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)

Hum Genet. 2016 Jan;135(1):69-87. doi: 10.1007/s00439-015-1610-1. Epub 2015 Nov 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Animals
  • Child
  • Child, Preschool
  • Exome*
  • Female
  • GTPase-Activating Proteins / chemistry
  • GTPase-Activating Proteins / genetics*
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Infant
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Sequence Homology, Amino Acid
  • Urogenital Abnormalities / genetics*
  • Vesico-Ureteral Reflux / genetics*
  • Young Adult


  • GTPase-Activating Proteins
  • TBC1D1 protein, human

Supplementary concepts

  • Cakut