Open research questions in Genetic and Kidney Cyst Diseases
28 unresolved questions extracted from the limitations and future-work sections of 74 Genetic and Kidney Cyst Diseases papers in our library. Each links back to the study that raised it.
What the literature leaves open
To date, pseudoexon activation has not been reported in IFT172, and most previously described pathogenic vari- ants are coding or canonical splice site changes. However, establishing the pathogenicity of such variants requires functional vali- dation, as in silico prediction alone is insufficient [19, 20].
A deep intronic IFT172 variant causing pseudoexon inclusion identified by whole-genome sequencing in nephronophthisis · 2026 · DOICyst-type composition varied widely across patients and in an orthologous mouse model (Pkd1RC/RC) in which the burden of AQP2-positive cysts correlated with responsiveness to tolvaptan.
The study found that small molecular chaperones 4-PBA/TUDCA and SERCA activator CDN1163 could only partially restore contractile deficiency, and further optimization of these therapeutic agents is needed for complete restoration of function.
Investigating PKD2 deficiency-associated cardiomyopathies using hESC-cardiomyocytes and bioengineered 3D ventricular cardiac tissue strips · 2026 · DOIThe appropriateness of hESC-CMs and hvCTS as disease models for cardiomyopathies in adult ADPKD patients needs further investigation, as these models better represent fetal and infant cardiac development rather than adult cardiac physiology.
Investigating PKD2 deficiency-associated cardiomyopathies using hESC-cardiomyocytes and bioengineered 3D ventricular cardiac tissue strips · 2026 · DOIWhile 3D hvCTS are more mature than 2D hESC-CMs, they still contain a mixture of cell types and lack in vivo chemokines/cytokines and interacting endothelial cells, which may elevate ER stress in the tissue construct.
Investigating PKD2 deficiency-associated cardiomyopathies using hESC-cardiomyocytes and bioengineered 3D ventricular cardiac tissue strips · 2026 · DOIhESC-CMs are relatively immature compared to native human adult cardiomyocytes, displaying smaller amplitude and slower kinetics in Ca2+ transients, lack of T-tubule structure, and more depolarized resting membrane potential than adult cardiomyocytes.
Investigating PKD2 deficiency-associated cardiomyopathies using hESC-cardiomyocytes and bioengineered 3D ventricular cardiac tissue strips · 2026 · DOIThe extent of mechanistic parallels between endosome-mediated GPCR retrieval in non-ciliary cells and GPCR exit from cilia remains uncharacterized. Future studies should systematically compare ubiquitin-dependent sorting mechanisms, vesicular trafficking pathways, and cargo recognition principles between these two distinct cellular compartments.
The multi-step ubiquitination pathway controlling ciliary GPCR exit requires identification of ciliary and ciliary-associated E3 ligases that coordinate this process. Current understanding does not specify which ubiquitination steps occur within the cilium versus the cytoplasm, necessitating localization and functional studies of these ligases.
While BBSome-mediated ubiquitinated protein exit is conserved evolutionarily (demonstrated in mouse retina and Chlamydomonas), it is unknown whether the ubiquitin ligases responsible are conserved across cilia types, whether they are relocated to the cilium, or whether they evolved as cilia-specific variants.
The mechanism controlling Smoothened-specific retention in cilia despite K63-ubiquitination needs clarification. Future work should determine whether K63-chain ubiquitin removal, conformational changes that prevent ubiquitination, or ciliary deubiquitinases that distinguish between active and inactive ubiquitinated GPCRs are responsible for Smo protection from BBSome-mediated exit.
The cellular fate of K63-tagged GPCRs after exiting the cilium into the cytoplasm remains unknown. Specifically, it is unclear whether exiting ciliary GPCRs reintegrate into a ciliary vesicular pool to support dynamic signaling control, or whether they are targeted for proteasomal degradation as part of downregulation, as occurs with non-ciliary GPCRs.
This is very substantial progress, but the pathogenesis of the renal disorder, the relationship of the gene abnormality to the extrarenal signs of the disorder, the possibility of locus heterogeneity within Alport syndrome, and the molecular genetics of the other inherited nephritides all remain to be elucidated.
