Novel variants in <i>TUBB8</i> gene cause multiple phenotypic abnormalities in human oocytes and early embryos

作者全名："Hu, Tingwenyi; Li, Chong; Qiao, Sen; Liu, Weiwei; Han, Wei; Li, Wei; Shi, Rong; Xue, Xia; Shi, Juanzi; Huang, Guoning; Lin, Tingting"

作者地址："[Hu, Tingwenyi; Li, Chong; Liu, Weiwei; Han, Wei; Huang, Guoning; Lin, Tingting] Chongqing Med Univ, Women & Childrens Hosp, Ctr Reprod Med, Chongqing Key Lab Human Embryo Engn, Chongqing 400010, Peoples R China; [Hu, Tingwenyi; Li, Chong; Liu, Weiwei; Han, Wei; Huang, Guoning; Lin, Tingting] Chongqing Hlth Ctr Women & Children, Chongqing Clin Res Ctr Reprod Med, Chongqing 400010, Peoples R China; [Qiao, Sen; Li, Wei; Shi, Rong; Xue, Xia; Shi, Juanzi] Northwest Womens & Childrens Hosp, Reprod Ctr, Xian 710003, Shaanxi, Peoples R China"

通信作者："Huang, GN; Lin, TT (通讯作者)，Chongqing Med Univ, Women & Childrens Hosp, Ctr Reprod Med, Chongqing Key Lab Human Embryo Engn, Chongqing 400010, Peoples R China.; Huang, GN; Lin, TT (通讯作者)，Chongqing Hlth Ctr Women & Children, Chongqing Clin Res Ctr Reprod Med, Chongqing 400010, Peoples R China.; Shi, JZ (通讯作者)，Northwest Womens & Childrens Hosp, Reprod Ctr, Xian 710003, Shaanxi, Peoples R China."

来源：JOURNAL OF OVARIAN RESEARCH

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001109369300003

JCR分区：Q1

影响因子：3.8

年份：2023

卷号：16

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Primary female infertility; Oocyte maturation arrest; TUBB8 gene; Genetic counselling

摘要："Background The genotype-phenotype relationships between TUBB8 variants and female infertility are difficult to clearly define due to the complex inheritance patterns and the highly heterogeneous phenotypes. This study aims to identify novel TUBB8 variants and relevant phenotypes in more infertile females. Methods A total of 35 females with primary infertility were recruited from two reproductive centers and investigated for identifying variants in TUBB8. Pedigree analysis, in-silico analysis and molecular remodeling were performed to assess their clinical significance. The effects of the variants on human oocytes and embryos as well as HeLa cells were analyzed by morphological observations, immunostaining and Western blot. Results We totally identified five novel variants (p.G13R, p.Y50C, p.T136I, p.F265V and p.T366A) and five previously reported variants (p.I4L, p.L42V, p.Q134*, p.V255M and p.V349I) in TUBB8 from 9 unrelated females with primary infertility. These variants were rare and highly conserved among different species, and were inherited in autosomal dominant/recessive patterns, or occurred de novo. In vitro functional assays in HeLa cells revealed that exogenous expression of mutant TUBB8 proteins caused different degrees of microtubule structural disruption. The existence of these pathogenic TUBB8 variants finally induced oocyte maturation arrest or morphological abnormalities, fertilization failure, cleavage failure, embryonic development defects and implantation failure in the affected females. Conclusion These findings enriched the variant spectrum of TUBB8 gene and could contribute to optimize genetic counselling and clinical management of females with primary infertility."

基金机构：Natural Science Foundation of Chongqing

基金资助正文：We would like to thank all the participants enrolled in this study and all the researchers of included studies.