Oocyte Maturation Defect 3

A number sign (#) is used with this entry because of evidence that oocyte maturation defect-3 (OOMD3) is caused by heterozygous mutation in the ZP3 gene (182889) on chromosome 7q11.

Description

Oocyte maturation defect-3 is characterized by infertility, caused by absence of the zona pellucida that results in degeneration of oocytes and 'empty follicle syndrome' on in vitro fertilization procedures (Chen et al., 2017).

For a discussion of genetic heterogeneity of oocyte maturation defects, see OOMD1 (615774).

Clinical Features

Chen et al. (2017) studied 2 sisters from a 4-generation Chinese family segregating autosomal dominant female-limited infertility. The proband was a 28-year-old woman who had normal ovarian reserves and regular menstrual cycles, with normal sex hormone levels and no abnormalities on infertility-related assessments. Both sisters underwent multiple in vitro fertilization (IVF) attempts, during which egg retrieval yielded mostly empty cumulus-oocyte complexes; the few oocytes detected had degenerated and lacked zonae pellucidae. Histologic analysis of ovarian tissue from the proband showed absence of the zona pellucida as well as morphologic abnormalities of the oocyte in preantral follicles. Noting that these results indicated degeneration of the oocytes before ovulation, the authors concluded that complete collapse of the proband's oocytes explained the empty cumulus-oocyte complexes retrieved during in vitro fertilization procedures. In the family, 2 paternal aunts and 2 female cousins also had unexplained primary infertility.

Zhou et al. (2019) studied a 29-year-old infertile Chinese woman (family 6) who had normal ovarian reserves and regular menstrual cycles, and whose basal sex hormone levels and other infertility-related examinations did not reveal any abnormalities. However, IVF attempts retrieved only oocytes without a zona pellucida, including some cumulus-oocyte complexes with only small fragments of ooplasm.

Mapping

In a 4-generation Chinese family segregating autosomal dominant female-limited infertility, Chen et al. (2017) performed genomewide linkage analysis that yielded a maximum lod score of 2.35 on chromosome 7, with the common minimal region at 7p12.3-q21.13.

Molecular Genetics

In 4-generation Chinese family segregating autosomal dominant female-limited infertility mapping to chromosome 7p12.3-q21.13, Chen et al. (2017) performed whole-exome sequencing and identified a heterozygous missense mutation in the ZP3 gene (A134T; 182889.0001) that segregated fully with disease, with heterozygous male carriers being unaffected. Sanger sequencing of ZP3 in 16 members of a second, similarly affected Chinese family revealed cosegregation of the A134T mutation with female infertility in that family as well. Haplotype analysis indicated that the mutation arose independently in each family. Analysis of ZP3 in a cohort of 21 women who exhibited empty follicle syndrome during IVF attempts identified 2 unrelated patients who were heterozygous for the A134T variant. The mutation arose de novo in 1 of the sporadic patients; DNA was unavailable from the parents of the second sporadic patient.

In a 29-year-old Chinese woman (family 6) with infertility due to absence of oocyte zona pellucida, who was negative for mutation in the ZP1 gene (195000), Zhou et al. (2019) sequenced the ZP2 (182888) and ZP3 genes and identified heterozygosity for a missense mutation in ZP3 (R255G; 182889.0002).