ClinVar

In a 33-year-old infertile Chinese woman (family 6) with an oocyte maturation defect (OZEMA2; 616780), Feng et al. (2016) identified heterozygosity for a c.5G-A transition (c.5G-A, NM_177987) in exon 1 of the TUBB8 gene, resulting in an arg2-to-lys (R2K) substitution at an evolutionarily conserved residue located at the alpha-beta interface within the heterodimer. The proband inherited the mutation from her fertile father. Functional analysis in transfected HeLa cells demonstrated complete loss of the microtubule network with the R2K mutant. Spores of S. cerevisiae bearing the R2K mutation were viable, but showed growth impairment. Yeast strains with the R2K mutation also showed decreased resistance to the microtubule-destabilizing drug benomyl compared to control, suggesting that the mutation dominantly destabilizes microtubules in vivo. In addition, astral microtubules in heterozygous R2K cells depolymerized nearly twice as quickly and the rescue frequency was markedly reduced, compared to wildtype. Microinjection of R2K mutant TUBB8 RNA into mouse oocytes resulted in maturation arrest and a misshapen spindle, as well as a reduction in the rate of extrusion of the first polar body compared to wildtype.