Perturbations of genes essential for Mullerian duct and Wolffian duct development in Mayer-Rokitansky-Kuster-Hauser syndrome

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Chen, Na ^[1] ; Zhao, Sen ^{[2, 3]} ; Jolly, Angad ^{[4, 5]} ; Wang, Lianlei ^{[2, 3, 6]} ; Pan, Hongxin ^[7] ; Yuan, Jian ^[8] ; Chen, Shaoke ^[9] ; Koch, Andre ^[10] ; Ma, Congcong ^[1] ; Tian, Weijie ^[1] ; Jia, Ziqi ^[1] ; Kang, Jia ^[1] ; Zhao, Lina ^{[2, 3]} ; Qin, Chenglu ^[7] ; Fan, Xin ^[9] ; Rall, Katharina ^[10] ; Coban-Akdemir, Zeynep ^[4] ; Chen, Zefu ^{[2, 3]} ; Jhangiani, Shalini ^[4] ; Liang, Ze ^[1] ; Niu, Yuchen ^[3] ; Li, Xiaoxin ^[3] ; Yan, Zihui ^{[2, 3]} ; Wu, Yong ^[3] ; Dong, Shuangshuang ^[11] ; Song, Chengcheng ^[11] ; Qiu, Guixing ^{[2, 3, 12]} ; Zhang, Shuyang ^[13] ; Liu, Pengfei ^{[4, 14]} ; Posey, Jennifer E. ^[4] ; Zhang, Feng ^[11] ; Luo, Guangnan ^[7] ; Wu, Zhihong ^{[3, 12, 15]} ; Su, Jianzhong ^[8] ; Zhang, Jianguo ^{[2, 3]} ; Chen, Eugenia Y. ^{[16, 17, 18]} ; Rouskas, Konstantinos ^{[19, 20]} ; Glentis, Stavros ^{[19, 21]} ; Bacopoulou, Flora ^{[22, 23]} ; Deligeoroglou, Efthymios ^[24] ; Chrousos, George ^{[22, 23]} ; Lyonnet, Stanislas ^{[25, 26]} ; Polak, Michel ^{[25, 26]} ; Rosenberg, Carla ^[27] ; Dingeldein, Irene ^[28] ; Bonilla, Ximena ^[29] ; Borel, Christelle ^[29] ; Gibbs, Richard A. ^{[4, 30]} ; Dietrich, Jennifer E. ^{[31, 17, 18]} ; Dimas, Antigone S. ^[19] ; Antonarakis, Stylianos E. ^{[29, 32]} ; Brucker, Sara Y. ^[10] ; Lupski, James R. ^{[31, 4, 17, 30]} ; Wu, Nan ^{[4, 2, 3, 12, 15]} ; Zhu, Lan ^[1] ; Sc, Deciphering Disorders Involving

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^[1] Peking Union Med Coll & Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Obstet & Gynaecol, State Key Lab Complex Severe & Rare Dis, Beijing 100730 - Peoples R China

^[2] Peking Union Med Coll & Chinese Acad Med Sci, Peking Union Med Coll Hosp, State Key Lab Complex Severe & Rare Dis, Dept Orthoped Surg, Beijing 100730 - Peoples R China

^[3] Beijing Key Lab Genet Res Skeletal Deform, Beijing 100730 - Peoples R China

^[4] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 - USA

^[5] Baylor Coll Med, MD PhD Med Scientist Training Program, Houston, TX 77030 - USA

^[6] Shandong Univ, Dept Orthoped Surg, Qilu Hosp, Jinan 250012, Shandong - Peoples R China

^[7] Shenzhen Univ, Luohu Hosp, Affiliated Hosp 2, Dept Obstet & Gynaecol, Shenzhen 518000, Guangdong - Peoples R China

^[8] Wenzhou Med Univ, Inst Biomed Big Data, Wenzhou 325027 - Peoples R China

^[9] Guangxi Med Univ, Dept Pediat, Affiliated Hosp 2, Nanning 530003, Guangxi - Peoples R China

^[10] Tubingen Univ Hosp, Res Ctr Womens Hlth, Dept Gynecol & Obstet, D-72076 Tubingen - Germany

^[11] Shanghai Inst Planned Parenthood Res, Sch Life Sci, NHC Key Lab Reprod Regulat, Obstet & Gynecol Hosp, Shanghai 200011 - Peoples R China

^[12] Chinese Acad Med Sci, Key Lab Big Data Spinal Deform, Beijing 100730 - Peoples R China

^[13] Peking Union Med Coll & Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Cardiol, Beijing 100730 - Peoples R China

^[14] Baylor Genet, Houston, TX 77021 - USA

^[15] Peking Union Med Coll & Chinese Acad Med Sci, Peking Union Med Coll Hosp, Med Res Ctr, Beijing 100730 - Peoples R China

^[16] Baylor Coll Med, Houston, TX 77030 - USA

^[17] Baylor Coll Med, Dept Pediat, Houston, TX 77030 - USA

^[18] Texas Childrens Hosp, Dept Obstet & Gynecol, Houston, TX 77030 - USA

^[19] Biomed Sci Res Ctr AI Fleming, Inst Bioinnovat, Athens 16672 - Greece

^[20] Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki 57001 - Greece

^[21] Univ Athens, Aghia Sophia Childrens Hosp, Dept Pediat 1, Div Pediat Hematol Oncol, Athens 11527 - Greece

^[22] Natl & Kapodistrian Univ Athens, Aghia Sophia Childrens Hosp, Ctr Adolescent Med, Athens 11527 - Greece

^[23] Natl & Kapodistrian Univ Athens, Aghia Sophia Childrens Hosp, UNESCO Chair Adolescent Hlth Care, Dept Pediat 1, Sch Med, Athens 11527 - Greece

^[24] Natl & Kapodistrian Univ Athens, Aretaie Hosp, Sch Med, Dept Obstet & Gynecol 2, Div Pediat Adolescent Gyn, Athens 10679 - Greece

^[25] INSERM, Inst Imagine, UMR 1163, F-75015 Paris - France

^[26] Univ Paris, Hosp Univ Necker Enfants Malad, F-75015 Paris - France

^[27] Univ Sao Paulo, Inst Biosci, Dept Genet & Evolutionary Biol, BR-05508090 Sao Paulo - Brazil

^[28] Univ Bern, Inselspital, Frauen Klin, CH-3012 Bern - Switzerland

^[29] Univ Geneva, Med Sch, Dept Genet Med & Dev, CH-1205 Geneva - Switzerland

^[30] Baylor Coll Med, Human Genome Seuencing Ctr, Houston, TX 77030 - USA

^[31] Texas Childrens Hosp, Houston, TX 77030 - USA

^[32] Univ Geneva, Inst Genet & Genom Geneva, CH-1205 Geneva - Switzerland

• Tipo de documento: Artigo Científico
• Fonte: American Journal of Human Genetics; v. 108, n. 2, p. 337-345, FEB 4 2021.
• Citações Web of Science: 1

Resumo

Mayer-Rokitansky-Kuster-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 Mullerian ducts (MD)/Wolffian 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. (AU)

• Processo FAPESP: 17/16283-2 - Desenvolvimento de técnicas de bioengenharia de tecidos para a reconstrução funcional, ex vivo, de fígados, a partir de células iPSCs
• Beneficiário: Luiz Carlos de Caires Júnior
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 15/14821-1 - Desenvolvimento de by-pass vascular hepático funcionalizado com células humanas derivadas de iPSCs
• Beneficiário: Ernesto da Silveira Goulart Guimarães
• Modalidade de apoio: Bolsas no Brasil - Doutorado