Perturbations of genes essential for Müllerian duct and Wölffian duct development in Mayer-Rokitansky-Küster-Hauser syndrome.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
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.
Chen Na, Zhao Sen, Jolly Angad, Wang Lianlei, Pan Hongxin, Yuan Jian, Chen Shaoke, Koch André, Ma Congcong, Tian Weijie, Jia Ziqi, Kang Jia, Zhao Lina, Qin Chenglu, Fan Xin, Rall Katharina, Coban-Akdemir Zeynep, Chen Zefu, Jhangiani Shalini, Liang Ze, Niu Yuchen, Li Xiaoxin, Yan Zihui, Wu Yong, Dong Shuangshuang, Song Chengcheng, Qiu Guixing, Zhang Shuyang, Liu Pengfei, Posey Jennifer E, Zhang Feng, Luo Guangnan, Wu Zhihong, Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study group, Su Jianzhong, Zhang Jianguo, Chen Eugenia Y, Rouskas Konstantinos, Glentis Stavros, Bacopoulou Flora, Deligeoroglou Efthymios, Chrousos George, Lyonnet Stanislas, Polak Michel, Rosenberg Carla, Dingeldein Irene, Bonilla Ximena, Borel Christelle, Gibbs Richard A, Dietrich Jennifer E, Dimas Antigone S, Antonarakis Stylianos E, Brucker Sara Y, Lupski James R, Wu Nan, Zhu Lan
Аннотация
Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.