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Novel Stag3 Variant Associated With Primary Ovarian Insufficiency and Non-Obstructive Azoospermia in an Iranian Consanguineous Family Publisher Pubmed



Akbari A1 ; Zoha Tabatabaei S2 ; Salehi N3 ; Padidar K1 ; Almadani N1 ; Ali Sadighi Gilani M4 ; Mashayekhi M5 ; Motevaseli E2 ; Totonchi M1
Authors
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Authors Affiliations
  1. 1. Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
  2. 2. Department of Molecular Medicine, School of Advanced Medical Technologies in Medicine, Tehran, University of Medical Sciences, Tehran, Iran
  3. 3. School of Biological Science, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
  4. 4. Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
  5. 5. Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

Source: Gene Published:2022


Abstract

Non-obstructive azoospermia (NOA) and primary ovarian insufficiency (POI) present the most severe forms of male and female infertility. In the last decade, the increasing use of whole exome sequencing (WES) in genomics studies of these conditions has led to the introduction of a number of novel genes and variants especially in meiotic genes with restricted expression to gonads. In this study, exome sequencing of a consanguineous Iranian family with one POI and two NOA cases in three siblings showed that all three patients were double homozygous for a novel in-frame deletion and a novel missense variant in STAG3 (NM_001282717.1:c.1942G > A: p.Ala648Thr; NM_001282717.1:c.1951_1953del: p. Leu652del). Both variants occur within a short proximity of each other affecting the relatively conserved armadillo-type fold superfamily feature. STAG3 is a specific meiotic cohesin complex component that interacts with the α-kleisin subunit through this feature. Protein homology modeling indicated that the in-frame deletion destabilizes kleisin biding by STAG3. Although the missense variant did not seem to affect the binding significantly, protein homology modeling suggests that it further destabilizes kleisin binding when in double homozygous state with the deletion. Our findings are in line with several other studies having associated deleterious variants affecting this region with male and female infertility in humans and mouse models. This is the first report associating an in-frame STAG3 variant with NOA and POI in a single family. Summary sentence: A patient with primary ovarian failure and her two brothers with non-obstructive azoospermia were double homozygous for a novel in-frame deletion and a novel missense variant in STAG3 that potentially disrupt the protein's meiotic functions. © 2022
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