Functional analysis of BMP4 mutations identified in pediatric CAKUT patients

• Published in: Pediatric nephrology (Berlin, West) Vol. 24; no. 12; pp. 2361 - 2368
• Main Authors: Tabatabaeifar, Mansoureh, Schlingmann, Karl-Peter, Litwin, Mieczyslaw, Emre, Sevinc, Bakkaloglu, Aysin, Mehls, Otto, Antignac, Corinne, Schaefer, Franz, Weber, Stefanie
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-12-2009; Springer; Springer Nature B.V
• Subjects: Animals; Bone Morphogenetic Protein 4 - analysis; Bone Morphogenetic Protein 4 - genetics; Bone Morphogenetic Protein 4 - metabolism; Cell Line; Cercopithecus aethiops; Child; Computational Biology - methods; Computer Simulation; COS Cells; Epitopes; Fluorescent Antibody Technique, Indirect; Genetic Vectors; Hospitals; Humans; Kidney - abnormalities; Kidney - cytology; Kidneys; Lysosomes - metabolism; Medicin och hälsovetenskap; Medicine & Public Health; Mutagenesis; Mutagenesis, Site-Directed; Mutation; Mutation, Missense; Nephrology; Original Article; Pediatrics; Proteins; RNA, Messenger - analysis; Subcellular Fractions - metabolism; Transfection; Urinary Tract - abnormalities; Urogenital system; Urology; Ankara Turkey; Istanbul Turkey; Turkey; United States > US; Germany; Abnormal protein complex; CAKUT; Bone morphogenetic protein 4; Subcellular localization; Kidney development
• ISSN: 0931-041X; 1432-198X; 1432-198X
• DOI: 10.1007/s00467-009-1287-6

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.