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DRC1 deficiency caused primary ciliary dyskinesia and MMAF in a Chinese patient

Abstract

Objective

Primary ciliary dyskinesia (PCD) is a heterogeneous disease characterized by the failure of mucociliary clearance. Dynein regulatory complex subunit 1 (DRC1) variants can cause PCD by disrupting the nexin link connecting the outer doublets. In this study, we aimed to investigate the clinical and functional impacts of DRC1 variants on respiratory cilia and sperm.

Methods

We identified and validated the DRC1 variant by using whole-exome and Sanger sequencing. High-speed video microscopy analysis (HSVA) was used to measure the nasal ciliary beating frequency and pattern in a patient and a healthy control. Hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM) were applied to analyze the morphological and ultrastructural sperm defects resulting from the DRC1 variant.

Results

NM_145038.5:c.1296 G>A, p.(Trp432*), a novel homozygous DRC1 nonsense variant, was identified in a patient from a consanguineous Chinese family. The patient exhibited bronchiectasis, chronic sinusitis, situs solitus, and male infertility. The markedly reduced nasal nitric oxide production rate (3.0 nL/min) was consistent with PCD diagnosis. HSVA showed reduced bending capacity and higher beating frequency of nasal cilia in the patient compared with those in healthy control. The diagnosis of multiple morphological abnormalities of the sperm flagella (MMAF) was confirmed through sperm HE staining and TEM analysis. Following the intracytoplasmic sperm injection treatment, the patient fathered a healthy daughter.

Conclusion

This report is the first to describe a novel DRC1 variant in a patient with PCD and MMAF, and in vitro fertilization was effective for treating infertility in this male patient. Our findings expand the genetic spectrum of PCD and MMAF, and provide a detailed clinical summary and functional analysis of patients with DRC1 variants.

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Fig. 1: Pedigree and clinical features of the patient.
Fig. 2: Variant analysis for the patient.
Fig. 3: Ciliary motility analysis, DRC1 protein structure, and the reported disease-associated variants.

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Data availability statement

The data presented in the study are deposited in the Genome Sequence Archive for Human (GSA-Human) repository, accession number HRA001117.

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Acknowledgements

We wish to thank the patient and medical staff of the department of Pulmonary and Critical Care Medicine for their help and collaboration, and we thank TopEdit (www.topeditsci.com) for English language editing of this paper.

Funding

This study was supported by the National Natural Science Foundation of China (81470202, 81770002 and 82070003 to HL, 81900002 to TG), Natural Science Foundation of Hunan Province, China (2020JJ5805 to TG, 2021JJ30943 to HL), the Science and Technology Program of Changsha, China (kq1901120 to HL), Xiangya Clinical Big Data System Construction Project in Pulmonary Inflammatory Disease of Central South University, and the National Key Clinical Specialty Construction Projects of China.

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Authors

Contributions

CL, DY, RW, SD, LW and TG performed the experiments, analyzed the data, and wrote the paper. TG and HL designed the study and performed the clinical assessment. All authors reviewed, edited, and approved the version to be submitted.

Corresponding authors

Correspondence to Ting Guo or Hong Luo.

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Ethics

The studies involving human participants were reviewed and approved by Review Board of the Second Xiangya Hospital of Central South University in China. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Lei, C., Yang, D., Wang, R. et al. DRC1 deficiency caused primary ciliary dyskinesia and MMAF in a Chinese patient. J Hum Genet 67, 197–201 (2022). https://doi.org/10.1038/s10038-021-00985-z

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