CASZ1 loss-of-function mutation contributes to familial dilated cardiomyopathy

2017 ◽  
Vol 55 (9) ◽  
Author(s):  
Xing-Biao Qiu ◽  
Xin-Kai Qu ◽  
Ruo-Gu Li ◽  
Hua Liu ◽  
Ying-Jia Xu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Activity ◽  
Autosomal Dominant ◽  
Cardiac Development ◽  
Index Patient ◽  
Loss Of Function ◽  
Zinc Finger Transcription Factor ◽  
Complete Penetrance ◽  
Familial Dilated Cardiomyopathy ◽  
Postnatal Adaptation

AbstractBackground:The zinc finger transcription factor CASZ1 plays a key role in cardiac development and postnatal adaptation, and in mice, deletion of theMethods:The coding exons and splicing junction sites of theResults:A novel heterozygous CASZ1 mutation, p.K351X, was identified in an index patient with DCM. Genetic analysis of the mutation carrier’s family showed that the mutation co-segregated with DCM, which was transmitted in an autosomal dominant pattern with complete penetrance. The nonsense mutation, which was absent in 400 referential chromosomes, altered the amino acid that was highly conserved evolutionarily. Biological investigations revealed that the mutant CASZ1 had no transcriptional activity.Conclusions:The current study reveals

MEF2C loss-of-function mutation associated with familial dilated cardiomyopathy

2018 ◽  
Vol 56 (3) ◽  
pp. 502-511 ◽  
Author(s):  
Fang Yuan ◽  
Zhao-Hui Qiu ◽  
Xing-Hua Wang ◽  
Yu-Min Sun ◽  
Jun Wang ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Cardiac Development ◽  
Index Patient ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Complete Penetrance ◽  
Familial Dilated Cardiomyopathy ◽  
Wild Type Counterpart ◽  
New Gene ◽  
Close Relatives

AbstractBackground:The MADS-box transcription factor myocyte enhancer factor 2C (MEF2C) is required for the cardiac development and postnatal adaptation and in mice-targeted disruption of theMEF2Cgene results in dilated cardiomyopathy (DCM). However, in humans, the association ofMEF2Cvariation with DCM remains to be investigated.Methods:The coding regions and splicing boundaries of theMEF2Cgene were sequenced in 172 unrelated patients with idiopathic DCM. The available close relatives of the index patient harboring an identifiedMEF2Cmutation and 300 unrelated, ethnically matched healthy individuals used as controls were genotyped forMEF2C. The functional effect of the mutant MEF2C protein was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system.Results:A novel heterozygous MEF2C mutation, p.Y157X, was detected in an index patient with adult-onset DCM. Genetic screen of the mutation carrier’s family members revealed that the mutation co-segregated with DCM, which was transmitted as an autosomal dominant trait with complete penetrance. The non-sense mutation was absent in 300 control individuals. Functional analyses unveiled that the mutant MEF2C protein had no transcriptional activity. Furthermore, the mutation abolished the synergistic transactivation between MEF2C and GATA4 as well as HAND1, two other transcription factors that have been associated with DCM.Conclusions:This study indicatesMEF2Cas a new gene responsible for human DCM, which provides novel insight into the mechanism underpinning DCM, suggesting potential implications for development of innovative prophylactic and therapeutic strategies for DCM, the most prevalent form of primary myocardial disease.

HAND1 loss-of-function mutation associated with familial dilated cardiomyopathy

2016 ◽  
Vol 54 (7) ◽  
Author(s):  
Yi-Meng Zhou ◽  
Xiao-Yong Dai ◽  
Xing-Biao Qiu ◽  
Fang Yuan ◽  
Ruo-Gu Li ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Molecular Mechanisms ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Loss Of Function ◽  
Coding Region ◽  
Helix Loop Helix ◽  
Complete Penetrance ◽  
Familial Dilated Cardiomyopathy ◽  
Synergistic Activation

