PUBLICATION
Biallelic DNAH9 mutations are identified in Chinese patients with defective left-right patterning and cilia-related complex congenital heart disease
- Authors
- Chen, W., Zhang, Y., Shen, L., Zhu, J., Cai, K., Lu, Z., Zeng, W., Zhao, J., Zhou, X.
- ID
- ZDB-PUB-220121-11
- Date
- 2022
- Source
- Human genetics 141(8): 1339-1353 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Axonemal Dyneins*/genetics
- Body Patterning/genetics
- China
- Cilia/genetics
- Ciliary Motility Disorders*/genetics
- Heart Defects, Congenital/genetics
- Heterotaxy Syndrome*/genetics
- Humans
- Mice
- Mice, Inbred C57BL
- Mutation
- Situs Inversus*/genetics
- Zebrafish/genetics
- Zebrafish Proteins*/genetics
- PubMed
- 35050399 Full text @ Hum. Genet.
Citation
Chen, W., Zhang, Y., Shen, L., Zhu, J., Cai, K., Lu, Z., Zeng, W., Zhao, J., Zhou, X. (2022) Biallelic DNAH9 mutations are identified in Chinese patients with defective left-right patterning and cilia-related complex congenital heart disease. Human genetics. 141(8):1339-1353.
Abstract
Defective left-right (LR) pattering results in a spectrum of laterality disorders including situs inversus totalis (SIT) and heterotaxy syndrome (Htx). Approximately, 50% of patients with primary ciliary dyskinesia (PCD) displayed SIT. Recessive variants in DNAH9 have recently been implicated in patients with situs inversus. Here, we describe six unrelated family trios and 2 sporadic patients with laterality defects and complex congenital heart disease (CHD). Through whole exome sequencing (WES), we identified compound heterozygous mutations in DNAH9 in the affected individuals of these family trios. Ex vivo cDNA amplification revealed that DNAH9 mRNA expression was significantly downregulated in these patients carrying biallelic DNAH9 mutations, which cause a premature stop codon or exon skipping. Transmission electron microscopy (TEM) analysis identified ultrastructural defects of the outer dynein arms in these affected individuals. dnah9 knockdown in zebrafish lead to the disturbance of cardiac left-right patterning without affecting ciliogenesis in Kupffer's vesicle (KV). By generating a Dnah9 knockout (KO) C57BL/6n mouse model, we found that Dnah9 loss leads to compromised cardiac function. In this study, we identified recessive DNAH9 mutations in Chinese patients with cardiac abnormalities and defective LR pattering.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping