The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans.
FKBP6
LINE-1
azoospermia
genetics
male infertility
meiosis
oligozoospermia
piRNA-pathway
round spermatid arrest
spermatogenesis
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
06 10 2022
06 10 2022
Historique:
received:
15
05
2022
accepted:
01
09
2022
pubmed:
24
9
2022
medline:
12
10
2022
entrez:
23
9
2022
Statut:
ppublish
Résumé
Infertility affects around 7% of the male population and can be due to severe spermatogenic failure (SPGF), resulting in no or very few sperm in the ejaculate. We initially identified a homozygous frameshift variant in FKBP6 in a man with extreme oligozoospermia. Subsequently, we screened a total of 2,699 men with SPGF and detected rare bi-allelic loss-of-function variants in FKBP6 in five additional persons. All six individuals had no or extremely few sperm in the ejaculate, which were not suitable for medically assisted reproduction. Evaluation of testicular tissue revealed an arrest at the stage of round spermatids. Lack of FKBP6 expression in the testis was confirmed by RT-qPCR and immunofluorescence staining. In mice, Fkbp6 is essential for spermatogenesis and has been described as being involved in piRNA biogenesis and formation of the synaptonemal complex (SC). We did not detect FKBP6 as part of the SC in normal human spermatocytes, but small RNA sequencing revealed that loss of FKBP6 severely impacted piRNA levels, supporting a role for FKBP6 in piRNA biogenesis in humans. In contrast to findings in piRNA-pathway mouse models, we did not detect an increase in LINE-1 expression in men with pathogenic FKBP6 variants. Based on our findings, FKBP6 reaches a "strong" level of evidence for being associated with male infertility according to the ClinGen criteria, making it directly applicable for clinical diagnostics. This will improve patient care by providing a causal diagnosis and will help to predict chances for successful surgical sperm retrieval.
Identifiants
pubmed: 36150389
pii: S0002-9297(22)00405-0
doi: 10.1016/j.ajhg.2022.09.002
pmc: PMC9606565
pii:
doi:
Substances chimiques
FKBP6 protein, human
0
RNA, Small Interfering
0
Tacrolimus Binding Proteins
EC 5.2.1.-
FKBP6 protein, mouse
EC 5.2.1.8
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1850-1866Subventions
Organisme : Medical Research Council
ID : MC_UP_1605/2
Pays : United Kingdom
Organisme : NICHD NIH HHS
ID : R01 HD078641
Pays : United States
Organisme : Department of Health
Pays : United Kingdom
Organisme : NICHD NIH HHS
ID : P50 HD096723
Pays : United States
Organisme : Wellcome Trust
ID : 209451/Z/17/Z
Pays : United Kingdom
Informations de copyright
Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests C.N.J. has an Investigator-led grant from Logixx Pharma Ltd, UK.
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