AbstractThe basic helix-loop-helix transcription factor HAND1 is essential for cardiac development and structural remodeling, and mutations in HAND1 have been causally linked to various congenital heart diseases. However, whether genetically compromised HAND1 predisposes to dilated cardiomyopathy (DCM) in humans remains unknown.The whole coding region and splicing junctions of theA novel heterozygous HAND1 mutation, p.R105X, was identified in a family with DCM transmitted as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. The nonsense mutation was absent in 520 control chromosomes. Functional analyses unveiled that the mutant HAND1 had no transcriptional activity. Furthermore, the mutation abolished the synergistic activation between HAND1 and GATA4, another crucial cardiac transcription factors that has been associated with various congenital cardiovascular malformations and DCM.This study firstly reports the association of HAND1 loss-of-function mutation with increased susceptibility to DCM in humans, which provides novel insight into the molecular mechanisms underpinning DCM.

scholarly journals The apple C2H2-type zinc finger transcription factor MdZAT10 positively regulates JA-induced leaf senescence by interacting with MdBT2

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Kuo Yang ◽  
Jian-Ping An ◽  
Chong-Yang Li ◽  
Xue-Na Shen ◽  
Ya-Jing Liu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Transcription Factor ◽  
Liquid Chromatography ◽  
Zinc Finger ◽  
Leaf Senescence ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Liquid Chromatography Mass Spectrometry ◽  
Zinc Finger Transcription Factor ◽  
Insight Into

AbstractJasmonic acid (JA) plays an important role in regulating leaf senescence. However, the molecular mechanisms of leaf senescence in apple (Malus domestica) remain elusive. In this study, we found that MdZAT10, a C2H2-type zinc finger transcription factor (TF) in apple, markedly accelerates leaf senescence and increases the expression of senescence-related genes. To explore how MdZAT10 promotes leaf senescence, we carried out liquid chromatography/mass spectrometry screening. We found that MdABI5 physically interacts with MdZAT10. MdABI5, an important positive regulator of leaf senescence, significantly accelerated leaf senescence in apple. MdZAT10 was found to enhance the transcriptional activity of MdABI5 for MdNYC1 and MdNYE1, thus accelerating leaf senescence. In addition, we found that MdZAT10 expression was induced by methyl jasmonate (MeJA), which accelerated JA-induced leaf senescence. We also found that the JA-responsive protein MdBT2 directly interacts with MdZAT10 and reduces its protein stability through ubiquitination and degradation, thereby delaying MdZAT10-mediated leaf senescence. Taken together, our results provide new insight into the mechanisms by which MdZAT10 positively regulates JA-induced leaf senescence in apple.

scholarly journals Mutations in transcription factor CP2-like 1 may cause a novel syndrome with distal renal tubulopathy in humans

2020 ◽  
Author(s):  
Verena Klämbt ◽  
Max Werth ◽  
Ana C Onuchic-Whitford ◽  
Maike Getwan ◽  
Thomas M Kitzler ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Activity ◽  
Kidney Development ◽  
Renal Tubules ◽  
Loss Of Function ◽  
Distal Nephron ◽  
Truncating Mutation ◽  
Whole Exome ◽  
Hypokalemic Alkalosis ◽  
Echogenic Kidneys

Abstract Background An underlying monogenic cause of early-onset chronic kidney disease (CKD) can be detected in ∼20% of individuals. For many etiologies of CKD manifesting before 25 years of age, >200 monogenic causative genes have been identified to date, leading to the elucidation of mechanisms of renal pathogenesis. Methods In 51 families with echogenic kidneys and CKD, we performed whole-exome sequencing to identify novel monogenic causes of CKD. Results We discovered a homozygous truncating mutation in the transcription factor gene transcription factor CP2-like 1 (TFCP2L1) in an Arabic patient of consanguineous descent. The patient developed CKD by the age of 2 months and had episodes of severe hypochloremic, hyponatremic and hypokalemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. We found that TFCP2L1 was localized throughout kidney development particularly in the distal nephron. Interestingly, TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1 in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient’s mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity. Conclusion Here, we identified a loss-of-function TFCP2L1 mutation as a potential novel cause of CKD in childhood accompanied by a salt-losing tubulopathy.

