PIH1D2 Loss‐of‐Function Directs Ciliary and Cell Cycle Defects Resulting in Left Isomerism With or Without Biliary Atresia
14 affiliations
- 1The Genetics Institute and Genomics Center Tel Aviv Sourasky University Medical Center Tel Aviv Israel
- 2Gray Faculty of Medical and Health Sciences Tel Aviv University Tel Aviv Israel
- 3The Simon Winter Institute for Human Genetics Bnai Zion Medical Center Haifa Israel
- 4Ruth and Bruce Rappaport Faculty of Medicine Technion—Israel Institute of Technology Haifa Israel
- 5Pediatric Gastroenterology Unit Hillel Yaffe Medical Center Hadera Israel
- 6Pediatric Pulmonology, Children's Hospital University of Duisburg‐Essen Essen Germany
- 7Institute of Human Genetics Galilee Medical Center Nahariya Israel
- 8The Genetics Institute Rambam Health Care Campus Haifa Israel
- 9Clinical Genetics Austin Health Melbourne Australia
- 10Department of Pediatric Surgery, Ruth Rappaport Children's Hospital Rambam Health Care Campus Haifa Israel
- 11Neonatal Intensive Care Unit Hillel Yaffe Medical Center Hadera Israel
- 12Department of Human Genetics Hannover Medical School Hannover Germany
- 13Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) German Center for Lung Research (DZL) Hannover Germany
- 14Community Genetics, Public Health Services Ministry of Health Jerusalem Israel
Abstract
Background & Aims: Laterality disorders are rare congenital conditions caused by disruption of left–right embryonic patterning, often associated with ciliary dysfunction. Despite the identification of numerous causative genes, the molecular basis remains unresolved in many patients. We aimed to identify the genetic cause of left isomerism heterotaxy in two unrelated patients, and investigate the functional consequences of the implicated gene.
Methods: Genome sequencing was performed in both patients. Candidate variants were validated by RNA and protein analyses in patient‐derived fibroblasts. To study the functional consequences, we conducted RNA‐seq, cell cycle assays (flow cytometry, EdU incorporation, Ki‐67 staining), rescue experiments with the wild‐type gene, and primary ciliogenesis studies.
Results: Both patients harboured biallelic loss‐of‐function variants in PIH1D2, a gene not previously associated with human disease. Transcript analyses confirmed aberrant splicing, and immunofluorescence staining revealed loss of PIH1D2 expression in Patient 1's primary fibroblasts. RNA‐seq demonstrated dysregulation of pathways related to cell cycle regulation and developmental signalling. Patient fibroblasts showed impaired cell cycle re‐entry from G0 following serum starvation and reduced S‐phase progression. Wild type PIH1D2 overexpression partially rescued these defects. Furthermore, patient cells exhibited significantly reduced primary ciliogenesis compared to controls.
Conclusions: Our findings establish PIH1D2 as a novel disease gene for left isomerism heterotaxy, with biliary atresia observed in one of the patients. Loss of PIH1D2 impairs ciliogenesis and cell cycle progression, providing a mechanistic link between ciliary defects and abnormal left–right patterning. These results expand the spectrum of cilia‐related laterality disorders and identify PIH1D2 as a critical regulator of human development.
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BibTeX
@article{kurolap2026pih1d2,
title = {{PIH1D2 Loss‐of‐Function Directs Ciliary and Cell Cycle Defects Resulting in Left Isomerism With or Without Biliary Atresia}},
author = {Alina Kurolap and Chofit Chai Gadot and Adel Shalata and Orly Eshach Adiv and Yam Amir and Bar Levy Lando and Florian Stehling and Tova Hershkovitz and Khaled Osman and Clair Habib and Hila Mintz and Ran Steinberg and Amit Hochberg and Uri Hamiel and Adi Mory and Daphna Marom and Sandra von Hardenberg and Amihood Singer and Bernd Auber and Hagit Baris Feldman},
journal = {Liver International},
year = {2026},
month = oct,
doi = {10.1111/liv.70951},
url = {https://doi.org/10.1111/liv.70951},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - PIH1D2 Loss‐of‐Function Directs Ciliary and Cell Cycle Defects Resulting in Left Isomerism With or Without Biliary Atresia
AU - Alina Kurolap
AU - Chofit Chai Gadot
AU - Adel Shalata
AU - Orly Eshach Adiv
AU - Yam Amir
AU - Bar Levy Lando
AU - Florian Stehling
AU - Tova Hershkovitz
AU - Khaled Osman
AU - Clair Habib
AU - Hila Mintz
AU - Ran Steinberg
AU - Amit Hochberg
AU - Uri Hamiel
AU - Adi Mory
AU - Daphna Marom
AU - Sandra von Hardenberg
AU - Amihood Singer
AU - Bernd Auber
AU - Hagit Baris Feldman
PY - 2026
DA - 2026/10/27
JO - Liver International
DO - 10.1111/liv.70951
UR - https://doi.org/10.1111/liv.70951
AB - Background & Aims: Laterality disorders are rare congenital conditions caused by disruption of left–right embryonic patterning, often associated with ciliary dysfunction. Despite the identification of numerous causative genes, the molecular basis remains unresolved in many patients. We aimed to identify the genetic cause of left isomerism heterotaxy in two unrelated patients, and investigate the functional consequences of the implicated gene. Methods: Genome sequencing was performed in both patients. Candidate variants were validated by RNA and protein analyses in patient‐derived fibroblasts. To study the functional consequences, we conducted RNA‐seq, cell cycle assays (flow cytometry, EdU incorporation, Ki‐67 staining), rescue experiments with the wild‐type gene, and primary ciliogenesis studies. Results: Both patients harboured biallelic loss‐of‐function variants in PIH1D2, a gene not previously associated with human disease. Transcript analyses confirmed aberrant splicing, and immunofluorescence staining revealed loss of PIH1D2 expression in Patient 1's primary fibroblasts. RNA‐seq demonstrated dysregulation of pathways related to cell cycle regulation and developmental signalling. Patient fibroblasts showed impaired cell cycle re‐entry from G0 following serum starvation and reduced S‐phase progression. Wild type PIH1D2 overexpression partially rescued these defects. Furthermore, patient cells exhibited significantly reduced primary ciliogenesis compared to controls. Conclusions: Our findings establish PIH1D2 as a novel disease gene for left isomerism heterotaxy, with biliary atresia observed in one of the patients. Loss of PIH1D2 impairs ciliogenesis and cell cycle progression, providing a mechanistic link between ciliary defects and abnormal left–right patterning. These results expand the spectrum of cilia‐related laterality disorders and identify PIH1D2 as a critical regulator of human development.
SN - 1478-3223
SN - 1478-3231
ER -