A recurrent ZP1 variant is responsible for oocyte maturation defect with degenerated oocytes in infertile females

Abstract

A female factor is present in approximately 70% of couple infertility, often due to ovulatory disorders. In oocyte maturation defect (OMD), affected patients have a primary infertility with normal menstrual cycles but produce no oocyte, degenerated (atretic) or abnormal oocytes blocked at different stages of maturation. Four genes have so far been associated with OMD: PATL2, TUBB8, WEE2, and ZP1. In our initial study, 6 out of 23 OMD subjects were shown to carry the same PATL2 homozygous loss of function variant and one patient had a TUBB8 truncating variant. Here, we included four additional OMD patients and reanalyzed all 27 subjects. In addition to the seven patients with a previously identified defect, five carried the same deleterious homozygous ZP1 variant (c.1097G>A; p.Arg366Gln). All the oocytes from ZP1-associated patients appeared shriveled and dark indicating that the abnormal ZP1 protein induced oocyte death and degeneration. Overall ZP1-associated patients had degenerated or absent oocytes contrary to PATL2-associated subjects who had immature oocytes blocked mainly at the germinal vesicle stage. In this cohort of North African OMD patients, whole exome sequencing permitted to diagnose 44% of the patients studied and to identify a new frequent ZP1 variant.

ZP1-Y262C mutation causes abnormal zona pellucida formation and female infertility in humans

“…However, various issues related to the ZP are commonly observed in clinical settings, including thinning, excessive thickness, dark coloration, appearance of separations, serrations, gel-like consistency, or complete absence of the ZP. Genetic mutations in the ZP proteins (ZP1-4) can lead to ZP thinning or loss, resulting in infertility in patients ( Mannikko et al, 2005 ; Dai et al, 2019 ; Yuan et al, 2019 ; Cao et al, 2020 ; Luo et al, 2020 ; Okutman et al, 2020 ; Wassarman and Litscher, 2021 ; Loeuillet et al, 2022 ; Shen et al, 2022 ; Pujalte et al, 2023 ).…”

“…Female mice with Zp1 gene deletion exhibit a reduced number of two-cell embryos compared to the normal control group, and the number of offspring born from Zp1 -deficient mice is significantly decreased, leading to decreased fertility ( Rankin et al, 1999 ). Some points mutations in the ZP1 protein have been identified to cause functional impairments of ZP1 ( Jovine et al, 2005 ; Litscher and Wassarman, 2020a ; Luo et al, 2020 ; Wassarman and Litscher, 2021 ; Wu et al, 2021 ; Loeuillet et al, 2022 ) ( Table 1 ). Mutations in the ZP1 gene are commonly observed as homozygous or compound heterozygous mutations, with some cases showing heterozygous mutations.…”

“…On the other hand, in the context of assisted reproductive treatments, the color, thickness, and refractive index of the zona pellucida (ZP) are often used as indicators of oocyte quality. However, the genetic factors underlying ZP defects remain unclear, and recent advancements in high-throughput sequencing, particularly whole-exome sequencing (WES), have made it possible to identify pathogenic gene mutation sites ( Dai et al, 2019 ; Yuan et al, 2019 ; Cao et al, 2020 ; Luo et al, 2020 ; Okutman et al, 2020 ; Loeuillet et al, 2022 ; Pujalte et al, 2023 ).…”

La zone pellucide

“…REVUES sont retrouvées dans ce gène. Un variant homozygote faux-sens (p.R366Q) a été décrit chez 5 des 27 patientes d'une cohorte nord-africaine présentant un défaut de maturation ovocytaire [29]. Les patientes infertiles porteuses de cette mutation présentent une altération de sécrétion de ZP1, ce qui provoque l'absence de réticulation des filaments [30].…”

High carrier frequency of pathogenic PATL2 gene mutations predicted in population: a bioinformatics-based approach

“…Infertility issues are faced by 15% of couples worldwide, and almost half are estimated to have a genetic background. At present, >200 casual genes have been identified for female infertility, and genes related to oocyte maturation defect (OOMD) such as ZP1 (OOMD1), TUBB8 (OOMD2), ZP3 (OOMD3), PATL2 (OOMD4), WEE2 (OOMD5), ZP2 (OOMD6), PANX1 (OOMD7), BTG4 (OOMD8), TRIP13 (OOMD9), REC114 (OOMD10), ASTL (OOMD11), FBXO43 (OOMD12) and TBPL2 have been discovered by high-throughput sequencing ( Chen et al, 2017 ; Sang et al, 2018 ; Wang et al, 2020 ; Zhang et al, 2020 ; Zheng et al, 2020 ; Cao et al, 2021 ; Sang et al, 2021 ; Yang et al, 2021 ; Capalbo et al, 2022 ; Loeuillet et al, 2022 ; Maddirevula et al, 2022 ). Topoisomerase II homologue 2 ( PATL2 ) is a major pathogenic gene that is associated with germinal vesicle (GV) arrest and oocyte cleavage defects.…”