scholarly journals In addition to being a marker for muscle connective tissue, Odd skipped-related 2 (OSR2) is expressed in differentiated muscle cells during chick development

2018 ◽  
Author(s):  
Sonya Nassari ◽  
Mickael Orgeur ◽  
Cédrine Blavet ◽  
Sigmar Stricker ◽  
Claire Fournier-Thibault ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Connective Tissue ◽  
Muscle Cells ◽  
Muscle Fibres ◽  
Chick Embryos ◽  
Loss Of Function ◽  
Zinc Finger Transcription Factor ◽  
Chick Development ◽  
Undifferentiated Cells

ABSTRACTThe zinc finger transcription factor, Odd skipped-related 2 (OSR2) is a recognized marker of connective tissue in chick embryos. OSR2 gain- and loss-of-function experiments indicate a role in irregular connective tissue differentiation in chick limb undifferentiated cells. Re-investigation of OSR2 transcript location during chick development with in situ hybridization experiments showed that OSR2 was also expressed in differentiated muscle cells in limbs and head. OSR2 expression was also observed in differentiated myotubes in chick foetal myoblast cultures. This shows that in addition to being a marker of connective tissue, OSR2 is also expressed in muscle fibres during chick development.

TBX20 loss-of-function mutation associated with familial dilated cardiomyopathy

2016 ◽  
Vol 54 (2) ◽  
Author(s):  
Cui-Mei Zhao ◽  
Bing-Sun ◽  
Hao-Ming Song ◽  
Juan Wang ◽  
Wen-Jun Xu ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Loss Of Function ◽  
Coding Regions ◽  
Complete Penetrance ◽  
Familial Dilated Cardiomyopathy ◽  
Genetic Components ◽  
Synergistic Activation ◽  
Autosomal Dominant Fashion ◽  
The Family ◽  
First Time

AbstractDilated cardiomyopathy (DCM) is a major cause of congestive heart failure, sudden cardiac death and cardiac transplantation. Aggregating evidence highlights the genetic origin of DCM. However, DCM is a genetically heterogeneous disorder, and the genetic components underlying DCM in most cases remain unknown.The coding regions and splicing junction sites of theA novel heterozygous TBX20 mutation, p.F256I, was identified in a family with DCM transmitted in an autosomal dominant fashion, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 600 control chromosomes and the altered amino acid was completely conserved evolutionarily among various species. Functional assays revealed that the mutant TBX20 had significantly diminished transcriptional activity. Furthermore, the mutation markedly reduced the synergistic activation of TBX20 with NKX2-5 or GATA4.This study links TBX20 loss-of-function mutation to idiopathic DCM in humans for the first time, providing novel insight into the molecular mechanism underpinning DCM.

scholarly journals Neuroimaging Findings in Patients with EBF3 Mutations: Report of Two Cases

2021 ◽  
pp. 1-8
Author(s):  
Mar Jiménez de la Peña ◽  
Ana Jiménez de Domingo ◽  
Pilar Tirado ◽  
Beatriz Calleja-Pérez ◽  
Luis A. Alcaraz ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Autosomal Dominant ◽  
De Novo ◽  
Diffusion Tensor ◽  
Loss Of Function ◽  
Normal Range ◽  
Early B Cell Factor ◽  
And Diffusion

Early B cell factor 3 (EBF3) is a transcription factor involved in brain development. Heterozygous, loss-of-function mutations in <i>EBF3</i> have been reported in an autosomal dominant neurodevelopmental syndrome characterized by hypotonia, ataxia, and developmental delay (sometimes described as “HADD”s). We report 2 unrelated cases with novel de novo <i>EBF3</i> mutations: c.455G&#x3e;T (p.Arg152Leu) and c.962dup (p.Tyr321*) to expand the genotype/phenotype correlations of this disorder; clinical, neuropsychological, and MRI studies were used to define the phenotype. IQ was in the normal range and diffusion tensor imaging revealed asymmetric alterations of the longitudinal fasciculus in both cases. Our results demonstrate that <i>EBF3</i> mutations can underlie neurodevelopmental disorders without intellectual disability. Long tract abnormalities have not been previously recognized and suggest that they may be an unrecognized and characteristic feature in this syndrome.

