A Homozygous Loss-of-Function Mutation in MSH5 Abolishes MutSγ Axial Loading and Causes Meiotic Arrest in NOA-Affected Individuals

被引：7

作者：

Gong, Chenjia ^{[1
,2
,3
]}

Abbas, Tanveer ^{[1
,2
,3
]}

Muhammad, Zubair ^{[1
,2
,3
]}

Zhou, Jianteng ^{[1
,2
,3
]}

Khan, Ranjha ^{[1
,2
,3
]}

Ma, Hui ^{[1
,2
,3
]}

Zhang, Huan ^{[1
,2
,3
]}

Shi, Qinghua ^{[1
,2
,3
,4
]}

Shi, Baolu ^{[1
,2
,3
,4
]}

机构：

[1] Univ Sci & Technol China, Affiliated Hosp 1, Hefei 230001, Peoples R China

[2] Univ Sci & Technol China, CAS Key Lab Innate Immun & Chron Dis, Hefei 230027, Peoples R China

[3] Univ Sci & Technol China, Sch Basic Med Sci, Div Life Sci & Med, Hefei 230027, Peoples R China

[4] Univ Sci & Technol China, Biomed Sci & Hlth Lab Anhui Prov, Hefei 230027, Peoples R China

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2022年 / 23卷 / 12期

基金：

中国国家自然科学基金;

关键词：

male infertility; non-obstructive azoospermia; meiotic arrest; recombination; synapsis; MSH5; MutS gamma; DNA MISMATCH REPAIR; CHROMOSOME SYNAPSIS; SACCHAROMYCES-CEREVISIAE; RECOMBINATION; HOMOLOG; PROTEIN; MEIOSIS; DMC1; LOCALIZATION; AZOOSPERMIA;

D O I：

10.3390/ijms23126522

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Non-obstructive azoospermia (NOA), characterized by spermatogenesis failure and the absence of sperm in ejaculation, is the most severe form of male infertility. However, the etiology and pathology between meiosis-associated monogenic alterations and human NOA remain largely unknown. A homozygous MSH5 mutation (c.1126del) was identified from two idiopathic NOA patients in the consanguineous family. This mutation led to the degradation of MSH5 mRNA and abolished chromosome axial localization of MutS gamma in spermatocytes from the affected males. Chromosomal spreading analysis of the patient's meiotic prophase I revealed that the meiosis progression was arrested at a zygotene-like stage with extensive failure of homologous synapsis and DSB repair. Therefore, our study demonstrates that the MSH5 c.1126del could cause meiotic recombination failure and lead to human infertility, improving the genetic diagnosis of NOA clinically. Furthermore, the study of human spermatocytes elucidates the meiosis defects caused by MSH5 variant, and reveals a conserved and indispensable role of MutS gamma in human synapsis and meiotic recombination, which have not previously been well-described.

引用

页数：14