Pkhd1l1, encoding Polycystic Kidney and Hepatic Disease 1-Like 1 protein, is a large transmembrane protein. It has diverse functions, being essential for maintaining normal physiological states in the nervous and auditory systems. In the CNS, it may regulate neuronal excitability, and in the cochlea, it is involved in maintaining the structure and function of sensory hair cell stereocilia bundles [1,2,3,4].

In mice, disruption of Pkhd1l1 in the dentate gyrus of the hippocampus leads to over-activation of the MAPK/ERK-Calpain pathway. This is accompanied by decreased cytoplasmic and membrane KCC2 levels, impairing the inhibitory function of GABA receptors and increasing seizure susceptibility [1]. In Pkhd1l1-deficient mice, starting from 6 weeks of age, there are missing stereocilia, disrupted bundle coherence, high-frequency hearing loss progressing to lower frequencies with age, and increased susceptibility to permanent hearing loss after moderate acoustic overexposure [2,3,4]. Zebrafish double mutants of its paralogous genes also show hearing loss from the larval stage, highlighting a conserved function in hearing [5].

In conclusion, Pkhd1l1 is crucial for maintaining neuronal excitability in the CNS and for durable hearing function by ensuring the integrity of stereocilia bundles. Mouse knockout models have been instrumental in revealing its role in epilepsy-related seizures and hearing-loss-associated pathologies, providing insights into potential therapeutic targets for PKD-related seizures and sensorineural hearing loss [1,2,3,5].

References:

1. Yu, Jiangning, Wang, Guoxiang, Chen, Zhiyun, Liu, Xu, Wang, Yun. . Deficit of PKHD1L1 in the dentate gyrus increases seizure susceptibility in mice. In Human molecular genetics, 32, 506-519. doi:10.1093/hmg/ddac220. https://pubmed.ncbi.nlm.nih.gov/36067019/

2. Strelkova, Olga S, Osgood, Richard T, Tian, Chunjie, Hathaway, Daniel M, Indzhykulian, Artur A. 2024. PKHD1L1 is required for stereocilia bundle maintenance, durable hearing function and resilience to noise exposure. In Communications biology, 7, 1423. doi:10.1038/s42003-024-07121-5. https://pubmed.ncbi.nlm.nih.gov/39482437/

3. Strelkova, Olga S, Osgood, Richard T, Tian, Chunjie J, Hathaway, Daniel M, Indzhykulian, Artur A. 2024. PKHD1L1 is required for stereocilia bundle maintenance, durable hearing function and resilience to noise exposure. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.02.29.582786. https://pubmed.ncbi.nlm.nih.gov/38496629/

4. Wu, Xudong, Ivanchenko, Maryna V, Al Jandal, Hoor, Indzhykulian, Artur A, Corey, David P. 2019. PKHD1L1 is a coat protein of hair-cell stereocilia and is required for normal hearing. In Nature communications, 10, 3801. doi:10.1038/s41467-019-11712-w. https://pubmed.ncbi.nlm.nih.gov/31444330/

5. Makrogkikas, Stylianos, Cheng, Ruey-Kuang, Lu, Hao, Roy, Sudipto. 2023. A conserved function of Pkhd1l1, a mammalian hair cell stereociliary coat protein, in regulating hearing in zebrafish. In Journal of neurogenetics, 37, 85-92. doi:10.1080/01677063.2023.2187792. https://pubmed.ncbi.nlm.nih.gov/36960824/