Comprehensive Transcriptomic and Proteomic Profiling of CILD40 with Novel Compound Heterozygous Mutations of DNAH9.
4 affiliations
- 1Center for Clinical and Translational Science, School of Clinical Medicine, Beijing Tsinghua Changgung Hospital, Tsinghua Medicine, Tsinghua University, Beijing, 102218 China.
- 2School of Clinical Medicine, Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua Medicine, Tsinghua University, Beijing, 102218 China.
- 3Faculty of Environment and Life, Beijing University of Technology, Beijing, 100124 China.
- 4Precision Hepatobiliary Center, School of Clinical Medicine, Beijing Tsinghua Changgung Hospital, Tsinghua Medicine, Tsinghua University, Beijing, 102218 China.
Abstract
Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by impaired ciliary motility that leads to respiratory symptoms, laterality defects, and other systemic abnormalities. Despite significant advancements in genetic research identifying over 50 causative genes and enabling genetic diagnosis in approximately 90% of cases, comprehensive phenotypic characterization remains underexplored. We investigated two respiratory asymptomatic individuals (sisters) who exhibited laterality defects in a three-generation family, both of whom harbored novel compound heterozygous mutations (NM_001372.4:c.308del and NM_001372.4:c.11845G > A) in the dynein axonemal heavy chain 9 (DNAH9) gene associated with primary ciliary dyskinesia-40 (CILD40). Structural modeling and western blotting analysis of HEK-293T cells demonstrated that the frameshift mutation abolished DNAH9 stability, whereas the missense mutation disrupted hydrogen bonds, leading to partial protein destabilization. Peripheral blood RNA sequencing revealed extensive dysregulation of axonemal and intraflagellar transport genes, implicating defects in microtubule-based motility in the two affected siblings with biallelic DNAH9 mutations, but not in their heterozygous family members or one unaffected relative. Plasma proteomic analysis of patients with CILD40 identified significant enrichment of pathways related to platelet activation, complement and coagulation cascades. Further comparative analysis with a patient with PCD caused by a CCDC40 mutation (CILD15 subtype) revealed differential signatures in CILD40, highlighting the potential of plasma proteomics for understanding distinct pathogenic mechanisms across PCD subtypes. These findings underscore the critical role of DNAH9 compound heterozygous mutations in CILD40 and provide new insights into the genetic, transcriptional, and proteomic phenotypic heterogeneity of PCD. The online version contains supplementary material available at https://doi.org/10.1007/s43657-026-00318-0.
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BibTeX
@article{kong2026comprehensive,
title = {{Comprehensive Transcriptomic and Proteomic Profiling of CILD40 with Novel Compound Heterozygous Mutations of DNAH9.}},
author = {Siming Kong and Mingshuo Wang and Xuedong Wang and Yakun Liu and Pengfei Wang and Wenyan Song and Ziye Chen and Yuxin Su and Canhong Xiang and Yunfang Wang and Hui Bai},
journal = {Phenomics (Cham, Switzerland)},
year = {2026},
month = jul,
doi = {10.1007/s43657-026-00318-0},
url = {https://europepmc.org/article/MED/42999755},
note = {CC BY},
}
RIS
TY - JOUR
TI - Comprehensive Transcriptomic and Proteomic Profiling of CILD40 with Novel Compound Heterozygous Mutations of DNAH9.
AU - Siming Kong
AU - Mingshuo Wang
AU - Xuedong Wang
AU - Yakun Liu
AU - Pengfei Wang
AU - Wenyan Song
AU - Ziye Chen
AU - Yuxin Su
AU - Canhong Xiang
AU - Yunfang Wang
AU - Hui Bai
PY - 2026
DA - 2026/07/28
JO - Phenomics (Cham, Switzerland)
DO - 10.1007/s43657-026-00318-0
UR - https://europepmc.org/article/MED/42999755
AB - Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by impaired ciliary motility that leads to respiratory symptoms, laterality defects, and other systemic abnormalities. Despite significant advancements in genetic research identifying over 50 causative genes and enabling genetic diagnosis in approximately 90% of cases, comprehensive phenotypic characterization remains underexplored. We investigated two respiratory asymptomatic individuals (sisters) who exhibited laterality defects in a three-generation family, both of whom harbored novel compound heterozygous mutations (NM_001372.4:c.308del and NM_001372.4:c.11845G > A) in the dynein axonemal heavy chain 9 (DNAH9) gene associated with primary ciliary dyskinesia-40 (CILD40). Structural modeling and western blotting analysis of HEK-293T cells demonstrated that the frameshift mutation abolished DNAH9 stability, whereas the missense mutation disrupted hydrogen bonds, leading to partial protein destabilization. Peripheral blood RNA sequencing revealed extensive dysregulation of axonemal and intraflagellar transport genes, implicating defects in microtubule-based motility in the two affected siblings with biallelic DNAH9 mutations, but not in their heterozygous family members or one unaffected relative. Plasma proteomic analysis of patients with CILD40 identified significant enrichment of pathways related to platelet activation, complement and coagulation cascades. Further comparative analysis with a patient with PCD caused by a CCDC40 mutation (CILD15 subtype) revealed differential signatures in CILD40, highlighting the potential of plasma proteomics for understanding distinct pathogenic mechanisms across PCD subtypes. These findings underscore the critical role of DNAH9 compound heterozygous mutations in CILD40 and provide new insights into the genetic, transcriptional, and proteomic phenotypic heterogeneity of PCD. The online version contains supplementary material available at https://doi.org/10.1007/s43657-026-00318-0.
SN - 2730-583X
SN - 2730-5848
ER -