FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy

Al-Yacoub, Nadya; Shaheen, Ranad; Awad, Salma Mahmoud; Kunhi, Mohammed; Dzimiri, Nduna; Nguyen, Henry C.; Xiong, Yong; Al-Buraiki, Jehad; AlHabeeb, Waleed; Poizat, Coralie

doi:10.1186/s13059-015-0861-4

Cited by 36 publications

(28 citation statements)

References 34 publications

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“…; Al‐Yacoub et al . ). A homozygous mutation (Gly243Arg) in the cardiac E3 ligase, FBXO32 (Atrogin 1/MAFbx), was recently found to be associated with DCM (Watanabe et al .…”

Section: Introductionmentioning

confidence: 97%

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Proteasome dysfunction in cardiomyopathies

Gilda

Gomes

2017

The Journal of Physiology

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The ubiquitin-proteasome system (UPS) plays a critical role in removing unwanted intracellular proteins and is involved in protein quality control, signalling and cell death. Because the heart is subject to continuous metabolic and mechanical stress, the proteasome plays a particularly important role in the heart, and proteasome dysfunction has been suggested as a causative factor in cardiac dysfunction. Proteasome impairment has been detected in cardiomyopathies, heart failure, myocardial ischaemia, and hypertrophy. Proteasome inhibition is also sufficient to cause cardiac dysfunction in healthy pigs, and patients using a proteasome inhibitor for cancer therapy have a higher incidence of heart failure. In this Topical Review we discuss the experimental data which suggest UPS dysfunction is a common feature of cardiomyopathies, with an emphasis on hypertrophic cardiomyopathy caused by sarcomeric mutations. We also propose potential mechanisms by which cardiomyopathy-causing mutations may lead to proteasome impairment, such as altered calcium handling and increased oxidative stress due to mitochondrial dysfunction.

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“…; Al‐Yacoub et al . ). A homozygous mutation (Gly243Arg) in the cardiac E3 ligase, FBXO32 (Atrogin 1/MAFbx), was recently found to be associated with DCM (Watanabe et al .…”

Section: Introductionmentioning

confidence: 97%

“…; Al‐Yacoub et al . ). There are also reports of protein aggregation in DCM, which may be linked to UPS function (Hamada et al .…”

Section: Introductionmentioning

confidence: 97%

Proteasome dysfunction in cardiomyopathies

Gilda

Gomes

2017

The Journal of Physiology

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“…Our top associated marker in the current study was in FBXO32 (rs2280915; p = 2.70E − 12). FBXO32 constitutes one of the four subunits of the SCF (SKP1‐cullin‐F‐box) ubiquitin protein ligase complex (Al‐Yacoub et al, ). It has previously been suggested that the ubiquitin proteasome system is dysregulated in schizophrenia, schizoaffective disorder, BD, and psychosis (Arion et al, ; Bousman et al, , ; Scott, Rubio, Haroutunian, & Meador‐Woodruff, ).…”

