Functional analysis of BMP4 mutations identified in pediatric CAKUT patients
- 348 Downloads
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.
KeywordsKidney development CAKUT Bone morphogenetic protein 4 Abnormal protein complex Subcellular localization
The authors acknowledge the Nikon Imaging Center at the University of Heidelberg. Financial support for this study was obtained from the Thyssen Foundation (AZ-10.07.2.173), the Dietmar Hopp Foundation, and the European Commission (5th Framework Program, QLG1-CT-2002 00908).
- 2.Weber S, Taylor JC, Winyard P, Baker KF, Sullivan-Brown J, Schild R, Knüppel T, Zurowska AM, Caldas-Alfonso A, Litwin M, Emre S, Ghiggeri GM, Bakkaloglu A, Mehls O, Antignac C, Network E, Schaefer F, Burdine RD (2008) SIX2 and BMP4 mutations associate with anomalous kidney development. J Am Soc Nephrol 19:891–903CrossRefPubMedGoogle Scholar
- 22.Greenberg ME, Belasco JG (1993) Control of decay of labile protooncogene and cytokine mRNAs. In: Belasco J, Brawerman G (eds) Control of messenger RNA stability. Academic Press, New York, pp 199–215Google Scholar
- 27.Kostova Z, Wolf DH (2003) From whom the bell tolls: protein quality control of the endoplasmic reticulum and the ubiquitin-proteasome connection. EMBO J 22:2309–2317Google Scholar
- 30.Suzuki S, Marazita ML, Cooper ME, Miwa N, Hing A, Jugessur A, Natsume N, Shimozato K, Ohbayashi N, Suzuki Y, Niimi T, Minami K, Yamamoto M, Altannamar TJ, Erkhembaatar T, Furukawa H, Daack-Hirsch S, L’heureux J, Brandon CA, Weinberg SM, Neiswanger K, Deleyiannis FW, de Salamanca JE, Vieira AR, Lidral AC, Martin JF, Murray JC (2009) Mutation in BMP4 are associated with subepithelial, microform and overt cleft lip. Am J Hum Genet 84:406–411CrossRefPubMedGoogle Scholar
- 31.Bakrania P, Efthymiou M, Klein JC, Salt A, Bunyan DJ, Wyatt A, Ponting CP, Martin A, Williams S, Lindley V, Gilmore J, Restori J, Robson AG, Neveu MM, Holder GE, Collin JR, Robinson DO, Farndon P, Johansen-Berg H, Gerrelli D, Ragge NK (2008) Mutation in BMP4 cause eye, brain and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways. Am J Hum Genet 82:304–3192CrossRefPubMedGoogle Scholar