OBJECTIVE: To analyze the genotype and clinical phenotype of a 3-month-old female infant featuring unresponsiveness. METHODS: The infant was subjected to genetic testing, and her clinical features were compared with syndromes associated with variants of the candidate gene. RESULTS: The patient has featured long fingers, long and overlapped toes, musk-like face, blepharophimosis, ptosis, and lacrimal duct anomaly. She was found to harbor a heterozygous de novo variant NM_012330.3: c.3040C>T (p.Gln1014*) in exon 16 of the KAT6B gene. Her clinical phenotype and genotype have both conformed to Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS). CONCLUSION The child was diagnosed with SBBYSS syndrome due to the c.3040C>T (p.Gln1014*) variant of the the KAT6B gene. Discovery of the unique features has expanded the phenotypic spectrum of this syndrome.
Female ; Humans ; Blepharophimosis/genetics* ; Blepharoptosis ; Genotype ; Histone Acetyltransferases ; Infant

OBJECTIVE: To explore the genetic etiology for a child featuring mental retardation and speech delay. METHODS: Clinical data of the child was collected. DNA was extracted from peripheral blood samples of the child and members of his pedigree. Whole exome sequencing was carried out for the child, and candidate variants were verified by Sanger sequencing. Prenatal diagnosis was provided for his mother upon her subsequent pregnancy. RESULTS: The child has mainly featured mental retardation, speech delay, ptosis, strabismus, photophobia, hyperactivity, and irritability. Whole exome sequencing revealed that he has harbored a pathogenic heterozygous variant of the KAT6A gene, namely c.5314dupA (p.Ser1772fs*20), which was not detected in either of his parents. The child was diagnosed with Arboleda-Tham syndrome. The child was also found to harbor a hemizygous c.56T>G (p.Leu19Trp) variant of the AIFM1 gene, for which his mother was heterozygous and his phenotypically normal maternal grandfather was hemizygous. Pathogenicity was excluded. Prenatal diagnosis has excluded the c.5314dupA variant of the KAT6A gene in the fetus. CONCLUSION The heterozygous c.5314dupA (p.Ser1772fs*20) variant of the KAT6A gene probably underlay the Arboleda-Tham syndrome in this child. Above finding has enabled genetic counseling and prenatal diagnosis for this pedigree.
Child ; Humans ; Male ; Pregnancy ; Histone Acetyltransferases ; Intellectual Disability/genetics* ; Language Development Disorders ; Pedigree

During the past few years, gene expression studies have shown that the perturbation of transcription frequently results in neuronal dysfunction in polyglutamine (PolyQ) diseases such as Huntington's disease (HD). Histone deacetylases (HDACs) act as repressors of transcription through interaction with co-repressor complexes, leading to chromatin remodelling. Aberrant interaction between PolyQ proteins and regulators of transcription could be one mechanism by which transcriptional dysregulation occurs. Here, the authors discuss the possible mechanism of transcriptional dysfunction in PolyQ disease, including the effect of histone acetyltransferases (HATs) and HDACs on pathogenesis, and the potential therapeutic pathways through which histone deacetylase inhibitors (HDACIs) might act to correct the aberrant transcription observed in HD and other PolyQ diseases.
Animals ; Histone Acetyltransferases ; genetics ; metabolism ; Histone Deacetylase Inhibitors ; therapeutic use ; Histone Deacetylases ; genetics ; metabolism ; Humans ; Huntington Disease ; drug therapy ; enzymology ; metabolism ; Peptides ; metabolism

OBJECTIVE: To explore the genetic basis for a child suspected for Say-Barber-Biesecker-Young-Simpson syndrome. METHODS: Genomic DNA was extracted from peripheral blood samples of the child and her parents. Whole exome sequencing was carried out for the proband. Suspected variants were validated by Sanger sequencing. The impact of the variants was predicted by bioinformatic analysis. RESULTS: The child was found to harbor a de novo missense variant c.2623C>T (p.Asp875Tyr) in exon 13 of the KAT6B gene. The variant was previously unreported, and was not recorded in the major allele frequency database and predicted to be pathogenic based on PolyPhen-2, MutationTaster and PROVEAN analysis. As predicted by UCSF chimera and CASTp software, the variant can severely impact the substrate-binding pocket of histone acetyltransferase, resulting in loss of its enzymatic activity. Based on standards and guidelines by the American College of Medical Genetics and Genomics, the variant was classified to be likely pathogenic (PS2+PM2+PP3). CONCLUSION The child's condition may be attributed to the de novo missense c.2623C>T (p.Asp875Tyr) variant of the KAT6B gene.
Blepharophimosis ; Child ; Congenital Hypothyroidism ; Facies ; Female ; Heart Defects, Congenital ; Histone Acetyltransferases/genetics* ; Humans ; Intellectual Disability ; Joint Instability ; Mutation ; Phenotype

