Rare homozygous mutation in TUBB8 associated with oocyte maturation defect-2 in a consanguineous mating family

Abstract

Purpose: Variations in many genes may lead to the occurrence of oocyte maturation defects. To investigate the genetic basis of oocyte maturation defects, we performed clinical and genetic analysis of a pedigree. Methods: The proband with oocyte maturation defect-2 receiving ovulation induction therapy and her parents were selected for clinical detection, whole exome sequencing and Sanger sequencing. One unrelated healthy woman received ovulation induction therapy as control. Mutations were assessed after frequency screening of public exome databases. Then homozygous variants shared by the proband and her parents were selected. Results: Arrest of oocytes maturation was observed. A new missense mutation in TUBB8 (TUBB8: NM_177,987: exon 2: c. C161T: p. A54V) was identified, which was shown to be rare compared with public databases. The variant was highly conserved among primates, and was suggested to be deleterious by online software prediction. Conclusions: The homozygote of this variant (TUBB8: NM_ 177,987: exon 2:c.C161T: p.A54V) might affect spindle assembly, cause arrest of oocyte maturation and lead to oocyte maturation defect-2.

Mutation analysis of the TUBB8 gene in primary infertile women with oocyte maturation arrest

“…According to the existing data, the variants of the TUBB8 gene account for 31.96% of all participants (109/341). A few recurrent mutations were found in these studies, including c.10A > C, c.292G > A, c.527C > T, and c.763G > A, suggesting that these TUBB8 mutations have a higher incidence in patients with oocyte maturation disorders [ 15 – 17 , 22 , 26 – 28 ]. TUBB8 mutations have been linked to phenotypic variability, according to recent research.…”

“…Almost all previous research has shown that heterozygous TUBB8 missense mutations cause oocyte maturation arrest via dominant-negative effects. However, in a consanguineous mating family where the proband underwent primary infertility, a novel TUBB8 variant was discovered [ 26 ]. The patient with homozygous p.A54V TUBB8 was infertile, but her parents were not affected by the heterozygous p.A54V missense mutations.…”

The Recurrent Mutation in PATL2 Inhibits Its Degradation Thus Causing Female Infertility Characterized by Oocyte Maturation Defect Through Regulation of the Mos-MAPK Pathway

“…TUBB8 mutations and TRIP13 mutations were identified to cause human oocyte MI arrest (Feng et al, 2016 ; Zhang et al, 2020 ). With increasing attention, other variable phenotypes of the TUBB8 mutations have also been discovered (Chen et al, 2017a ; Huang et al, 2017 ; Wang et al, 2018 ; Xiang et al, 2018 ; Yuan et al, 2018 ; Jia et al, 2020 ; Xing et al, 2020 ). The same as TUBB8 gene, pathogenic variants in PATL2 was first found to result in GV arrest (Chen et al, 2017b ; Maddirevula et al, 2017 ), and then similar but slightly variable phenotypes were reported (Chen et al, 2017b ; Maddirevula et al, 2017 ; Christou-Kent et al, 2018 ; Huang et al, 2018 ; Wu et al, 2019 ; Liu et al, 2020 ).…”

Gene mutations impede oocyte maturation, fertilization, and early embryonic development

“…Previously, 14 studies have identified 104 different mutations in TUBB8 (Table S1). [90,[94][95][96][97][98][99][100][101][102][103][104][105][106] We summarized the phenotypes of oocytes or embryos of patients with TUBB8 mutations, including I: oocytes arrested at the MI stage; II: PB1 oocytes that could not be fertilized; III: PB1 oocytes that could be fertilized but the zygotes were uncleaved; IV: PB1 oocytes that could be fertilized and the zygotes could be cleaved, but the ensuing embryos arrested at an early stage; and V: the early embryos developed normally and had the potential for implantation, but failed to implant in the uterus. Immunostaining of MI oocytes from some patients showed that the spindle was abnormal or not detectable (Figure 2).…”