Abstract
Original language | English |
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Pages (from-to) | 5374-5380 |
Number of pages | 7 |
Journal | Journal of clinical investigation |
Volume | 129 |
Issue number | 12 |
DOIs | |
Publication status | Published - 2 Dec 2019 |
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In: Journal of clinical investigation, Vol. 129, No. 12, 02.12.2019, p. 5374-5380.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Loss-of-function variants in myocardin cause congenital megabladder in humans and mice
AU - Houweling, Arjan C.
AU - Beaman, Glenda M.
AU - Postma, Alex V.
AU - Blair Gainous, T.
AU - Lichtenbelt, Klaske D.
AU - Brancati, Francesco
AU - Lopes, Filipa M.
AU - van der Made, Ingeborg
AU - Polstra, Abeltje M.
AU - Robinson, Michael L.
AU - Wright, Kevin D.
AU - Ellingford, Jamie M.
AU - Jackson, Ashley R.
AU - Overwater, Eline
AU - Genesio, Rita
AU - Romano, Silvio
AU - Camerota, Letizia
AU - D'Angelo, Emanuela
AU - Meijers-Heijboer, Elizabeth J.
AU - Christoffels, Vincent M.
AU - McHugh, Kirk M.
AU - Black, Brian L.
AU - Newman, William G.
AU - Woolf, Adrian S.
AU - Creemers, Esther E.
N1 - 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? (PGR00229-919 and Farmindustria to FB). We acknowledge Marilina Scalona and Fulvio De Simone for family B ascertainment. Funding Information: 1Department of Clinical Genetics, Amsterdam UMC, Amsterdam, Netherlands. 2School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom. 3Manchester Centre for Genomic Medicine and Royal Manchester Children’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom. 4Department of Medical Biology, Amsterdam UMC, Amsterdam, Netherlands. 5Cardiovascular Research Institute, UCSF, San Francisco, California, USA. 6Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands. 7Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Rome, Italy. 8Department of Life, Health and Environmental Sciences, University of L’Aquila, Aquila, Italy. 9Department of Experimental Cardiology, Amsterdam UMC, Amsterdam, Netherlands. 10Department of Biology, Miami University, Oxford, Ohio, USA. 11Center for Clinical and Translational Research, The Research Institute, Nationwide Children’s Hospital, Columbus, Ohio, USA. 12Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy. 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 Sanità (PGR00229-919 and Far-mindustria to FB). We acknowledge Marilina Scalona and Fulvio De Simone for family B ascertainment. Publisher Copyright: © 2019, Houweling et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2019/12/2
Y1 - 2019/12/2
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85075961425&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31513549
UR - http://www.scopus.com/inward/record.url?scp=85075961425&partnerID=8YFLogxK
U2 - https://doi.org/10.1172/JCI128545
DO - https://doi.org/10.1172/JCI128545
M3 - Article
C2 - 31513549
SN - 0021-9738
VL - 129
SP - 5374
EP - 5380
JO - Journal of clinical investigation
JF - Journal of clinical investigation
IS - 12
ER -