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TBC1D1 is a Rab GTPase-activating protein that regulates GLUT4 translocation and has been implicated in renal development. Congenital anomaly of kidney and urinary tract (CAKUT) encompasses a spectrum of malformations leading to pediatric chronic kidney disease and kidney replacement therapy.
Whole-exome sequencing in two patient–parent trios identified a heterozygous de novo frameshift variant in TBC1D1, and targeted follow-up in 100 additional CAKUT cases revealed three novel or rare inherited missense variants predicted to be pathogenic, totaling four unrelated probands (PMID:26572137). These findings support an autosomal dominant inheritance pattern.
The variant spectrum includes one truncating frameshift and three missense changes affecting Ser237 phosphorylation or protein stability. A representative variant, c.1069G>C (p.Glu357Gln), disrupts RabGAP activity and impairs GLUT4 translocation in vitro.
Functional studies demonstrate widespread Tbc1d1 expression in the developing murine urogenital tract, and Tbc1d1−/− mice exhibit mild CAKUT-like renal and ureteral anomalies with significantly reduced Glut4 levels in kidney tissue, recapitulating patient phenotypes and indicating a hypomorphic mechanism (PMID:26572137).
Collectively, heterozygous loss-of-function and hypomorphic TBC1D1 variants impair GLUT4-mediated glucose homeostasis during kidney development, contributing to CAKUT. While larger cohorts could augment segregation data, the current genetic and experimental concordance supports a Moderate clinical validity classification.
Key take-home: TBC1D1 hypomorphic variants represent an autosomal dominant, potentially actionable cause of CAKUT and should be included in diagnostic gene panels.
Gene–Disease AssociationModerateFour unrelated probands with heterozygous TBC1D1 variants (one de novo frameshift, three missense) and concordant functional evidence in murine models (PMID:26572137) Genetic EvidenceModerateOne de novo truncating variant and three missense hypomorphic variants identified in four CAKUT probands, consistent with autosomal dominant inheritance (PMID:26572137) Functional EvidenceModerateTbc1d1 knockout mice show CAKUT-like anomalies and reduced Glut4 in kidney; patient variants impair Ser237 phosphorylation and GLUT4 translocation (PMID:26572137) |