Genetics
Abstract
Achondroplasia, the most prevalent short-stature disorder, is caused by missense variants overactivating the fibroblast growth factor receptor 3 (FGFR3). As current surgical and pharmaceutical treatments only partially improve some disease features, we sought to explore a genetic approach. We show that an enhancer located 29 kb upstream of mouse Fgfr3 (–29E) is sufficient to confer a transgenic mouse reporter with a domain of expression in cartilage matching that of Fgfr3. Its CRISPR/Cas9-mediated deletion in otherwise WT mice reduced Fgfr3 expression in this domain by half without causing adverse phenotypes. Importantly, its deletion in mice harboring the ortholog of the most common human achondroplasia variant largely normalized long bone and vertebral body growth, markedly reduced spinal canal and foramen magnum stenosis, and improved craniofacial defects. Consequently, mouse achondroplasia is no longer lethal, and adults are overall healthy. These findings, together with high conservation of –29E in humans, open a path to develop genetic therapies for people with achondroplasia.
Authors
Marco Angelozzi, Arnaud Molin, Anirudha Karvande, Ángela Fernández-Iglesias, Samantha Whipple, Andrew M. Bloh, Véronique Lefebvre
Abstract
Nasopharyngeal carcinoma (NPC) presents a substantial clinical challenge due to the limited understanding of its genetic underpinnings. Here we conduct the largest scale whole-exome sequencing association study of NPC to date, encompassing 6,969 NPC cases and 7,100 controls. We unveil 3 germline genetic variants linked to NPC susceptibility: a common rs2276868 in RPL14, a rare rs5361 in SELE, and a common rs1050462 in HLA-B. We also underscore the critical impact of rare genetic variants on NPC heritability and introduce a refined composite polygenic risk score (rcPRS), which outperforms existing models in predicting NPC risk. Importantly, we reveal that the polygenic risk for NPC is mediated by EBV infection status. Utilizing a comprehensive multiomics approach that integrates both bulk-transcriptomic (n = 356) and single-cell RNA sequencing (n = 56) data with experimental validations, we demonstrate that the RPL14 variant modulates the EBV life cycle and NPC pathogenesis. Furthermore, our data indicate that the SELE variant contributes to modifying endothelial cell function, thereby facilitating NPC progression. Collectively, our study provides crucial insights into the intricate genetic architecture of NPC, spotlighting the vital interplay between genetic variations and tumor microenvironment components, including EBV and endothelial cells, in predisposing to NPC. This study opens new avenues for advancements in personalized risk assessments, early diagnosis, and targeted therapies for NPC.
Authors
Yanni Zeng, Chun-Ling Luo, Guo-Wang Lin, Fugui Li, Xiaomeng Bai, Josephine Mun-Yee Ko, Lei Xiong, Yang Liu, Shuai He, Jia-Xin Jiang, Wen-Xin Yan, Enya Hui Wen Ong, Zheng Li, Ya-Qing Zhou, Yun-He Zhou, An-Yi Xu, Shu-Qiang Liu, Yun-Miao Guo, Jie-Rong Chen, Xi-Xi Cheng, Yu-Lu Cao, Xia Yu, Biaohua Wu, Pan-Pan Wei, Zhao-Hui Ruan, Qiu-Yan Chen, Lin-Quan Tang, James D. McKay, Wei-Hua Jia, Hai-Qiang Mai, Soon Thye Lim, Jian-Jun Liu, Dong-Xin Lin, Chiea Chuen Khor, Melvin Lee Kiang Chua, Mingfang Ji, Maria Li Lung, Yi-Xin Zeng, Jin-Xin Bei
Abstract
Heterozygous truncating variants in the sarcomere protein titin (TTN) are the most common genetic cause of heart failure. To understand mechanisms that regulate abundant cardiomyocyte TTN expression we characterized highly conserved intron 1 sequences that exhibited dynamic changes in chromatin accessibility during differentiation of human cardiomyocytes from induced pluripotent stem cells (hiPSC-CMs). Homozygous deletion of these sequences in mice caused embryonic lethality while heterozygous mice demonstrated allele-specific reduction in Ttn expression. A 296 bp fragment of this element, denoted E1, was sufficient to drive expression of a reporter gene in hiPSC-CMs. Deletion of E1 downregulated TTN expression, impaired sarcomerogenesis, and decreased contractility in hiPSC-CMs. Site-directed mutagenesis of predicted NKX2-5- and MEF2-binding sites within E1 abolished its transcriptional activity. Embryonic mice expressing E1 reporter gene constructs validated in vivo cardiac-specific activity of E1 and the requirement for NKX2-5 and MEF2 binding sequences. Moreover, isogenic hiPSC-CMs containing a rare E1 variant in the predicted MEF2 binding motif that was identified in a patient with unexplained DCM showed reduced TTN expression. Together these discoveries define an essential, functional enhancer that regulates TTN expression. Manipulation of this element may advance therapeutic strategies to treat DCM caused by TTN haploinsufficiency.
