Gene-based genome-wide association studies and meta-analyses of conotruncal heart defects
PLOS ONE
Authors: Sewda, Anshuman; Agopian, A. J.; Goldmuntz, Elizabeth; Hakonarson, Hakon; Morrow, Bernice E.; Taylor, Deanne; Mitchell, Laura E.; Kim, Richard; Srivastava, Deepak; Bernstein, Daniel; Brueckner, Martina; Lifton, Richard; Newburger, Jane; Roberts, Amy; Seidman, Christine; Seidman, Jonathan; Tennstedt, Sharon; Dandreo, Kimberly; Miller, Julie; Romano-Adesman, Angela; Gelb, Bruce; Chung, Wendy; Porter, George; King, Eileen C.; Goldmuntz, Elizabeth; Tristani-Firouzi, Martin; Yost, H. Joseph
Abstract
Conotruncal heart defects (CTDs) are among the most common and severe groups of congenital heart defects. Despite evidence of an inherited genetic contribution to CTDs, little is known about the specific genes that contribute to the development of CTDs. We performed gene-based genome-wide analyses using microarray-genotyped and imputed common and rare variants data from two large studies of CTDs in the United States. We performed two case-parent trio analyses (N = 640 and 317 trios), using an extension of the family-based multi-marker association test, and two case-control analyses (N = 482 and 406 patients and comparable numbers of controls), using a sequence kernel association test. We also undertook two meta-analyses to combine the results from the analyses that used the same approach (i.e. family-based or case-control). To our knowledge, these analyses are the first reported gene-based, genome-wide association studies of CTDs. Based on our findings, we propose eight CTD candidate genes (ARF5, EIF4E, KPNA1, MAP4K3, MBNL1, NCAPG, NDFUS1 and PSMG3). Four of these genes (ARF5, KPNA1, NDUFS1 and PSMG3) have not been previously associated with normal or abnormal heart development. In addition, our analyses provide additional evidence that genes involved in chromatin-modification and in ribonucleic acid splicing are associated with congenital heart defects.
Nuclear Import of Serum Response Factor in Airway Smooth Muscle
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Authors: McConville, John F.; Fernandes, Darren J.; Churchill, Jason; Dewundara, Samantha; Kogut, Paul; Shah, Shardul; Fuchs, Gregory; Kedainis, Dalius; Bellam, Shashi K.; Patel, Nina M.; McCauley, Joel; Dulin, Nickolai O.; Gupta, Mahesh P.; Adam, Stephen; Yoneda, Yoshihiro; Camoretti-Mercado, Blanca; Solway, Julian
Abstract
We have previously shown that the transcription-promoting activity of serum response factor (SRF) is partially regulated by its extranuclear redistribution. In this study, we examined the cellular mechanisms that facilitate SRF nuclear entry in canine tracheal smooth muscle cells. We used in vitro pull-down assays to determine which karyopherin proteins bound SRF and found that SRF binds KPNA1 and KPNB1 through its nuclear localization sequence. Immunoprecipitation studies also demonstrated direct SRF-KPNA1 interaction in HEK293 cells. Import assays demonstrated that KPNA1 and KPNB1 together were sufficient to mediate rapid nuclear import of SRF-GFP. Our studies also suggest that SRF is able to gain nuclear entry through an auxiliary, nuclear localization sequence-independent mechanism.
COA
Publication 
Loading ......
