Functional characteristics of a broad spectrum of TBX6 variants in Mayer-Rokitansky-Küster-Hauser syndrome.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Ma Congcong, Chen Na, Jolly Angad, Zhao Sen, Coban-Akdemir Zeynep, Tian Weijie, Kang Jia, Ye Yang, Wang Yuan, Koch André, Zhang Yuanqiang, Qin Chenglu, Bonilla Ximena, Borel Christelle, Rall Katharina, Chen Zefu, Jhangiani Shalini, Niu Yuchen, Li Xiaoxin, Qiu Guixing, Zhang Shuyang, Luo Guangnan, Wu Zhihong, Bacopoulou Flora, Deligeoroglou Efthymios, Zhang Terry Jianguo, Rosenberg Carla, Gibbs Richard A, Dietrich Jennifer E, Dimas Antigone S, Liu Pengfei, Antonarakis Stylianos E, Brucker Sara Y, Posey Jennifer E, Lupski James R, Wu Nan, Zhu Lan, Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) Study Group
Аннотация
METHODS: Rare variants in TBX6 were called from a combined multiethnic cohort of 622 probands with MRKHS who underwent exome sequencing or genome sequencing. Multiple in vitro functional experiments were performed, including messenger RNA analysis, western blotting, transcriptional activity assay, and immunofluorescence staining.
RESULTS: We identified 16 rare variants in TBX6 from the combined cohort, including 1 protein-truncating variant reported in our previous study and 15 variants with unknown effects. By comparing the prevalence of TBX6 variants in the Chinese MRKHS cohort vs 1038 female controls, we observed a significant mutational burden of TBX6 in affected individuals (P = .0004, odds ratio = 5.25), suggesting a causal role of TBX6 variants in MRKHS. Of the 15 variants with uncertain effects, 7 were shown to induce a loss-of-function effect through various mechanisms. The c.423G>A (p.Leu141=) and c.839+5G>A variants impaired the normal splicing of TBX6 messenger RNA, c.422T>C (p.Leu141Pro) and c.745G>A (p.Val249Met) led to decreased protein expression, c.10C>T (p.Pro4Ser) and c.400G>A (p.Glu134Lys) resulted in perturbed transcriptional activity, and c.356G>A (p.Arg119His) caused protein mislocalization. We observed incomplete penetrance and variable expressivity in families carrying deleterious variants, which indicates a more complex genetic mechanism than classical Mendelian inheritance.
CONCLUSION: Our study expands the mutational spectrum of TBX6 in MRKHS and delineates the molecular pathogenesis of TBX6 variants, supporting the association between deleterious variants in TBX6 and MRKHS.