OBJECTIVETo investigate the expression and amplification of steroid receptor coactivator- 3(SRC- 3) gene in colorectal carcinoma (CRC) and its clinicopathological significance.

METHODSImmunohistochemistry and fluorescence in situ hybridization (FISH) were used to detect the expression and amplification of SRC- 3 gene in CRC, and its association with patient's clinical pathological features was analyzed.

RESULTSA total of 60 patients with CRC were studied. SAR- 3 proteins were overexpressed in 23 cases (38% ). There was a significant association between SAR- 3 overexpression and neoplasm staging (P< 0.01). SRC- 3 protein was overexpressed in 62% of patients with Dukes C or D stage, whereas SRC- 3 protein was normally expressed in 74% of patients with Dukes A or B stage. As for FISH study, 47 cases were informative. High- level amplification of SRC- 3 gene was detected in 6 cases(13% ) and all showed overexpression of SRC- 3 protein. Low- level amplification of SRC- 3 was observed in 9 cases (19% ). Overexpression of SRC- 3 was detected in 6 cases. The remaining 9 of 32 patients(28% ) without amplification of SRC- 3 gene were observed with overexpression of SRC- 3 protein. In addition, 91% patients with CRC were found overexpression of SRC- 3 as well as overexpression of P53.

CONCLUSIONThe abnormal expression of SRC- 3 gene might impact on the function of P53 and development of CRC. There might exist some unknown mechanisms other than gene amplification of SRC- 3 to regulate its encoded protein expression in CRC.

Biomarkers, Tumor ; genetics ; Colorectal Neoplasms ; genetics ; pathology ; Female ; Gene Expression ; Histone Acetyltransferases ; genetics ; Humans ; Male ; Middle Aged ; Neoplasm Staging ; Nuclear Receptor Coactivator 3 ; Trans-Activators ; genetics

OBJECTIVETo study the expression of histone acetyltransferases (HATs) and histone deacetylases (HDACs) in children with tetralogy of Fallot (TOF), and to investigate the role of histone acetylation and acetylation-related enzymes in the pathogenesis of TOF.

METHODSMyocardial tissue samples in the TOF group were obtained from 46 children with TOF who underwent radical operation, and myocardial tissue samples in the control group were obtained from 16 children who suffered accidental deaths and had no cardiac anomalies as shown by autopsy. The acetylation of H3K9, H3K18 and H3K27 was evaluated by immunohistochemistry. The mRNA expression of HATs and HDACs in the myocardium was measured by real-time PCR. The correlation between mRNA expression of HATs and HDACs and histone acetylation was analyzed.

RESULTSCompared with the control group, the TOF group showed significantly increased acetylation of H3K9 (P=0.0165) and significantly decreased acetylation of H3K18 (P=0.0048) and H3K27 (P=0.0084). As to 4 HATs and 6 HDACs, the mRNA expression of EP300 and CBP was significantly higher in the TOF group than in the control group (P=0.025; P=0.017), and there was no significant difference in the mRNA expression of other HATs and HDACs between the two groups. The correlation analysis revealed a positive correlation between H3K9 acetylation and mRNA expression of EP300 (r=0.71, P<0.01) and CBP (r=0.72, P<0.01).

CONCLUSIONSUpregulated mRNA expression of EP300 and CBP may be associated with increased H3K9 acetylation, suggesting that EP300 and CBP might affect cardiac development by regulating H3K9 acetylation.

