Loss of MeCP2 Causes Urological Dysfunction and Contributes to Death by Kidney Failure in Mouse Models of Rett Syndrome.
Rett Syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills during development, autonomic dysfunction, and an increased risk for premature lethality. Clinical experience identified a subset of individuals with RTT that present with urological dysfunction including individuals with frequent urinary tract infections, kidney stones, and urine retention requiring frequent catheterization for bladder voiding. To determine if urologic dysfunction is a feature of RTT, we queried the Rett Syndrome Natural History Study, a repository of clinical data from over 1000 individuals with RTT and found multiple instances of urological dysfunction. We then evaluated urological function in a mouse model of RTT and found an abnormal pattern of micturition. Both male and female mice possessing Mecp2 mutations show a decrease in urine output per micturition event. Furthermore, we identified signs of kidney failure secondary to urethral obstruction. Although genetic strain background significantly affects both survival and penetrance of the urethral obstruction phenotype, survival and penetrance of urethral obstruction do not directly correlate. We have identified an additional phenotype caused by loss of MeCP2, urological dysfunction. Furthermore, we urge caution in the interpretation of survival data as an endpoint in preclinical studies, especially where causes of mortality are poorly characterized.
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States of America.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States of America.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, United States of America.
Christopher S
CS
Ward
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, United States of America.
Teng-Wei
TW
Huang
Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, United States of America.
José A
JA
Herrera
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States of America.|Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, United States of America.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, United States of America.
Rodney C
RC
Samaco
Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, United States of America.
Meagan R
MR
Pitcher
Center for Comparative Medicine, Baylor College of Medicine, Houston, TX 77030, United States of America.
Alan
A
Herron
Greenwood Genetic Center, Greenwood, SC 29646, United States of America.
Steven A
SA
Skinner
Greenwood Genetic Center, Greenwood, SC 29646, United States of America.|Boston Children's Hospital, Boston, MA 02115, United States of America.
Walter E
WE
Kaufmann
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States of America.
Daniel G
DG
Glaze
University of Alabama, Birmingham, Birmingham, AL 35294, United States of America.
Alan K
AK
Percy
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States of America.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States of America.|Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, United States of America.|Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, United States of America.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, United States of America.
Jeffrey L
JL
Neul
D000818:Animals; D016208:Databases, Factual; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D009154:Mutation; D019683:Penetrance; D051437:Renal Insufficiency / Q000150:complications / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D015518:Rett Syndrome / Q000150:complications / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D013045:Species Specificity; D016019:Survival Analysis; D014524:Urethral Obstruction / Q000150:complications / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D016055:Urinary Retention / Q000150:complications / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology
C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2