title: Whole-exome sequencing identifies mutations of TBC1D1 encoding a Rab-GTPase-activating protein in patients with congenital anomalies of the kidneys and urinary tract (CAKUT).
abstract: Congenital anomalies of the kidneys and urinary tract (CAKUT) are genetically highly heterogeneous leaving most cases unclear after mutational analysis of the around 30 causative genes known so far. Assuming that phenotypes frequently showing dominant inheritance, such as CAKUT, can be caused by de novo mutations, de novo analysis of whole-exome sequencing data was done on two patient-parent-trios to identify novel CAKUT genes. In one case, we detected a heterozygous de novo frameshift variant in TBC1D1 encoding a Rab-GTPase-activating protein regulating glucose transporter GLUT4 translocation. Sequence analysis of 100 further CAKUT cases yielded three novel or rare inherited heterozygous TBC1D1 missense variants predicted to be pathogenic. TBC1D1 mutations affected Ser237-phosphorylation or protein stability and thereby act as hypomorphs. Tbc1d1 showed widespread expression in the developing murine urogenital system. A mild CAKUT spectrum phenotype, including anomalies observed in patients carrying TBC1D1 mutations, was found in kidneys of some Tbc1d1 (-/-) mice. Significantly reduced Glut4 levels were detected in kidneys of Tbc1d1 (-/-) mice and the dysplastic kidney of a TBC1D1 mutation carrier versus controls. TBC1D1 and SLC2A4 encoding GLUT4 were highly expressed in human fetal kidney. The patient with the truncating TBC1D1 mutation showed evidence for insulin resistance. These data demonstrate heterozygous deactivating TBC1D1 mutations in CAKUT patients with a similar renal and ureteral phenotype, and provide evidence that TBC1D1 mutations may contribute to CAKUT pathogenesis, possibly via a role in glucose homeostasis.
authors.affiliation: Department of Human Genetics, OE 6300, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Kosfeld
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Kreuzer
authors.affiliation: Department of Nephropathology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Daniel
authors.affiliation: Department of Human Genetics, OE 6300, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Brand
authors.affiliation: Institute of Molecular Biology, Hannover Medical School, Hannover, Germany.
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Schäfer
authors.affiliation: German Diabetes Center, Leibniz Center for Diabetes Research at the Heinrich-Heine-University, Düsseldorf, Germany.|German Center for Diabetes Research (DZD), Düsseldorf, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Chadt
authors.affiliation: Institute of Molecular Biology, Hannover Medical School, Hannover, Germany.
authors.forename: Anna-Carina
authors.initials: AC
authors.lastname: Weiss
authors.affiliation: Department of Human Genetics, OE 6300, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Riehmer
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR1163, Hôpital Necker-Enfants Malades, 75015, Paris, France.|Institut Imagine, Université Paris Descartes - Sorbonne Paris Cité, 75015, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Jeanpierre
authors.affiliation: Department of Legal Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Klintschar
authors.affiliation: Department of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Jan Hinrich
authors.initials: JH
authors.lastname: Bräsen
authors.affiliation: Department of Nephropathology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Pape
authors.affiliation: Institute of Molecular Biology, Hannover Medical School, Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
authors.affiliation: German Diabetes Center, Leibniz Center for Diabetes Research at the Heinrich-Heine-University, Düsseldorf, Germany.|German Center for Diabetes Research (DZD), Düsseldorf, Germany.
authors.forename: Hadi
authors.initials: H
authors.lastname: Al-Hasani
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Haffner
authors.affiliation: Department of Human Genetics, OE 6300, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. weber.ruthild@mh-hannover.de.
authors.forename: Ruthild G
authors.initials: RG
authors.lastname: Weber
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005260:Female; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D014564:Urogenital Abnormalities / Q000235:genetics*; D014718:Vesico-Ureteral Reflux / Q000235:genetics*; D055815:Young Adult
chemical_list: D020690:GTPase-Activating Proteins; C526441:TBC1D1 protein, human