title: Genome-wide expression profiling of urinary bladder implicates desmosomal and cytoskeletal dysregulation in the bladder exstrophy-epispadias complex.
abstract: The bladder exstrophy-epispadias complex (BEEC) represents a spectrum of urological abnormalities where part, or all, of the distal urinary tract fails to close during development, becoming exposed on the outer abdominal wall. While the etiology of BEEC remains unknown, strong evidence exists that genetic factors are implicated. To understand the pathways regulating embryonic bladder development and to identify high-probability BEEC candidate genes, we conducted a genome-wide expression profiling (GWEP) study using normal and exstrophic human urinary bladders and human and mouse embryologic bladder-precursor tissues. We identified 162 genes differentially expressed in both embryonic and postnatal human samples. Pathway analysis of these genes revealed 11 biological networks with top functions related to skeletal and muscular system development, cellular assembly and development, organ morphology, or connective tissue disorders. The two most down-regulated genes desmin (DES, fold-change, -74.7) and desmuslin (DMN, fold-change, -53.0) are involved in desmosome mediated cell-cell adhesion and cytoskeletal architecture. Intriguingly, the sixth most overexpressed gene was desmoplakin (DSP, fold-change, +48.8), the most abundant desmosomal protein. We found 30% of the candidate genes to be directly associated with desmosome structure/function or cytoskeletal assembly, pointing to desmosomal and/or cytoskeletal deregulation as an etiologic factor for BEEC. Further findings indicate that p63, PERP, SYNPO2 and the Wnt pathway may also contribute to BEEC etiology. This study provides the first expression profile of urogenital genes during bladder development and points to the high-probability candidate genes for BEEC.
authors: Rowe Program in Human Genetics, University of California-Davis, 2825 50th Street, Sacramento, CA 95817, USA.
authors: Lihong
authors: L
authors: Qi
authors: Kun
authors: K
authors: Chen
authors: David J
authors: DJ
authors: Hur
authors: Garima
authors: G
authors: Yagnik
authors: Yegappan
authors: Y
authors: Lakshmanan
authors: Lori E
authors: LE
authors: Kotch
authors: Gerald H
authors: GH
authors: Ashrafi
authors: Francisco
authors: F
authors: Martinez-Murillo
authors: Jeanne
authors: J
authors: Kowalski
authors: Cyrill
authors: C
authors: Naydenov
authors: Lars
authors: L
authors: Wittler
authors: John P
authors: JP
authors: Gearhart
authors: Markus
authors: M
authors: Draaken
authors: Heiko
authors: H
authors: Reutter
authors: Michael
authors: M
authors: Ludwig
authors: Simeon A
authors: SA
authors: Boyadjiev
mesh_terms: D000818:Animals; D001746:Bladder Exstrophy / Q000235:genetics* / Q000378:metabolism; D003599:Cytoskeleton / Q000235:genetics* / Q000378:metabolism; D003893:Desmin / Q000235:genetics; D003896:Desmosomes / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D004842:Epispadias / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D016678:Genome; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics; D051379:Mice; D001743:Urinary Bladder / Q000378:metabolism*
chemical_list: D003893:Desmin; D007381:Intermediate Filament Proteins; C430456:desmuslin