title: Functional analysis of BMP4 mutations identified in pediatric CAKUT patients.
abstract: 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.
authors.affiliation: Pediatric Nephrology, University of Heidelberg Children's Hospital, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Tabatabaeifar
authors.forename: Karl-Peter
authors.initials: KP
authors.lastname: Schlingmann
authors.forename: Mieczyslaw
authors.initials: M
authors.lastname: Litwin
authors.forename: Sevinc
authors.initials: S
authors.lastname: Emre
authors.forename: Aysin
authors.initials: A
authors.lastname: Bakkaloglu
authors.forename: Otto
authors.initials: O
authors.lastname: Mehls
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.forename: Franz
authors.initials: F
authors.lastname: Schaefer
authors.forename: Stefanie
authors.initials: S
authors.lastname: Weber
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000032:analysis* / Q000235:genetics* / Q000378:metabolism; D019556:COS Cells; D002460:Cell Line; D002648:Child; D002522:Chlorocebus aethiops; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D000939:Epitopes; D019084:Fluorescent Antibody Technique, Indirect; D005822:Genetic Vectors; D006801:Humans; D007668:Kidney / Q000002:abnormalities / Q000166:cytology; D008247:Lysosomes / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D012333:RNA, Messenger / Q000032:analysis; D013347:Subcellular Fractions / Q000378:metabolism; D014162:Transfection; D014551:Urinary Tract / Q000002:abnormalities
chemical_list: D055415:Bone Morphogenetic Protein 4; D000939:Epitopes; D012333:RNA, Messenger
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