Bartram, Malte P., Habbig, Sandra, Pahmeyer, Caroline, Hoehne, Martin, Weber, Lutz T., Thiele, Holger, Altmueller, Janine, Kottoor, Nina, Wenzel, Andrea, Krueger, Marcus, Schermer, Bernhard ORCID: 0000-0002-5194-9000, Benzing, Thomas, Rinschen, Markus M. and Beck, Bodo B. (2016). Three-layered proteomic characterization of a novel ACTN4 mutation unravels its pathogenic potential in FSGS. Hum. Mol. Genet., 25 (6). S. 1152 - 1165. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

Genetic diseases constitute the most important cause for end-stage renal disease in children and adolescents. Mutations in the ACTN4 gene, encoding the actin-binding protein alpha-actinin-4, are a rare cause of autosomal dominant familial focal segmental glomerulosclerosis (FSGS). Here, we report the identification of a novel, disease-causing ACTN4 mutation (p.G195D, de novo) in a sporadic case of childhood FSGS using next generation sequencing. Proteome analysis by quantitative mass spectrometry (MS) of patient-derived urinary epithelial cells indicated that ACTN4 levels were significantly decreased when compared with healthy controls. By resolving the peptide bearing the mutated residue, we could proof that the mutant protein is less abundant when compared with the wild-type protein. Further analyses revealed that the decreased stability of p.G195D is associated with increased ubiquitylation in the vicinity of the mutation site. We next defined the ACTN4 interactome, which was predominantly composed of cytoskeletal modulators and LIM domain-containing proteins. Interestingly, this entire group of proteins, including several highly specific ACTN4 interactors, was globally decreased in the patient-derived cells. Taken together, these data suggest a mechanistic link between ACTN4 instability and proteome perturbations of the ACTN4 interactome. Our findings advance the understanding of dominant effects exerted by ACTN4 mutations in FSGS. This study illustrates the potential of genomics and complementary, high-resolution proteomics analyses to study the pathogenicity of rare gene variants.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Bartram, Malte P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Habbig, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pahmeyer, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoehne, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, Lutz T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kottoor, NinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wenzel, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schermer, BernhardUNSPECIFIEDorcid.org/0000-0002-5194-9000UNSPECIFIED
Benzing, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rinschen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beck, Bodo B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-281410
DOI: 10.1093/hmg/ddv638
Journal or Publication Title: Hum. Mol. Genet.
Volume: 25
Number: 6
Page Range: S. 1152 - 1165
Date: 2016
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2083
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ACTIN-BINDING DOMAIN; PROTEIN STABILITY CHANGES; ALPHA-ACTININ; CRYSTAL-STRUCTURE; NEPHROTIC SYNDROME; GENOME BROWSER; CROSS-LINKING; LIM DOMAIN; ALPHA-ACTININ-4; DYNAMICSMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/28141

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