Loss-of-function variants in myocardin cause congenital megabladder in humans and mice

J Clin Invest. 2019 Dec 2;129(12):5374-5380. doi: 10.1172/JCI128545.

Arjan C Houweling ¹, Glenda M Beaman ² ³, Alex V Postma ¹ ⁴, T Blair Gainous ⁵, Klaske D Lichtenbelt ⁶, Francesco Brancati ⁷ ⁸, Filipa M Lopes ² ³, Ingeborg van der Made ⁹, Abeltje M Polstra ¹, Michael L Robinson ¹⁰, Kevin D Wright ¹⁰, Jamie M Ellingford ² ³, Ashley R Jackson ¹¹, Eline Overwater ¹, Rita Genesio ¹², Silvio Romano ⁸, Letizia Camerota ⁸, Emanuela D'Angelo ⁸, Elizabeth J Meijers-Heijboer ¹, Vincent M Christoffels ⁴, Kirk M McHugh ¹¹, Brian L Black ⁵, William G Newman ² ³, Adrian S Woolf ² ³, Esther E Creemers ⁹

Affiliations

1 Department of Clinical Genetics, Amsterdam UMC, Amsterdam, Netherlands.
2 School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
3 Manchester Centre for Genomic Medicine and Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
4 Department of Medical Biology, Amsterdam UMC, Amsterdam, Netherlands.
5 Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
6 Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands.
7 Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Rome, Italy.
8 Department of Life, Health and Environmental Sciences, University of L'Aquila, Aquila, Italy.
9 Department of Experimental Cardiology, Amsterdam UMC, Amsterdam, Netherlands.
10 Department of Biology, Miami University, Oxford, Ohio, USA.
11 Center for Clinical and Translational Research, The Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.
12 Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.

PMID: 31513549 DOI: 10.1172/JCI128545

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.

Keywords

Genetic diseases; Molecular genetics; Muscle Biology; Urology.

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