouts
including cell alignment, nuclear shape, actin organization, ECM production and formation, and force generation
will be measured and allow for quantification of the remodeling processes that are crucial for valve
morphogenesis. In vivo epistasis experiments performed in Aim 3 will add credence to each approach and will
define the genetic interaction between Dchs1 and Lix1L and their role in our proposed pathway. These studies
are significant since they are based on mutations identified in MVP patients and will define the molecular and
cellular origins of one of the most common cardiovascular diseases in the world.

## Key facts

- **NIH application ID:** 10383138
- **Project number:** 5F31HL152494-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Kelsey Schuyler Moore
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $13,340
- **Award type:** 5
- **Project period:** 2020-04-01 → 2021-07-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10383138

## Citation

> US National Institutes of Health, RePORTER application 10383138, Dchs1 and the Septin Cytoskeleton: a Molecular and Developmental Etiology Underlying Mitral Valve Prolapse (5F31HL152494-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10383138. Licensed CC0.

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