Acetylation ; E1A-Associated p300 Protein ; genetics ; Female ; Histone Acetyltransferases ; genetics ; Histone Deacetylases ; genetics ; Histones ; metabolism ; Humans ; Infant ; Male ; Myocardium ; metabolism ; Peptide Fragments ; genetics ; RNA, Messenger ; analysis ; Sialoglycoproteins ; genetics ; Tetralogy of Fallot ; metabolism

OBJECTIVETo explore the effects of histone acetylation modification on the regulation of mesenchymal stem cells (MSCs) differentiation into cardiomyocytes in myocardium microenvironment, by detecting the acetylase activity, expression of histone acetylation gene Gcn5 and myocardial gene GATA4 in myocardium transplanted by MSCs transfected with plasmid ZJ3.

METHODSExtracted the plasmid containing short hairpin RNA (shRNA) against Gcn5 gene (ZJ3) and transfected it into MSCs. After 24 hours, the MSCs were transplanted into the rat myocardium tissues and the acetylase activity, the expression of acetylation gene and myocardium development gene were detected after two weeks.

RESULTSThe acetylase activity in the experimental group was significantly lower than all control groups; Gcn5 and GATA4 expression in myocardium of experimental group had significant reduction compared with the control groups.

CONCLUSIONInhibition of histone acetylation in the MSC cells can inhibit the transcription process of specialized myocardium in the myocardium microenvironment. The result establishes foundation for researches of histone acetylation and mechanisms of MSCs differentiation.

Acetylation ; Animals ; Cell Differentiation ; genetics ; physiology ; Cells, Cultured ; Histone Acetyltransferases ; genetics ; Histones ; metabolism ; Mesenchymal Stromal Cells ; cytology ; metabolism ; RNA Interference ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo observe the temporal modification of transcription factor Mef2c by histone acetylases (HATs) P300, PCAF, and SRC1 during cardiogenesis and to provide a basis for investigating the pathogenesis of congenital heart disease.

METHODSThe normal heart tissues from embryonic mice (embryonic days 14.5 and 16.5) and neonatal mice (postnatal days 0.5 and 7) were collected. The binding of P300, PCAF, and SRC1 to Mef2c gene and level of histone H3 acetylation in the promoter region of Mef2c were evaluated by chromatin immunoprecipitation assays. Meanwhile, real-time PCR was used to measure the mRNA expression of Mef2c.

RESULTSP300, PCAF, SRC1 were involved in histone acetylation in the promoter region of Mef2c during cardiogenesis in mice, and binding of P300, PCAF, and SRC1 to the promoter of Mef2c varied significantly in different stages of cardiogenesis (P<0.01). The level of histone H3 acetylation and mRNA expression of Mef2c in the promoter region of Mef2c also varied significantly in different stages of cardiac development (P<0.01). The levels of acetylated H3, Mef2c mRNA, and HATs (P300, PCAF, SRC1) changed over time. They were highest on embryonic day 14.5 (P<0.01), decreased gradually with cardiac development, and were maintained at low levels after birth.

CONCLUSIONSThe mRNA expression of Mef2c varies during cardiogenesis in mice, which indicates that Mef2c plays an important role in the process of cardiac development. Meanwhile, histone acetylation in the promoter region of Mef2c is regulated temporally by HATs P300, PCAF, and SRC1.

Animals ; Female ; Gene Expression Regulation, Developmental ; Heart ; embryology ; Histone Acetyltransferases ; physiology ; MEF2 Transcription Factors ; genetics ; physiology ; Male ; Mice ; Promoter Regions, Genetic ; RNA, Messenger ; analysis

Acetylation ; Animals ; Child ; DNA Methylation ; Epigenesis, Genetic ; Heart ; physiology ; Heart Defects, Congenital ; etiology ; genetics ; metabolism ; Histone Acetyltransferases ; metabolism ; Histone Deacetylases ; metabolism ; Histones ; chemistry ; genetics ; physiology ; Humans ; Protein Processing, Post-Translational ; Transcription Factors ; metabolism

Animals ; Cytidine ; analogs & derivatives ; pharmacology ; DNA Methylation ; drug effects ; DNA Modification Methylases ; metabolism ; Gene Knockout Techniques ; Histone Acetyltransferases ; metabolism ; Histone Deacetylase Inhibitors ; pharmacology ; Humans ; Hydroxamic Acids ; pharmacology ; Neoplasms ; genetics ; physiopathology ; therapy ; RNA Interference ; Valproic Acid ; pharmacology