Original Article

Pediatric Nephrology

, 24:2361

First online:

Functional analysis of BMP4 mutations identified in pediatric CAKUT patients

  • Mansoureh TabatabaeifarAffiliated withPediatric Nephrology, University of Heidelberg Children’s Hospital
  • , Karl-Peter SchlingmannAffiliated withPediatric Nephrology, University of Marburg Children’s Hospital
  • , Mieczyslaw LitwinAffiliated withNephrology and Kidney Transplantation Department, Children’s Memorial Health Hospital Warsaw
  • , Sevinc EmreAffiliated withDepartment of Pediatrics, Istanbul Medical Faculty, University of Istanbul
  • , Aysin BakkalogluAffiliated withFaculty of Medicine, Hacettepe University
  • , Otto MehlsAffiliated withPediatric Nephrology, University of Heidelberg Children’s Hospital
  • , Corinne AntignacAffiliated withINSERM U574, Hôpital Necker-Enfants Malades
  • , Franz SchaeferAffiliated withPediatric Nephrology, University of Heidelberg Children’s Hospital
  • , Stefanie WeberAffiliated withPediatric Nephrology, University of Heidelberg Children’s HospitalUniversity of Essen Children’s Hospital Email author 

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Human congenital anomalies of the kidney and urinary tract (CAKUT) represent the major causes of chronic renal failure (CRF) in children. This set of disorders comprises renal agenesis, hypoplasia, dysplastic or double kidneys, and/or malformations of the ureter. It has recently been shown that mutations in several genes, among them BMP4, are associated with hereditary renal developmental diseases. In BMP4, we formerly identified three missense mutations (S91C, T116S, N150K) in five pediatric CAKUT patients. These BMP4 mutations were subsequently studied in a cellular expression system, and here we present functional data demonstrating a lower level of messenger RNA (mRNA) abundance in Bmp4 mutants that indicates a possible negative feedback of the mutants on their own mRNA expression and/or stability. Furthermore, we describe the formation of alternative protein complexes induced by the S91C-BMP4 mutation, which results in perinuclear endoplasmic reticulum (ER) accumulation and enhanced lysosomal degradation of Bmp4. This work further supports the role of mutations in BMP4 for abnormalities of human kidney development.


Kidney development CAKUT Bone morphogenetic protein 4 Abnormal protein complex Subcellular localization