Section: Discussionmentioning

confidence: 99%

Fine‐mapping scan of bipolar disorder susceptibility loci in Latino pedigrees

Gonzalez

Villa

Rodriguez

et al. 2019

American J of Med Genetics Pt B

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We previously identified bipolar disorder (BD) susceptibility loci on 8q24, 14q32, and 2q12-14 in a genome-wide nonparametric linkage screen in a Latino cohort. We now perform a fine mapping analysis using a dense map of additional SNPs to identify BD susceptibility genes within these regions. One thousand nine hundred and thirty-eight individuals with Latino ancestry (880 individuals with BD Type I or Schizoaffective, Bipolar Type) from 416 Latino pedigrees from the United States, Mexico, Costa Rica, and Guatemala were genotyped with 3,074 SNPs to provide dense coverage of the 8q24 (11.5 cM), 14q32 (7.5 cM), and 2q12-14 (6.5 cM) chromosomal loci. Single-marker association tests in the presence of linkage were performed using the LAMP software. The top linkage peak (rs7834818; LOD = 5.08, p = 3.30E − 5) and associated single marker (rs2280915, p = 2.70E − 12) were located within FBXO32 on 8q24. On chromosome 2, the top linkage peak (rs6750326; LOD = 5.06, p = 3.50E − 5) and associated single marker (rs11887088, p = 2.90E − 6) were located in intragenic regions near ACTR3 and DPP10.None of the additional markers in the region around chromosome 14q32 met significance levels for linkage or association. We identified six SNPs on 2q12-q14 and one SNP in FBXO32 on 8q24 that were significantly associated with BD in this Latino cohort. K E Y W O R D SACTR3, bipolar disorder, DPP10, FBXO32, Latino ancestry

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“…8,[10][11][12][13][14][15][16][17][18][19][20] Although we made a genetic analysis of several cardiac core transcriptional factor genes in the two mutation carriers with DCM, including GATA4, GATA5, GATA6, TBX5, TBX20, and HAND1, as described previously, [22][23][24][25][26][27][28][29][30][31] and found no mutations, we cannot rule out the possibility that the genetic variants in other genes may also contribute to DCM in these two patients. Genome sequencing analysis may help to explain the possibility for these patients.…”

Section: Discussionmentioning

confidence: 99%

“…8,9) At present, an increasing number of causative mutations in > 50 genes have been causally linked to idiopathic DCM. 8,[10][11][12][13][14][15][16][17][18][19][20] Among these well established DCM-associated genes, most encode contractile sarcomeric proteins as well as cytoskeletal/sarcolemmal and nuclear envelope proteins. 8) Nevertheless, these DCM-causing genes can explain only about one-third of patients and for most genes, the mutational frequency is low, with genetic mutation occurring in < 1% of DCM patients.…”

Section: Ilated Cardiomyopathy (Dcm) Which Is Defined Bymentioning

confidence: 99%

Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy

Guo

et al. 2017

Int. Heart J.

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SummaryDilated cardiomyopathy (DCM), the most common form of primary myocardial disease, is a leading cause of congestive heart failure and the most common indication for heart transplantation. Recently, NKX2-5 mutations have been involved in the pathogenesis of familial DCM. However, the prevalence and spectrum of NKX2-5 mutations associated with sporadic DCM remain to be evaluated. In this study, the coding regions and flanking introns of the NKX2-5 gene, which encodes a cardiac transcription factor pivotal for cardiac development and structural remodeling, were sequenced in 210 unrelated patients with sporadic adult-onset DCM. A total of 300 unrelated healthy individuals used as controls were also genotyped for NKX2-5. The functional effect of the mutant NKX2-5 was investigated using a dual-luciferase reporter assay system. As a result, two novel heterozygous NKX2-5 mutations, p.R139W and p.E167X, were identified in 2 unrelated patients with sporadic adult-onset DCM, with a mutational prevalence of approximately 0.95%. The mutations were absent in 600 referential chromosomes and the altered amino acids were completely conserved evolutionarily across species. Functional assays revealed that the NKX2-5 mutants were associated with significantly reduced transcriptional activity. Furthermore, the mutations abrogated the synergistic activation between NKX2-5 and GATA4 as well as TBX20, two other cardiac key transcription factors that have been causally linked to adult-onset DCM. This study is the first to associate NKX2-5 loss-of-function mutations with enhanced susceptibility to sporadic DCM, which provides novel insight into the molecular etiology underpinning DCM, and suggests the potential implications for the genetic counseling and personalized treatment of the DCM patients. (Int Heart J 2017; 58: 521-529)

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FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy

Cited by 36 publications

References 34 publications

Proteasome dysfunction in cardiomyopathies

Proteasome dysfunction in cardiomyopathies

Fine‐mapping scan of bipolar disorder susceptibility loci in Latino pedigrees

Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy

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