The comprehensive mutational and phenotypic spectrum of TUBB8 in female infertility

Abstract

Human oocyte maturation is a precondition for fertilization and ensuing embryonic development. Previously, we identified TUBB8 variants as a genetic determinant of human oocyte maturation arrest and showed that these variants cause variable and mixed phenotypes in oocyte maturation and early embryo development. We also estimated that rare inherited or de novo variants in the TUBB8 gene accounted for 30% of individuals in a small cohort of patients affected by oocyte maturation arrest. In the present study, we recruited a further 87 patients from unrelated families diagnosed with oocyte maturation or early embryonic arrest and identified 30 patients carrying TUBB8 variants. The corresponding phenotypes not only include oocyte maturation arrest, failure of fertilization, and early embryonic arrest, but also extend to the new phenotype of failure of embryo implantation. These observations provide the most detailed mutational and phenotypic spectrum of TUBB8, further extend the spectrum of variants and dysfunctional oocyte and embryo phenotypes caused by TUBB8 variants, and confirm previous findings for a critical role of TUBB8 during oocyte maturation and early embryonic development. Thus, TUBB8 mutation screening might not only be a genetic diagnostic marker for patients with oocyte maturation arrest, but might also have clinical implications for evaluating the competence of patients' functional oocytes with first polar body (PB1).

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

“…In previous studies, researchers have found several inheritance patterns of TUBB8 mutations, including heterozygous mutations [6,16,9,10,[19][20][21], homozygous mutations [6,10,16,22], compound heterozygous mutations [16,21], and homozygous deletions [16]. These mutations affect folding and assembly of alpha/beta-tubulin isodimers.…”

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

“…Female primary infertility was the clinical trait of OOMD2. The corresponding phenotype includes arrest at MI or MII of oocytes, fertilization failure, stagnation of early embryonic development, and failure of embryo implantation [16]. Expression of TUBB8 protein is unique to oocytes and early embryos.…”

“…In previous studies, researchers have found several inheritance patterns of TUBB8 mutations, including heterozygous mutations [6,9,10,16,[19][20][21], homozygous mutations [6,10,16,22], compound heterozygous mutations [16,21], and homozygous deletions [16]. These mutations affect folding and assembly of alpha/ beta-tubulin isodimers.…”

Novel homozygous mutation in TUBB8 associated with oocyte maturation defect-2 in a consanguineous marriage family

“…The corresponding phenotype includes not only arrest at MI or MII of oocytes, fertilization failure, and stagnation of early embryonic development, but also failure of embryo implantation. [16] Expression of TUBB8 protein is unique to oocytes and early embryos. Therefore, male carriers of the TUBB8 mutation are fertile [9].…”