The genetic interactions of PKHD1 and ATMIN in autosomal recessive polycystic kidney disease (ARPKD)

The main gene associated with Autosomal Recessive Polycystic Kidney Disease (ARPKD) is PKHD1 which encodes a ciliary protein associated with planar cell polarity. In mice, mutations in the transcription factor Atmin can present with an ARPKD-like phenotype with kidney disease similar to an early manifestation of ARPKD. Like the mouse gene Pkhd1, mutations in Atmin are associated with altered WNT/PCP expression. Previous work has suggested that Atmin and Pkhd1 do not physically interact, but Atmin may modulate Pkhd1 expression. However, the mechanisms governing this relationship are unknown. ARPKD is a rare disorder typically associated with severe kidney and liver disease in children. The disease has considerable clinical and familial variability, but little is known regarding genotype-phenotype relationships. It has been proposed that genetic modifiers may influence disease severity. Next-generation sequencing (NGS) using ChIP-Seq and RNA-Seq techniques in mouse kidneys and intermedullary collecting duct (mIMCD3) cells identified new transcriptional targets of Atmin, which did not include Pkhd1 but included genes associated with cystic kidneys in animal models (Camk2g and G6pc). NGS in Atmin and Pkhd1 KDs identified a common transcriptional network between the two genes. Gene enrichment analysis suggests this common network is associated with immune system processes. Dysregulated genes associated with double KDs showed greater enrichment of processes associated with the actin cytoskeleton, cell cycle and energy metabolism. Loss of Atmin expression negatively impacts the ciliary localisation of Fibrocystin, suggesting that Atmin may be needed for the proper localisation of Fibrocystin to the cilium. NGS in ARPKD kidneys highlights mutations in ATMIN as a potential regulator of disease severity, associated with reduced ARPKD severity. Expression differences in WNT genes may be present between severe and moderate ARPKD and transcriptomic profiling identified candidate diagnostic markers in ARPKD which included MSC, FGA, WNT4, WNT9B and KIF26B. This work indicates that Atmin and Pkhd1 interact in a similar transcriptional network in mice. Atmin is not a transcription factor of Pkhd1 but may modulate its function by governing its ciliary localisation by a yet unknown mechanism. Additionally, ATMIN mutations may modulate ARPKD disease severity, and the amount of differential expression in WNT/PCP genes may be a marker of disease severity.

Name dc:type.qualificationname

PhD

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Wolverhampton

Year dc:date.issued

2023

Author dc:creator

• Richards, Taylor

Advisor dc:contributor.advisor

• Goggolidou, Paraskevi

• ARPKD
• autosomal recessive polycystic kidney disease
• Atmin
• ChIP-Seq
• next generation sequencing
• polycystic kidney disease
• PKD
• RNA-seq
• WNT
• WES
• PKHD1

Statement dc:rights

• Attribution-NonCommercial-NoDerivatives 4.0 International

Licence

• https://wlv.dspace7.openrepository.com/bitstreams/5a3e63fc-02bf-43b8-9eb5-9ad5645ca511/download