Authors
Yuri Kim, Seong Won Kim, David Saul, Meraj Neyazi, Manuel Schmid, Hiroko Wakimoto, Neil Slaven, Joshua H. Lee, Olivia G. Layton, Lauren K. Wasson, Justin H. Letendre, Feng Xiao, Jourdan K. Ewoldt, Konstantinos Gkatzis, Peter Sommer, Bénédicte Gobert, Nicolas Wiest-Daesslé, Quentin McAfee, Nandita Singhal, Mingyue Lun, Joshua M. Gorham, Zoltan Arany, Arun Sharma, Christopher N. Toepfer, Gavin Y. Oudit, William T. Pu, Diane E. Dickel, Len A. Pennacchio, Axel Visel, Christopher S. Chen, J.G. Seidman, Christine E. Seidman
Abstract
Authors
Mark Elliott, Krzysztof Kiryluk, Ali Gharavi
Abstract
Authors
Kristine Bousset, Stefano Donega, Najim Ameziane, Tabea Fleischhammer, Dhanya Ramachandran, Miriam Poley-Gil, Detlev Schindler, Ingrid M. van de Laar, Franco Pagani, Thilo Dörk
Abstract
Authors
Hong Wang, Maria Miranda, Eizo Marutani, Paul Lichtenegger, Gregory R. Wojtkiewicz, Fumito Ichinose, Vamsi K. Mootha
Abstract
Activating transcription factor 6 (Atf6) is a key regulator of the unfolded protein response (UPR) and is important for endoplasmic reticulum (ER) function and protein homeostasis in metazoan cells. Patients carrying loss-of-function ATF6 disease alleles develop the cone dysfunction disorder, achromatopsia. The impact of loss of ATF6 function on other cell types, organs, and diseases in people remains unclear. Here, we reported that progressive sensorineural hearing loss was a notable complaint in some patients carrying ATF6 disease alleles and that Atf6-/- mice also showed progressive auditory deficits affecting both genders. In mice with hearing deficits, we found disorganized stereocilia on hair cells and focal loss of outer hair cells. Transcriptomic analysis of Atf6-/- cochleae revealed marked induction of UPR, especially through the PERK arm. These findings identify ATF6 as an essential regulator of cochlear health and function. Furthermore, they supported that ATF6 inactivation in people causes progressive sensorineural hearing loss as part of a blindness-deafness genetic syndrome targeting hair cells and cone photoreceptors. Lastly, our genetic findings support ER stress as an important pathomechanism underlying cochlear damage and hearing loss with clinical implications for patient lifestyle modifications that minimize environmental/physiologic sources of ER stress to the ear.
