PMID- 37234866
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240207
IS  - 1664-8021 (Print)
IS  - 1664-8021 (Electronic)
IS  - 1664-8021 (Linking)
VI  - 14
DP  - 2023
TI  - Genomic study of TEX15 variants: prevalence and allelic heterogeneity in men with 
      spermatogenic failure.
PG  - 1134849
LID - 10.3389/fgene.2023.1134849 [doi]
LID - 1134849
AB  - Introduction: Human spermatogenesis is a highly intricate process that requires 
      the input of thousands of testis-specific genes. Defects in any of them at any 
      stage of the process can have detrimental effects on sperm production and/or 
      viability. In particular, the function of many meiotic proteins encoded by germ 
      cell specific genes is critical for maturation of haploid spermatids and viable 
      spermatozoa, necessary for fertilization, and is also extremely sensitive to even 
      the slightest change in coding DNA. Methods: Here, using whole exome and genome 
      approaches, we identified and reported novel, clinically significant variants in 
      testis-expressed gene 15 (TEX15), in unrelated men with spermatogenic failure 
      (SPGF). Results: TEX15 mediates double strand break repair during meiosis. 
      Recessive loss-of-function (LOF) TEX15 mutations are associated with SPGF in 
      humans and knockout male mice are infertile. We expand earlier reports 
      documenting heterogeneous allelic pathogenic TEX15 variants that cause a range of 
      SPGF phenotypes from oligozoospermia (low sperm) to nonobstructive azoospermia 
      (no sperm) with meiotic arrest and report the prevalence of 0.6% of TEX15 
      variants in our patient cohort. Among identified possible LOF variants, one 
      homozygous missense substitution c.6835G>A (p.Ala2279Thr) co-segregated with 
      cryptozoospermia in a family with SPGF. Additionally, we observed numerous cases 
      of inferred in trans compound heterozygous variants in TEX15 among unrelated 
      individuals with varying degrees of SPGF. Variants included splice site, 
      insertions/deletions (indels), and missense substitutions, many of which resulted 
      in LOF effects (i.e., frameshift, premature stop, alternative splicing, or 
      potentially altered posttranslational modification sites). Conclusion: In 
      conclusion, we performed an extensive genomic study of familial and sporadic SPGF 
      and identified potentially damaging TEX15 variants in 7 of 1097 individuals of 
      our combined cohorts. We hypothesize that SPGF phenotype severity is dictated by 
      individual TEX15 variant's impact on structure and function. Resultant LOFs 
      likely have deleterious effects on crossover/recombination in meiosis. Our 
      findings support the notion of increased gene variant frequency in SPGF and its 
      genetic and allelic heterogeneity as it relates to complex disease such as male 
      infertility.
CI  - Copyright (c) 2023 Qureshi, Hardy, Pombar, Berman, Malcher, Gingrich, Hvasta, 
      Kuong, Munyoki, Hwang, Orwig, Ahmed, Olszewska, Kurpisz, Conrad, Jaseem Khan and 
      Yatsenko.
FAU - Qureshi, Sidra
AU  - Qureshi S
AD  - Department of Molecular Biology and Genetics, Institute of Basic Medical 
      Sciences, Khyber Medical University, Peshawar, Pakistan.
FAU - Hardy, Jimmaline J
AU  - Hardy JJ
AD  - Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Women's 
      Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, 
      United States.
FAU - Pombar, Christopher
AU  - Pombar C
AD  - Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Women's 
      Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, 
      United States.
FAU - Berman, Andrea J
AU  - Berman AJ
AD  - Department of Biological Sciences, Dietrich School of Arts and Sciences, 
      University of Pittsburgh, Pittsburgh, PA, United States.
FAU - Malcher, Agnieszka
AU  - Malcher A
AD  - Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Gingrich, Tara
AU  - Gingrich T
AD  - Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Women's 
      Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, 
      United States.
FAU - Hvasta, Rachel
AU  - Hvasta R
AD  - Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Women's 
      Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, 
      United States.
FAU - Kuong, Jannah
AU  - Kuong J
AD  - Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Women's 
      Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, 
      United States.
FAU - Munyoki, Sarah
AU  - Munyoki S
AD  - Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Women's 
      Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, 
      United States.
FAU - Hwang, Kathleen
AU  - Hwang K
AD  - Department of Urology, School of Medicine, University of Pittsburgh, Pittsburgh, 
      PA, United States.
FAU - Orwig, Kyle E
AU  - Orwig KE
AD  - Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Women's 
      Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, 
      United States.
FAU - Ahmed, Jawad
AU  - Ahmed J
AD  - Department of Molecular Biology and Genetics, Institute of Basic Medical 
      Sciences, Khyber Medical University, Peshawar, Pakistan.
FAU - Olszewska, Marta
AU  - Olszewska M
AD  - Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Kurpisz, Maciej
AU  - Kurpisz M
AD  - Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Conrad, Donald F
AU  - Conrad DF
AD  - Department of Genetics, Oregon National Primate Research Center, Oregon Health 
      and Science University, Beaverton, OR, United States.
FAU - Jaseem Khan, Muhammad
AU  - Jaseem Khan M
AD  - Department of Molecular Biology and Genetics, Institute of Basic Medical 
      Sciences, Khyber Medical University, Peshawar, Pakistan.
FAU - Yatsenko, Alexander N
AU  - Yatsenko AN
AD  - Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Women's 
      Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, 
      United States.
AD  - Department of Pathology, School of Medicine, University of Pittsburgh, 
      Pittsburgh, PA, United States.
AD  - Department of Genetics, School of Public Health, University of Pittsburgh, 
      Pittsburgh, PA, United States.
LA  - eng
GR  - P50 HD096723/HD/NICHD NIH HHS/United States
PT  - Journal Article
DEP - 20230510
PL  - Switzerland
TA  - Front Genet
JT  - Frontiers in genetics
JID - 101560621
PMC - PMC10206016
OTO - NOTNLM
OT  - TEX15
OT  - male infertility
OT  - next-generation sequencing
OT  - non-obstructive azoospermia (NOA)
OT  - oligozoospermia
COIS- 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.
EDAT- 2023/05/26 19:15
MHDA- 2023/05/26 19:16
PMCR- 2023/05/10
CRDT- 2023/05/26 12:18
PHST- 2023/01/03 00:00 [received]
PHST- 2023/04/12 00:00 [accepted]
PHST- 2023/05/26 19:16 [medline]
PHST- 2023/05/26 19:15 [pubmed]
PHST- 2023/05/26 12:18 [entrez]
PHST- 2023/05/10 00:00 [pmc-release]
AID - 1134849 [pii]
AID - 10.3389/fgene.2023.1134849 [doi]
PST - epublish
SO  - Front Genet. 2023 May 10;14:1134849. doi: 10.3389/fgene.2023.1134849. eCollection 
      2023.