# ANO5 Functions and Mechanisms of LGMD2L

> **NIH NIH F32** · EMORY UNIVERSITY · 2020 · $64,518

## Abstract

PROJECT SUMMARY
Limb-girdle muscular dystrophies (LGMDs) are a debilitating group of diseases characterized by progressive
weakness of the proximal limb muscles (typically the hips and shoulders). LGMD2L, caused by recessive
mutations in Anoctamin-5 (ANO5), is a common but poorly understood subtype of LGMD. The clinical course of
LGMD2L often advances from difficulties in performing stressful muscle activities (e.g. heavy lifting, athletics)
and generalized myalgia to loss of ambulation. The disease represents a clear and significant burden to patient
quality of life. Currently, no effective treatments exist for LGMD2L; furthermore, very little is known about ANO5
function (and consequently the pathogenesis of LGMD2L), making the identification of therapeutic targets
virtually impossible. Recent work has uncovered an unexpected role for other Anoctamin family members as
Ca2+-activated phospholipid scramblases (Ca2+-PLSases), enzymes that facilitate movement of lipids from one
leaflet of the plasma membrane bilayer to the other. This process is important for externalizing
phosphatidylserine (PtdSer), which serves as a signaling molecule in a variety of physiological contexts including
fusion of myoblasts to form multi-nucleated myotubes. Fusion is a central step in muscle differentiation but is
impaired ANO5-/- myoblasts, which may be a key aspect of LGMD2L. While ANO5 has not been definitively
characterized as a PLSase, it is highly homologous to other ANO PLSases and, as with fusion, Ca2+-dependent
phospholipid scrambling (Ca2+-PLS) is reduced in cells lacking ANO5. ANO5 is thus circumstantially linked to
PLS, but some evidence suggests that it may not be a resident plasma membrane protein, which would be hard
to reconcile with a role as a PLSase. Furthermore, other PLSases are expressed in muscle and could be
responsible for pro-fusogenic PtdSer exposure during muscle differentiation; it is likewise possible that a specific
PLS-independent mechanism is used by muscle to regulate PtdSer on the outer leaflet. In order to investigate
the link between ANO5, PLS, and fusion, muscle-expressed PLSases will be knocked down in a certain type of
muscle precursor cell (myoblasts), which will then be induced to differentiate. Additionally, the ability of individual
PLSases to overcome the fusion-deficit in ANO5-/- cells will be examined in overexpression studies (Aim 1). A
proteomics-based approach will be employed to clarify role(s) of ANO5 in muscle (Aim 2). This will complement
Aim 1 by elucidating ANO5 binding partners that help to mediate its relationship to PLS; more importantly, it will
provide an unbiased lens through which to view ANO5 biology and LGMD2L pathology. The long-term goal of
this work is to identify potential therapeutic targets for ANO5-MD by determining disease mechanisms.

## Key facts

- **NIH application ID:** 9907852
- **Project number:** 5F32AR074249-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Steven Foltz
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $64,518
- **Award type:** 5
- **Project period:** 2019-04-01 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9907852

## Citation

> US National Institutes of Health, RePORTER application 9907852, ANO5 Functions and Mechanisms of LGMD2L (5F32AR074249-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9907852. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*