Prune Belly Syndrome: Mechanisms of Filamin A Mutations

Project Summary
The overall goal of this project is to expand the knowledge on the genetic basis and molecular
mechanisms of Prune Belly Syndrome (PBS), a severe human multi-system congenital urologic
anomaly with muscle and connective tissue deficiencies. Hallmark clinical features of PBS
include the triad of 1) wrinkled `prune' belly due to hypoplastic or absent abdominal wall skeletal
musculature, 2) megacystis secondary to bladder smooth muscle pathology, and 3) bilateral
undescended testes. We discovered three gain-of-function missense mutations in the X-linked
gene filamin A (FLNA) causing syndromic and isolated PBS. FLNA is an abundant intracellular
actin-crosslinking protein that functions as a crucial mechanosensor, transmitting force
bidirectionally between actin and integrins as well as binding and regulating other modulatory
transmembrane receptors or signaling molecules. FLNA regulates cell shape, adhesion, gene
transcription, hypoxic responses, embryonic morphogenesis, and cell contraction. To assess
the role of Flna mutations on mouse development and function, we will study our Flna gain-of-
function mutant mice that have a highly penetrant PBS-like phenotype when exposed to
gestational hypoxia (Aim 1). Using state-of-the-art structural and biochemical techniques, we
will characterize mutant FLNA protein structure and the impact on binding partners (Aim 2). As
the mouse-derived Flna gain-of-function bladder smooth muscle cells have a dysmorphic,
dysfunctional cell phenotype, we will subcellularly and molecularly define their cell form and
function when exposed to environmental stress and stimulants (Aim 3). This multidisciplinary
expert team with unique scientific expertise and advanced molecular tool sets will unite to
identify FLNA-based critical regulatory mechanisms modulating detrusor smooth muscle
function and dysfunction leading to PBS. This work may fill an important gap in our
understanding of FLNA signaling and yield greater mechanistic understanding of detrusor
myogenesis and detrusor underactivity, integrating signaling pathways, creating animal models
of PBS, and potentially impacting future management of detrusor underactivity by guiding future
rational therapeutic designs.

Grant Number: 5R01DK127589-06
NIH Institute/Center: NIH
Principal Investigator: LINDA BAKER