myoblasts incompetent encodes a zinc finger transcription factor required to specify fusion-competent myoblasts in Drosophila

Development ◽  
2002 ◽  
Vol 129 (1) ◽  
pp. 133-141 ◽  
Author(s):  
Mar Ruiz-Gómez ◽  
Nikola Coutts ◽  
Maximiliano L. Suster ◽  
Matthias Landgraf ◽  
Michael Bate
Keyword(s):  
Transcription Factor ◽  
Zinc Finger ◽  
Myoblast Fusion ◽  
Loss Of Function ◽  
Cubitus Interruptus ◽  
Zinc Finger Transcription Factor ◽  
General Pathway ◽  
Twist Expression ◽  
Fusion Competent Myoblasts ◽  
Normal Differentiation

We report a new gene, myoblasts incompetent, essential for normal myogenesis and myoblast fusion in Drosophila. myoblasts incompetent encodes a putative zinc finger transcription factor related to vertebrate Gli proteins and to Drosophila Cubitus interruptus. myoblasts incompetent is expressed in immature somatic and visceral myoblasts. Expression is predominantly in fusion-competent myoblasts and a loss-of-function mutation in myoblasts incompetent leads to a failure in the normal differentiation of these cells and a complete lack of myoblast fusion. In the mutant embryos, founder myoblasts differentiate normally and form mononucleate muscles, but genes that are specifically expressed in fusion-competent cells are not activated and the normal downregulation of twist expression in these cells fails to occur. In addition, fusion-competent myoblasts fail to express proteins characteristic of the general pathway of myogenesis such as myosin and Dmef2. Thus myoblasts incompetent appears to function specifically in the general pathway of myogenesis to control the differentiation of fusion-competent myoblasts.

scholarly journals Identification of ZBP-89 as a Novel GATA-1-Associated Transcription Factor Involved in Megakaryocytic and Erythroid Development

2008 ◽  
Vol 28 (8) ◽  
pp. 2675-2689 ◽  
Author(s):  
Andrew J. Woo ◽  
Tyler B. Moran ◽  
Yocheved L. Schindler ◽  
Seong-Kyu Choe ◽  
Nathaniel B. Langer ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Zinc Finger ◽  
Regulatory Elements ◽  
Loss Of Function ◽  
Zinc Finger Transcription Factor ◽  
Novel Proteins ◽  
Proteomic Approach ◽  
Primitive Erythropoiesis ◽  
Definitive Erythropoiesis

ABSTRACT A complete understanding of the transcriptional regulation of developmental lineages requires that all relevant factors be identified. Here, we have taken a proteomic approach to identify novel proteins associated with GATA-1, a lineage-restricted zinc finger transcription factor required for terminal erythroid and megakaryocytic maturation. We identify the Krüppel-type zinc finger transcription factor ZBP-89 as being a component of multiprotein complexes involving GATA-1 and its essential cofactor Friend of GATA-1 (FOG-1). Using chromatin immunoprecipitation assays, we show that GATA-1 and ZBP-89 cooccupy cis-regulatory elements of certain erythroid and megakaryocyte-specific genes, including an enhancer of the GATA-1 gene itself. Loss-of-function studies in zebrafish and mice demonstrate an in vivo requirement for ZBP-89 in megakaryopoiesis and definitive erythropoiesis but not primitive erythropoiesis, phenocopying aspects of FOG-1- and GATA-1-deficient animals. These findings identify ZBP-89 as being a novel transcription factor involved in erythroid and megakaryocytic development and suggest that it serves a cooperative function with GATA-1 and/or FOG-1 in a developmental stage-specific manner.

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