Authors
Eun-Jin Lee, Kyle Kim, Monica Sophia Diaz-Aguilar, Hyejung Min, Eduardo Chavez, Korina J. Steinbergs, Lance A. Safarta, Guirong Zhang, Allen F. Ryan, Jonathan H. Lin
Abstract
Although premature ovarian insufficiency (POI), a common cause of female infertility and subfertility, has a well-established hereditary component, the genetic factors currently implicated in POI account for only a limited proportion of cases. Here, using an exome-wide, gene-based case-control analysis in a discovery cohort comprising 1,027 POI cases and 2,733 ethnically matched women controls from China, we found that heterozygous loss-of-function (LoF) variants of MAX dimerization protein (MGA) were significantly enriched in the discovery cohort, accounting for 2.6% of POI cases, while no MGA LoF variants were found in the matched control females. Further exome screening was conducted in 4 additional POI cohorts (2 from China and 2 from the United States) for replication studies, and we identified heterozygous MGA LoF variants in 1.0%, 1.4%, 1.0%, and 1.0% of POI cases, respectively. Overall, a total of 37 distinct heterozygous MGA LoF variants were discovered in 38 POI cases, accounting for approximately 2.0% of the total 1,910 POI cases analyzed in this study. Accordingly, Mga+/− female mice were subfertile, exhibiting shorter reproductive lifespan and decreased follicle number compared with WT, mimicking the observed phenotype in humans. Our findings highlight the essential role of MGA deficiency for impaired female reproductive ability.
Authors
Shuyan Tang, Ting Guo, Chengcheng Song, Lingbo Wang, Jun Zhang, Aleksandar Rajkovic, Xiaoqi Lin, Shiling Chen, Yujun Liu, Weidong Tian, Bangguo Wu, Shixuan Wang, Wenwen Wang, Yunhui Lai, Ao Wang, Shuhua Xu, Li Jin, Hanni Ke, Shidou Zhao, Yan Li, Yingying Qin, Feng Zhang, Zi-Jiang Chen
Abstract
To identify novel genes responsible for recurrent hydatidiform moles (HMs), we performed exome sequencing on 75 unrelated patients who were negative for mutations in the known genes. We identified biallelic deleterious variants in 6 genes, FOXL2, MAJIN, KASH5, SYCP2, MEIOB, and HFM1, in patients with androgenetic HMs, including a familial case of 3 affected members. Five of these genes are essential for meiosis I, and their deficiencies lead to premature ovarian insufficiency. Advanced maternal age is the strongest risk factor for sporadic androgenetic HM, which affects 1 in every 600 pregnancies. We studied Hfm1–/– female mice and found that these mice lost all their oocytes before puberty but retained some at younger ages. Oocytes from Hfm1–/– mice initiated meiotic maturation and extruded the first polar bodies in culture; however, their meiotic spindles were often positioned parallel, instead of perpendicular, to the ooplasmic membrane at telophase I, and some oocytes extruded the entire spindle with all the chromosomes into the polar bodies at metaphase II, a mechanism we previously reported in Mei1–/– oocytes. The occurrence of a common mechanism in two mouse models argues in favor of its plausibility at the origin of androgenetic HM formation in humans.
Authors
Maryam Rezaei, Manqi Liang, Zeynep Yalcin, Jacinta H. Martin, Parinaz Kazemi, Eric Bareke, Zhao-Jia Ge, Majid Fardaei, Claudio Benadiva, Reda Hemida, Adnan Hassan, Geoffrey J. Maher, Ebtesam Abdalla, William Buckett, Pierre-Adrien Bolze, Iqbaljit Sandhu, Onur Duman, Suraksha Agrawal, JianHua Qian, Jalal Vallian Broojeni, Lavi Bhati, Pierre Miron, Fabienne Allias, Amal Selim, Rosemary A. Fisher, Michael J. Seckl, Philippe Sauthier, Isabelle Touitou, Seang Lin Tan, Jacek Majewski, Teruko Taketo, Rima Slim
Abstract
Authors
Jeffrey D. Steimle, Yi Zhao, Fansen Meng, Mikaela E. Taylor, Diwakar Turaga, Iki Adachi, Xiao Li, James F. Martin
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)