Further evidence for the involvement of<i>MYH9</i>in the etiology of non‐syndromic cleft lip with or without cleft palate

Birnbaum, Stefanie; Reutter, Heiko; Mende, Meinhard; Assis, Nilma Almeida de; Díaz-Lacava, Amalia; Herms, Stefan; Scheer, Martin; Lauster, Carola; Braumann, Bert; Schmidt, Gül; Martini, M.; Hemprich, Alexander; Pötzsch, Simone; Knapp, Michael; Nöthen, Markus M.; Kramer, Franz‐Josef; Mangold, Elisabeth

doi:10.1111/j.1600-0722.2008.00604.x

Cited by 23 publications

(20 citation statements)

References 13 publications

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“…10 Mechanistically, prolonged binding of R709C NMII-B to actin-filaments 11 could affect the dynamics of actomyosin stress fibers 27 which in general contain both NMII-A and NMII-B 28 . It is of interest that there have been several reports implicating a mutation in NMII-A 29-31 but not NMII-C 32 in the generation of a cleft palate in humans, consistent with our hypothesis that the mutant II-B is interfering with II-A. Of course we cannot rule out interference with a nonmuscle myosin of a different class.…”

Section: Discussionsupporting

confidence: 85%

A Point Mutation in Myh10 Causes Major Defects in Heart Development and Body Wall Closure

Adelstein

2014

Circ Cardiovasc Genet

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Background The three isoforms of nonmuscle myosin II (NMII-A, NMII-B and NMII-C) play various roles during mouse embryonic development. Previous work, using knockout and hypomorphic mice, showed that MYH10 encoding myosin heavy chain II-B is critical for cardiac and brain development. Ablating or decreasing NMII-B by 80% results in cardiac (ventricular septal defect, double outlet of the right ventricle) and brain defects but not midline fusion defects. Neither NMII-A nor II-C appear to play roles in early myocardial development. Methods and Results We had previously generated point mutant knock-in mice and now report novel findings due to expressing motor deficient NMII-B at wild-type levels. Homozygous mice die at E14.5 in cardiac failure exhibiting abnormalities not seen in NMII-B null and hypomorphic mice: a failure in midline fusion resulting in a cleft palate, ectopia cordis, and a large omphalocele. Fusion of the sternum and endocardial cushions is impaired in the mutant mice associated with a failure in apoptosis of the mesenchyme cells. Failure to disassemble myocyte cell-cell adhesions during cardiac outflow tract development contributes to impaired outflow tract myocardialization and displacement of the aorta to the right ventricle. Conclusions Expression of motor impaired NMII-B disrupts normal ventral body wall closure, due to a dominant negative effect. This is not due to the loss of NMII-B function but rather to a gain-of-function resulting from prolonged crosslinking of NMII-B to actin-filaments thereby interfering with the dynamics of actomyosin cytoskeletal structure. Moreover impaired NMII-B motor activity inhibits outflow tract myocardialization leading to mis-localization of the aorta.

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Section: Discussionsupporting

confidence: 85%

A Point Mutation in Myh10 Causes Major Defects in Heart Development and Body Wall Closure

Adelstein

2014

Circ Cardiovasc Genet

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“…However, this reasoning ignores the possibility that reduced fecundity in patients may be oVset by advantages to unaVected individuals, and there are now clear examples of common alleles that contribute to disorders like autism and cleft palate that are even more likely to inXuence reproductive Wtness (Birnbaum et al 2009;Wang et al 2009). Moreover, the hypothesis that schizophrenia and/or BD are attributable to a collection of single major genes has been tested several times in the past through comparisons of the observed recurrence risks in various classes of relative and those predicted by such a model.…”

Section: Molecular Genetics Prior To Genome-wide Associationmentioning

confidence: 96%

Genetics of psychosis; insights from views across the genome

2009

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The major psychotic illnesses, schizophrenia and bipolar disorder (BD), are among the most heritable common disorders, but finding specific susceptibility genes for them has not been straightforward. The reasons are widely assumed to include lack of valid phenotypic definition, absence of good theories of pathophysiology for candidate gene studies, and the involvement of many genes, each making small contributions to population risk. Within the last year or so, a number of genome wide association (GWAS) of schizophrenia and BD have been published. These have produced stronger evidence for association to specific risk loci than have earlier studies, specifically for the zinc finger binding protein 804A (ZNF804A) locus in schizophrenia and for the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) and ankyrin 3, node of Ranvier (ANK3) loci in bipolar disorder. The ZNF804A and CACNA1C loci appear to influence risk for both disorders, a finding that supports the hypothesis that schizophrenia and BD are not aetiologically distinct. In the case of schizophrenia, a number of rare copy number variants have also been detected that have fairly large effect sizes on disease risk, and that additionally influence risk of autism, mental retardation, and other neurodevelopmental disorders. The existing findings point to some likely pathophysiological mechanisms but also challenge current concepts of disease classification. They also provide grounds for optimism that larger studies will reveal more about the origins of these disorders, although currently, very little of the genetic risk of either disorder is explained.

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“…IIA and IIB are most important for migration (26). IIA and IIB also play a pivotal role in maintaining health, because mutations that affect these isoforms cause cleft lip and palate, hearing disorder, and cardiac disease (26,29,30). The role of NMM II in keloid pathogenesis is unknown.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin-II Mediates Nonmuscle Myosin II Activation and Expression and Contributes to Human Keloid Disease Progression

Bond

Bergeron

Thurlow

et al. 2011

Mol Med

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Aberrant fibroblast migration in response to fibrogenic peptides plays a significant role in keloid pathogenesis. Angiotensin II (Ang II) is an octapeptide hormone recently implicated as a mediator of organ fibrosis and cutaneous repair. Ang II promotes cell migration but its role in keloid fibroblast phenotypic behavior has not been studied. We investigated Ang II signaling in keloid fibroblast behavior as a potential mechanism of disease. Primary human keloid fibroblasts were stimulated to migrate in the presence of Ang II and Ang II receptor 1 (AT 1 ), Ang II receptor 2 (AT 2 ) or nonmuscle myosin II (NMM II) antagonists. Keloid and the surrounding normal dermis were immunostained for NMM IIA, NMM IIB, AT 2 and AT 1 expression. Primary human keloid fibroblasts were stimulated to migrate with Ang II and the increased migration was inhibited by the AT 1 antagonist EMD66684, but not the AT 2 antagonist PD123319. Inhibition of the promigratory motor protein NMM II by addition of the specific NMM II antagonist blebbistatin inhibited Ang II-stimulated migration. Ang II stimulation of NMM II protein expression was prevented by AT 1 blockade but not by AT 2 antagonists. Immunostaining demonstrated increased NMM IIA, NMM IIB and AT 1 expression in keloid fibroblasts compared with scant staining in normal surrounding dermis. AT 2 immunostaining was absent in keloid and normal human dermal fibroblasts. These results indicate that Ang II mediates keloid fibroblast migration and possibly pathogenesis through AT 1 activation and upregulation of NMM II.

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Further evidence for the involvement ofMYH9in the etiology of non‐syndromic cleft lip with or without cleft palate

Cited by 23 publications

References 13 publications

A Point Mutation in Myh10 Causes Major Defects in Heart Development and Body Wall Closure

A Point Mutation in Myh10 Causes Major Defects in Heart Development and Body Wall Closure

Genetics of psychosis; insights from views across the genome

Angiotensin-II Mediates Nonmuscle Myosin II Activation and Expression and Contributes to Human Keloid Disease Progression

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