Homozygous Splice Site Mutation in ZP1 Causes Familial Oocyte Maturation Defect

Abstract

In vitro fertilization (IVF) involves controlled ovarian hyperstimulation using hormones to produce large numbers of oocytes. The success of IVF is tightly linked to the availability of mature oocytes. In most cases, about 70% to 80% of the oocytes are mature at the time of retrieval, however, in rare instances, all of them may be immature, implying that they were not able to reach the metaphase II (MII) stage. The failure to obtain any mature oocytes, despite a well conducted ovarian stimulation in repeated cycles is a very rare cause of primary female infertility, for which the underlying suspected genetic factors are still largely unknown. In this study, we present the whole exome sequencing analysis of a consanguineous Turkish family comprising three sisters with a recurrent oocyte maturation defect. Analysis of the data reveals a homozygous splice site mutation (c.1775-3C>A) in the zona pellucida glycoprotein 1 (ZP1) gene. Minigene experiments show that the mutation causes the retention of the intron 11 sequence between exon 11 and exon 12, resulting in a frameshift and the likely production of a truncated protein.

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

“…Without strong functional data, it is always difficult to formally conclude that a missense variant is deleterious. Here, we have three strong arguments that permit to conclude without any doubt that the identified variant is responsible for the patient's infertility: (i) several publications have linked ZP1 defects with OMD and several missense variants were postulated to be deleterious 21 (Table 2); (ii) the identified variant is predicted by 20 out of 25 prediction softwares to be deleterious and (iii) this very rare variant is found in five affected subjects and the difference in the variant frequency between the patients' group and a control population is most highly significant (p. value = 2EÀ31). As all patients had the same mutation and all came from the same geographical region, we can expect them to have a common ancestor.…”

“…Numerous ZP mutations have been identified in infertile women with diverse types of infertilities such as PCOS (ZP4, 28 ), endometriosis ( ZP4 , 29 ), unexplained IVF attempts failures ( ZP1 30–32 ; ZP2 31,33 ; ZP3 32,34 ), OMD ( ZP1 21 ) and mainly with the Empty Follicle Syndrom (EFS) pathology ( ZP1 29,33,35–39 ; ZP2 29,38 and ZP3 29,40,41 ). Interestingly, the ZP1 gene is the most mutated ZP gene and an overview of the 27 ZP1 mutations according to the patients' clinical manifestations and to their position on the gene sequence and on the protein is shown in Table 2 and Figure 2.…”

“…EFS has also been related to mutations in the LH/choriogonadotropin receptor ( LHCGR ) gene 43,44 and is characterized by the inability of the operator to find any oocyte after follicular aspiration after hormonal stimulation with apparently normal follicular growth and steroidogenesis (for review see, 45 ). Some rare variants were also reported to be associated with zona free oocytes 29,30,32,38,46 and OMD 21 …”

“…27 Numerous ZP mutations have been identified in infertile women with diverse types of infertilities such as PCOS (ZP4, 28 ), endometriosis (ZP4, 29 ), unexplained IVF attempts failures (ZP1 [30][31][32] ; ZP2 31,33 ; Note: The patients P1, P2, and P3 correspond to the newly recruited OMD women, P4 and P5 correspond to patients P14 and P15 patients already described in our previous study. 5 T A B L E 2 ZP1 mutations described in the literature and the associated oocytes phenotypes ZP3 32,34 ), OMD (ZP1 21 ) and mainly with the Empty Follicle Syndrom (EFS) pathology (ZP1 29,33,[35][36][37][38][39] ; ZP2 29,38 and ZP3 29,40,41 ). Interestingly, the ZP1 gene is the most mutated ZP gene and an overview of the 27 ZP1 mutations according to the patients' clinical manifestations and to their position on the gene sequence and on the protein is shown in Table 2 and Figure 2.…”

Genes involved in recurrent oocyte maturation arrest: What do we know?

“…The abnormal ZP morphology observed in oocytes has been reported by several investigators. Notably, a recent report by Okutman et al (2) reported a homozygous splice site mutation (c.1775-3C>A) in the ZP1 gene associated with familial oocyte maturation arrest.…”