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)

Kosfeld A, Kreuzer M, Daniel C, Brand F, Schaefer AK, Chadt A, Weiss AC, Riehmer V, Jeanpierre C, Klintschar M, Braesen JH, Amann KU, Pape L, Kispert A, Al-Hasani H, Haffner D, Weber RG (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Human genetics Springer Verlag (Germany)

Book Volume: 135

Pages Range: 69-87

Journal Issue: 1

DOI: 10.1007/s00439-015-1610-1

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 with CRIS profile

Christoph Daniel Department of Nephropathology Kerstin Ute Amann Department of Nephropathology

Involved external institutions

Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) Heinrich-Heine-Universität Düsseldorf DE Germany (DE) Hôpital Necker-Enfants malades FR France (FR)

How to cite

APA:

Kosfeld, A., Kreuzer, M., Daniel, C., Brand, F., Schaefer, A.-K., Chadt, A.,... Weber, R.G. (2016). 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). Human genetics, 135(1), 69-87. https://doi.org/10.1007/s00439-015-1610-1

MLA:

Kosfeld, Anne, et al. "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)." Human genetics 135.1 (2016): 69-87.

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