Core Facility, West China Hospital, Sichuan University, Chengdu, China.
Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China.
Mol Genet Genomic Med. 2022 Dec;10(12):e2078. doi: 10.1002/mgg3.2078. Epub 2022 Nov 8.
Multiple morphological abnormalities of the sperm flagella (MMAF), which is characterized as asthenoteratospermia involving absent, short, bent, coiled, and/or irregular-caliber flagella, is a rare recessive inherited disorder associated with male infertility. To date, genetic causes of MMAF cases are not fully explored.
Whole-exome sequencing was conducted to identify pathogenic variants in a patient with MMAF. The functional effect of the identified mutations was investigated by immunofluorescence staining and western blotting. Intracytoplasmic sperm injection was used to assist fertilization for the patient with MMAF.
We identified novel biallelic mutations, a splicing variant NC_000004.12:g.146937593C>T (c.254+1G>A), and a nonsense mutation NM_001300761.4:c.1185C>G (NP_001287690.1:p.Tyr395*), in TTC29 from an infertile patient. In addition to the typical MMAF phenotype, the patient also presented aberrant morphology of sperm heads. Further functional experiments confirmed the absence of TTC29 expression in the spermatozoa. We also explored the specific expression pattern of TTC29 in human and mouse spermatogenesis. The outcome of intracytoplasmic sperm injection in the patient was unsuccessful, while additional female risk factors should not be excluded.
Our study revealed the novel biallelic mutations in TTC29 in a MMAF patient, which findings expand the mutational spectrum of TTC29 and further contribute to the diagnosis, genetic counseling, and prognosis of male infertility.
精子鞭毛多种形态异常（MMAF）的特征是表现为缺乏、短、弯曲、卷曲和/或不规则形态的鞭毛的弱精症和少精症，是一种与男性不育相关的罕见隐性遗传疾病。迄今为止，MMAF 病例的遗传原因尚未完全阐明。
对一位 MMAF 患者进行全外显子组测序，以鉴定致病变异。通过免疫荧光染色和 Western blot 研究鉴定突变的功能效应。采用卵胞浆内单精子注射技术协助 MMAF 患者受精。
我们在一名不育患者的 TTC29 中发现了新的双等位基因突变，一个剪接变异 NC_000004.12:g.146937593C>T（c.254+1G>A）和一个无义突变 NM_001300761.4:c.1185C>G（NP_001287690.1:p.Tyr395*）。除了典型的 MMAF 表型外，患者的精子头部也呈现出异常形态。进一步的功能实验证实了精子中 TTC29 的表达缺失。我们还探索了 TTC29 在人类和小鼠精子发生中的特异性表达模式。该患者卵胞浆内单精子注射的结果并不成功，然而不能排除其他女性风险因素的影响。
本研究在 MMAF 患者中揭示了 TTC29 的新型双等位基因突变，这些发现扩展了 TTC29 的突变谱，并进一步有助于男性不育的诊断、遗传咨询和预后。
