Oocyte Maturation Defect 2

A number sign (#) is used with this entry because of evidence that oocyte maturation defect-2 (OOMD2) is caused by heterozygous or homozygous mutation in the TUBB8 gene (616768) on chromosome 10p15.

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

Clinical Features

Feng et al. (2016) studied a Chinese family in which 5 women over 3 generations were infertile. The spouses of the affected women had normal sperm counts, with normal sperm morphologic features and motility. In vitro fertilization (IVF) attempts resulted in oocytes that were in metaphase I (MI) and failed to mature even after extended culture in vitro; none had a visible spindle on polarization microscopy. A morphologically abnormal oocyte that was observed failed to become fertilized. Feng et al. (2016) also studied infertile women from 6 additional Chinese families, each of whom had undergone 2 to 5 failed IVF or intracytoplasmic sperm injection attempts. Almost all oocytes harvested during those attempts were arrested at MI, and none had a visible spindle. Immunostaining of MI oocytes from 5 of these families revealed either an abnormal spindle or no detectable spindle.

Feng et al. (2016) studied 10 women from 9 families with primary infertility whose husbands had normal sperm counts, morphology, and motility. Each patient had undergone 2 to 7 failed in vitro fertilization attempts. In 4 patients, there were no morphologically identifiable metaphase II (MII) oocytes; in 4 others, some MII oocytes were present with an extruding first polar body, and the relative proportion of MII oocytes differed among those patients. Immunostaining of patient oocytes showed either no detectable spindle or an aberrant or disorganized spindle. Oocytes that were able to be fertilized showed no cleavage or underwent early embryonic arrest.

Molecular Genetics

In a 3-generation Chinese family segregating autosomal dominant primary infertility due to oocyte meiotic arrest, Feng et al. (2016) performed whole-exome sequencing and identified a heterozygous missense mutation in the TUBB8 gene (V229A; 616768.0001) that segregated with female infertility and was characterized by paternal transmission. Analysis of TUBB8 in patients from 23 families with metaphase I oocyte maturation arrest identified 7 patients from 6 families with heterozygous missense mutations in TUBB8 (see, e.g., 616768.0002 and 616768.0003), all of which were paternally inherited or occurred de novo. Functional analysis demonstrated that the mutations have dominant-negative effects that disrupt microtubule behavior and oocyte meiotic spindle assembly and maturation.

In 10 infertile Chinese women from 9 families, Feng et al. (2016) sequenced the TUBB8 gene and identified heterozygosity for missense mutations in 7 of the women (see, e.g., 616768.0004 and 616768.0005) as well as homozygosity for 2 null mutations in 3 women: a 21-bp deletion in 2 sisters (616768.0006) and a 1-bp insertion in 1 woman (616768.0007). The authors designated 3 classes of oocytes harboring TUBB8 mutations, including MI oocytes with an impaired spindle, and morphologic MII oocytes that either lack an identifiable spindle or contain an impaired spindle, in heterozygotes; and dysfunctional MI oocytes with a visible but morphologically defective spindle in homozygotes. Feng et al. (2016) stated that, together with their previously published work (Feng et al., 2016), they had identified TUBB8 mutations in 16 (36.3%) of 43 infertile women with MI oocyte arrest. The authors noted that heterozygous TUBB8 missense mutations appeared to exert a dominant-negative effect on microtubule behavior, whereas the homozygous mutations were functionally null.