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Truncating PICK1 Variant Identified in Azoospermia Affected Mitochondrial Dysfunction in Knockout Mice
Yao-Qiang Du1,2, Chong-Yi Shu3, Min Zheng3
1Laboratory Medicine Center, Department of Transfusion Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China.
Objective:
The protein interacting with C kinase 1 (PICK1) plays a critical role in vesicle trafficking, and its deficiency in sperm cells results in abnormal vesicle trafficking from Golgi to acrosome, which eventually disrupts acrosome formation and leads to male infertility.
Methods:
An azoospermia sample was filtered, and the laboratory detection and clinical phenotype indicated typical azoospermia in the patient. We sequenced all of the exons in the PICK1 gene and found that there was a novel homozygous variant in the PICK1 gene, c.364delA (p.Lys122SerfsX8), and this protein structure truncating variant seriously affected the biological function. Then we constructed a PICK1 knockout mouse model using clustered regularly interspaced short palindromic repeat cutting technology (CRISPRc).
Results:
The sperm from PICK1 knockout mice showed acrosome and nucleus abnormalities, as well as dysfunctional mitochondrial sheath formation. Both the total sperm and motility sperm counts were decreased in the PICK1 knockout mice compared to wild-type mice. Moreover, the mitochondrial dysfunction was verified in the mice. These defects in the male PICK1 knockout mice may have eventually led to complete infertility.
Conclusion:
The c.364delA novel variant in the PICK1 gene associated with clinical infertility, and pathogenic variants in the PICK1 may cause azoospermia or asthenospermia by impairing mitochondrial function in both mice and humans.
Insights
A novel variant in the PICK1 gene causes male infertility by disrupting sperm development and mitochondrial function. This PICK1 gene defect leads to azoospermia or asthenospermia in both mice and humans.
Area of Science:
- Reproductive biology
- Genetics
- Cell biology
Background:
- The protein interacting with C kinase 1 (PICK1) is essential for vesicle trafficking.
- PICK1 deficiency in sperm disrupts Golgi-to-acrosome vesicle transport, impairing acrosome formation and causing male infertility.
Purpose of the Study:
- To investigate the role of a novel homozygous variant (c.364delA) in the PICK1 gene in male infertility.
- To establish and analyze a PICK1 knockout mouse model to understand its impact on sperm function.
Main Methods:
- Sequencing of the PICK1 gene in an azoospermia patient identified a novel homozygous variant (c.364delA).
- A PICK1 knockout mouse model was generated using CRISPRc technology for functional analysis.
Main Results:
- PICK1 knockout mice exhibited sperm abnormalities, including acrosome and nucleus defects, and impaired mitochondrial sheath formation.
- Significantly reduced sperm counts and motility were observed in PICK1 knockout mice compared to wild-type.
- Mitochondrial dysfunction was confirmed in the sperm of knockout mice, correlating with infertility.
Conclusions:
- The novel c.364delA variant in the PICK1 gene is associated with clinical male infertility.
- Pathogenic variants in PICK1 can lead to azoospermia or asthenospermia by impairing mitochondrial function.
- These findings highlight PICK1's crucial role in human and murine male fertility.
