Oocyte Maturation Defect 6

A number sign (#) is used with this entry because of evidence that oocyte maturation defect-6 (OOMD6) is caused by homozygous mutation in the ZP2 gene (182888) on chromosome 16p12.

Description

Oocyte maturation defect-6 is characterized by primary infertility due to defective sperm-binding to an abnormally thin zona pellucida (ZP) in patient oocytes. Successful pregnancy may be achieved by intracytoplasmic sperm injection in these patients (Dai et al., 2019).

Clinical Features

Dai et al. (2019) reported 2 Chinese sisters, aged 28 (patient II-4) and 30 years (II-3), and an unrelated 32-year-old Chinese woman (II-1) with unexplained primary infertility. Patients II-4 and II-1 underwent in vitro fertilization (IVF) procedures, but none of their oocytes were fertilized 20 hours after insemination. Examination of patient oocytes after granulosa cell removal showed an abnormal zona pellucida, with a thinner matrix and an enlarged perivitelline space compared to normal oocytes. Transmission electron microscopy revealed a thin zona matrix with an irregular arrangement of filaments and large holes, and polscope imaging showed only a single layer of matrix, similar to but thinner than the inner layer of normal zonae. Analysis of sperm-ZP binding at 20 hours after IVF showed that sperm were loosely bound to the outer ZP surface and were relatively easily removed, in contrast to sperm tightly bound to normal oocytes, indicating defective sperm-binding to the thin ZP of patient oocytes as the cause of IVF failure. Patient II-4 underwent intracytoplasmic sperm injection, which resulted in a singleton pregnancy and live birth after 39 weeks' gestation.

Zhou et al. (2019) studied 2 Chinese sisters (family 5), aged 33 (patient II-3) and 34 years (patient II-2), with primary infertility. Both had normal ovarian reserves and regular menstrual cycles, and basal sex hormone levels and other infertility-related examinations did not reveal any abnormalities. However, in vitro fertilization (IVF) attempts in the sisters resulted in retrieval of few oocytes, most lacking a zona pellucida. In patient II-3, 2 mature oocytes with a thin ZP developed into poor-quality embryos with failed implantation, whereas other oocytes with thin ZP failed to develop into viable embryos. Her older sister had only 1 poor-quality embryo obtained after 4 IVF cycles; however, that embryo implanted and resulted in a successful pregnancy.

Molecular Genetics

In a 34-year-old Chinese woman with infertility due to very thin or absent zona pellucida of her oocytes, Liu et al. (2017) identified heterozygosity for a missense variant in the ZP2 gene (c.2092C-T, NM_003460.2) and a 1-bp insertion (c.1045_1046insT, NM_001110354.1) in the ZP3 gene (182889). Her father also carried both variants, and her mother was heterozygous for the ZP3 variant. Barbaux et al. (2017) suggested that because of sequence identity with the POM121/ZP3 fusion gene (POMZP3; 600587) and consequent technical difficulties in amplifying and sequencing the 3-prime end of the ZP3 gene, the additional T observed in heterozygous state reflects combined amplification of the ZP3 and POMZP3 genes; they noted that they had obtained the same results (the extra T) in 5 of 7 control individuals. However, Liu et al. (2017) stated that their sequencing methods using TA clones resolved that issue.

In 2 Chinese sisters (family 1, II-3 and II-4) with primary infertility due to a defective oocyte ZP, who were born of first-cousin parents, Dai et al. (2019) performed whole-exome sequencing and identified homozygosity for a splice site mutation in the ZP2 gene (182888.0001) that segregated with disease in the family. Screening for ZP2 mutations in 8 unrelated infertile women whose oocytes showed an abnormal ZP and who failed routine IVF identified 1 woman (family 2, II-1) who was homozygous for a 4-bp duplication (182888.0002). Her fertile brother was also homozygous for the duplication, indicating that loss of ZP2 does not affect male fertility. Neither mutation was found in 100 population-matched controls or in public variant databases.

In 2 Chinese sisters with primary infertility due to very thin or absent oocyte zona pellucida, who were negative for mutation in the ZP1 gene, Zhou et al. (2019) sequenced the ZP2 and ZP3 genes and identified homozygosity for a missense mutation in ZP2 (C372S; 182888.0003).