TY - JOUR
T1 - A familial study of azoospermic men identifies three novel causative mutations in three new human azoospermia genes
AU - Gershoni, Moran
AU - Hauser, Ron
AU - Yogev, Leah
AU - Lehavi, Ofer
AU - Azem, Foad
AU - Yavetz, Haim
AU - Pietrokovski, Shmuel
AU - Kleiman, Sandra E.
N1 - Publisher Copyright:
© American College of Medical Genetics and Genomics.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - Purpose:Up to 1% of all men experience azoospermia, a condition of complete absence of sperm in the semen. The mechanisms and genes involved in spermatogenesis are mainly studied in model organisms, and their relevance to humans is unclear because human genetic studies are very scarce. Our objective was to uncover novel human mutations and genes causing azoospermia due to testicular meiotic maturation arrest.Methods:Affected and unaffected siblings from three families were subjected to whole-exome or whole-genome sequencing, followed by comprehensive bioinformatics analyses to identify mutations suspected to cause azoospermia. These likely mutations were further screened in azoospermic and normozoospermic men and in men proven to be fertile, as well as in a reference database of local populations.Results:We identified three novel likely causative mutations of azoospermia in three genes: MEIOB, TEX14, and DNAH6. These genes are associated with different meiotic processes: meiotic crossovers, daughter cell abscission, and possibly rapid prophase movements.Conclusion:The genes and pathways we identified are fundamental for delineating common causes of azoospermia originating in mutations affecting diverse meiotic processes and have great potential for accelerating approaches to diagnose, treat, and prevent infertility.
AB - Purpose:Up to 1% of all men experience azoospermia, a condition of complete absence of sperm in the semen. The mechanisms and genes involved in spermatogenesis are mainly studied in model organisms, and their relevance to humans is unclear because human genetic studies are very scarce. Our objective was to uncover novel human mutations and genes causing azoospermia due to testicular meiotic maturation arrest.Methods:Affected and unaffected siblings from three families were subjected to whole-exome or whole-genome sequencing, followed by comprehensive bioinformatics analyses to identify mutations suspected to cause azoospermia. These likely mutations were further screened in azoospermic and normozoospermic men and in men proven to be fertile, as well as in a reference database of local populations.Results:We identified three novel likely causative mutations of azoospermia in three genes: MEIOB, TEX14, and DNAH6. These genes are associated with different meiotic processes: meiotic crossovers, daughter cell abscission, and possibly rapid prophase movements.Conclusion:The genes and pathways we identified are fundamental for delineating common causes of azoospermia originating in mutations affecting diverse meiotic processes and have great potential for accelerating approaches to diagnose, treat, and prevent infertility.
KW - azoospermia
KW - crossover
KW - meiosis
KW - rapid prophase movements
KW - whole-exome and whole-genome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85028947511&partnerID=8YFLogxK
U2 - 10.1038/gim.2016.225
DO - 10.1038/gim.2016.225
M3 - Article
C2 - 28206990
AN - SCOPUS:85028947511
SN - 1098-3600
VL - 19
SP - 998
EP - 1006
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 9
ER -