Abstract: PO1346
Pleiotropy of Congenital Anomalies of Kidney and Urinary Tract (CAKUT) Phenotypes in Human 16p11.2 Microdeletion Syndrome Is Recapitulated in Mouse Models of Tbx6 Deletion
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - II
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Whittemore, Gregory Baker, Columbia University Irving Medical Center, New York, New York, United States
- Martino, Jeremiah, Columbia University Irving Medical Center, New York, New York, United States
- Lim, Tze Yin, Columbia University Irving Medical Center, New York, New York, United States
- Gupta, Yask, Columbia University Irving Medical Center, New York, New York, United States
- Mendelsohn, Cathy L., Columbia University Irving Medical Center, New York, New York, United States
- Sanna-Cherchi, Simone, Columbia University Irving Medical Center, New York, New York, United States
Background
We showed that 16p11.2 microdeletions are a major contributor to congenital anomalies of the kidney and urinary tract (CAKUT), and identified TBX6 as the most likely culprit. It remains elusive what are the mechanisms by which gene dosage reduction causes CAKUT and what are the TBX6 downstream signaling pathways and targets.
Methods
We studied a Tbx6 allelic series for gene dosage using two independent alleles: a null allele and a hypomorph allele. We conducted detailed phenotypic analysis of these models across early and late development. We generated gene expression data from E9.5 tailbud mesenchyme and conducted in silico binding site analyses.
Results
Phenotypic analysis showed recapitulation of the whole CAKUT spectrum observed in 16p11.2 patients (renal agenesis and hypodysplasia, hydronephrosis, and duplications of the collecting system) but also profound lower urinary tract defects (rectovesical fistula, persistent cloaca, defects of nephric duct insertion into the urogenital sinus, urethral malformations and failed insertion of the Müllerian ducts). These defects implicate an early effect of Tbx6 in urinary tract development. Tbx6 insufficiency also promoted the occurrence of ectopic neural tubes that impaired the reciprocal interaction between the ureteric bud and metanephric mesenchyme, providing additional mechanisms linking Tbx6 to CAKUT and its pleiotropy. Differential gene expression analysis coupled with supervised and unsupervised geneset enrichment identified somite development and Notch signaling. Binding site and motif enrichment analyses recovered known and novel targets in the Tbx6 interactome including Aldh1a2, Eya1, Fgfr2, Lfng, and Reln.
Conclusion
Phenotypic investigation coupled with gene expression and binding site analyses provides support for causality for TBX6 and CAKUT as well as its pleiotropy; provides a mechanistic reason for causation; and identifies pathways and targets regulated by Tbx6. The involvement of Notch signaling is interesting as mutations in NOTCH2 cause Alagille syndrome, characterized by CAKUT and skeletal defects observed both in our Tbx6 mouse models and in patients that carry the 16p11.2 microdeletion. These data implicate loss of TBX6-mediated regulation of Notch as critical to the development of CAKUT and spine defects.
Funding
- NIDDK Support