@article{1b9c89861cf240f19ab80f39798061e0,
title = "Loss-of-function variants in myocardin cause congenital megabladder in humans and mice",
abstract = "Myocardin (MYOCD) is the founding member of a class of transcriptional coactivators that bind the serum-response factor to activate gene expression programs critical in smooth muscle (SM) and cardiac muscle development. Insights into the molecular functions of MYOCD have been obtained from cell culture studies, and to date, knowledge about in vivo roles of MYOCD comes exclusively from experimental animals. Here, we defined an often lethal congenital human disease associated with inheritance of pathogenic MYOCD variants. This disease manifested as a massively dilated urinary bladder, or megabladder, with disrupted SM in its wall. We provided evidence that monoallelic loss-of-function variants in MYOCD caused congenital megabladder in males only, whereas biallelic variants were associated with disease in both sexes, with a phenotype additionally involving the cardiovascular system. These results were supported by cosegregation of MYOCD variants with the phenotype in 4 unrelated families by in vitro transactivation studies in which pathogenic variants resulted in abrogated SM gene expression and by the finding of megabladder in 2 distinct mouse models with reduced Myocd activity. In conclusion, we have demonstrated that variants in MYOCD result in human disease, and the collective findings highlight a vital role for MYOCD in mammalian organogenesis.",
author = "Houweling, {Arjan C} and Beaman, {Glenda M} and Postma, {Alex V} and Gainous, {T Blair} and Lichtenbelt, {Klaske D} and Francesco Brancati and Lopes, {Filipa M} and {van der Made}, Ingeborg and Polstra, {Abeltje M} and Robinson, {Michael L} and Wright, {Kevin D} and Ellingford, {Jamie M} and Jackson, {Ashley R} and Eline Overwater and Rita Genesio and Silvio Romano and Letizia Camerota and Emanuela D'Angelo and Meijers-Heijboer, {Elizabeth J} and Christoffels, {Vincent M} and McHugh, {Kirk M} and Black, {Brian L} and Newman, {William G} and Woolf, {Adrian S} and Creemers, {Esther E}",
note = "Funding Information: We acknowledge support from the Medical Research Council (MR/L002744/1 to ASW and WGN); Horizon 2020 Marie Sklodowska-Curie RENALTRACT (942937 to ASW and FML); the Newlife Foundation (to ASW, GMB, and WGN); and the NIH (EY12995 to MLR; DK70907 and DK085242 to KMM; and HL064658, HL089707, and HL136182 to BLB). We also acknowledge an Out-of-the-Box Grant ACS (to ACH and EEC), a CVON CONCOR genes grant (to AVP and VMC), and support from Fondi di Ateneo, University of L'Aquila, and Undiagnosed Disease Network Italy at Istituto Superiore di Sanit{\`a} (PGR00229-919 and Farmindustria to FB). We acknowledge Marilina Scalona and Fulvio De Simone for family B ascertainment. Funding Information: We acknowledge support from the Medical Research Council (MR/L002744/1 to ASW and WGN); Horizon 2020 Marie Sklodowska-Curie RENALTRACT (942937 to ASW and FML); the Newlife Foundation (to ASW, GMB, and WGN); and the NIH (EY12995 to MLR; DK70907 and DK085242 to KMM; and HL064658, HL089707, and HL136182 to BLB). We also acknowledge an Out-of-the-Box Grant ACS (to ACH and EEC), a CVON CONCOR genes grant (to AVP and VMC), and support from Fondi di Ateneo, University of L{\textquoteright}Aquila, and Undiagnosed Disease Network Italy at Istituto Superiore di Sanit{\`a} (PGR00229-919 and Far-mindustria to FB). We acknowledge Marilina Scalona and Fulvio De Simone for family B ascertainment. Publisher Copyright: {\textcopyright} 2019, Houweling et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",
year = "2019",
month = dec,
day = "2",
doi = "10.1172/JCI128545",
language = "English",
volume = "129",
pages = "5374--5380",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "12",
}