Voclosporin (VCS), a CsA analog, is proposed to be less nephrotoxic, but mechanisms remain unclear.
Voclosporin Preserves Mitochondrial Function Compared With Cyclosporine A in Perfused Human Proximal Tubule Microphysiological Systems · 2026 · DOIPolycystins function as ion channel subunits in primary cilia but the mechanistic impact and cystogenic propensity of disease-associated variants remain poorly defined.
PKD2 structural destabilization drives primary cilia degeneration and ADPKD pathogenicity. · 2026 · DOIMyofibroblasts (MFs) often accumulate around cysts and promote fibrosis and cyst growth, but the cellular mechanisms enabling their pro-cystogenic activity remain unclear.
Myofibroblast- specific autophagy drives cyst growth in autosomal dominant polycystic kidney disease · 2026 · DOI
Most-cited papers in Genetic and Kidney Cyst Diseases
- An update on the use of tolvaptan for autosomal dominant polycystic kidney disease: consensus statement on behalf of the ERA Working Group on Inherited Kidney Disorders, the European Rare Kidney Disease Reference Network and Polycystic Kidney Disease International · KIDNEYS · 2022 · 4 citations
- Cilia Biology: You’re It! Tagging Proteins for Ciliary Removal · Current Biology · 2021 · 2 citations
- KDIGO 2025 Clinical Practice Guideline for ADPKD: a commentary on intracranial aneurysms and other vascular manifestations from the ERA Working Group Genes & Kidney · Nephrology Dialysis Transplantation · 2026 · 1 citations
- KDIGO 2025 Clinical Practice Guideline for the Evaluation, Management, and Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) · KIDNEYS · 2025 · 1 citations
- Investigating PKD2 deficiency-associated cardiomyopathies using hESC-cardiomyocytes and bioengineered 3D ventricular cardiac tissue strips · Cell Death and Disease · 2026 · 0 citations
- Bridging the gap: an emerging link between tubulinopathies and ciliopathies · npj Genomic Medicine · 2026 · 0 citations
- Aurora A kinase activation contributes to the fibrotic phenotype in systemic sclerosis through primary cilia shortening · Arthritis Research & Therapy · 2026 · 0 citations
- Identification of EVC variants and the preimplantation genetic testing in a Chinese family · Frontiers in Medicine · 2026 · 0 citations
- Modelling kidney cystogenesis using human kidney tubuloid cultures · BMC Molecular and Cell Biology · 2026 · 0 citations
- ASD mutations in the ciliary gene CEP41 impact development of projection neurons and interneurons in a human cortical organoid model · Molecular Psychiatry · 2026 · 0 citations
Most recent work
- KDIGO 2025 Clinical Practice Guideline for ADPKD: a commentary on intracranial aneurysms and other vascular manifestations from the ERA Working Group Genes & Kidney · Nephrology Dialysis Transplantation · 2026
- Investigating PKD2 deficiency-associated cardiomyopathies using hESC-cardiomyocytes and bioengineered 3D ventricular cardiac tissue strips · Cell Death and Disease · 2026
- Bridging the gap: an emerging link between tubulinopathies and ciliopathies · npj Genomic Medicine · 2026
- Aurora A kinase activation contributes to the fibrotic phenotype in systemic sclerosis through primary cilia shortening · Arthritis Research & Therapy · 2026
- Identification of EVC variants and the preimplantation genetic testing in a Chinese family · Frontiers in Medicine · 2026
- Modelling kidney cystogenesis using human kidney tubuloid cultures · BMC Molecular and Cell Biology · 2026
- ASD mutations in the ciliary gene CEP41 impact development of projection neurons and interneurons in a human cortical organoid model · Molecular Psychiatry · 2026
- Cyst-type epithelial heterogeneity shapes therapeutic responsiveness in ADPKD · bioRxiv · 2026
- Ciliogenesis associated kinase 1 accumulates in its inactive form during polycystic kidney disease progression · bioRxiv · 2026
- Fluid dynamic models in the kidney during health and disease · Journal of Nephrology · 2026
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