ABSTRACT
Recently we reported that Rearranged L-Myc Fusion, RLF, acts as an epigenetic modifier maintaining low levels of DNA methylation at CpG island shores and enhancers across the genome. Here we focus on the phenotype of Rlf null mutant mice generated via an ENU mutagenesis screen, to identify genes required for epigenetic regulation. RLF is expressed in a range of fetal mouse tissues, including the fetal heart. Comprehensive timed-mating studies are consistent with our previously reported findings that Rlf homozygous mutant mice rarely survive to adulthood, with the majority dying shortly after birth. Histological analysis of two independent Rlf ENU mutant lines at E11.5-E14.5 showed heart defects resembling those present in humans with Left Ventricular Non-Compaction (LVNC). In situ hybridisation analysis localized expression of Rlf to the endocardium and epicardium of embryonic and postnatal hearts, and transiently to cardiomyocytes during heart looping and early chamber formation stages. RNA-seq analysis of Rlf mutant hearts highlighted defective NOTCH pathway signalling, recently describe as one cause of LVNC. This study provides the first evidence that RLF is required for normal heart development in the mouse. The heart morphological defects present at high penetrance in Rlf mutants are consistent with features of LVNC in humans, and molecular analysis identified attenuated JAGGED 1 expression and NOTCH signalling as likely contributors to these defects. Our study highlights the importance of RLF-dependent epigenetic modifications to DNA for maintaining correct gene regulatory network and intercellular signalling interactions during heart chamber and septal development. Further investigations are needed to define the biochemical role of RLF in the developing heart, and whether RLF mutations are a cause of heart defects in humans.
Subject(s)
Cell Differentiation/genetics , Heart/growth & development , Organogenesis/genetics , Transcription Factors/genetics , Animals , DNA Methylation/genetics , Epigenesis, Genetic , Gene Regulatory Networks/genetics , Guanine Nucleotide Exchange Factors , Humans , Jagged-1 Protein/genetics , Mice , Mutation , Receptors, Notch/geneticsABSTRACT
The novel HLA-B*5813 allele was identified in the cord blood of a Korean baby by sequence-based typing. This allele shows a sequence identical to that of HLA-B*5801, except for a nucleotide substitution that changes GAG to AAG at codon 128, resulting in an amino acid change from glutamic acid to lysine in the protein.
Subject(s)
Fetal Blood/metabolism , HLA-B Antigens/genetics , Polymorphism, Genetic , Sequence Analysis, DNA/methods , Asian People , Base Sequence , Genetic Variation , Histocompatibility Testing , Humans , Infant, Newborn , Introns , Korea , Molecular Sequence Data , Sequence Homology, Nucleic AcidSubject(s)
Alleles , Asian People/genetics , HLA-A Antigens/genetics , Amino Acid Sequence , Amino Acid Substitution , Base Sequence , Exons , Histocompatibility Testing , Humans , Introns , Korea , Molecular Sequence Data , Polymorphism, Single Nucleotide , Protein Structure, Secondary , Sequence Analysis, DNASubject(s)
Alleles , HLA-B Antigens/chemistry , HLA-B Antigens/genetics , Peptide Fragments/metabolism , Sequence Analysis, DNA , Tryptophan/metabolism , Amino Acid Substitution , Binding Sites , HLA-B Antigens/metabolism , Hematopoietic Stem Cell Transplantation , Histocompatibility Testing , Humans , Hydrogen Bonding , Korea , Models, Molecular , Polymerase Chain Reaction , Protein Binding , Tryptophan/chemistry , Tryptophan/genetics , Water/chemistrySubject(s)
Alleles , HLA-C Antigens/genetics , Sequence Analysis, DNA , Amino Acid Substitution , Base Sequence , Child, Preschool , HLA-C Antigens/immunology , Hematopoietic Stem Cell Transplantation , Histocompatibility Testing , Humans , Korea , Male , Molecular Sequence Data , Polymerase Chain Reaction , Sequence Homology, Nucleic AcidABSTRACT
In this report, we describe the identification of an human leucocyte antigen-Cw*06 (HLA-Cw*06) nucleotide sequence variant, a new HLA-Cw*0612. The new allele was detected during routine HLA typing by high-resolution sequence-based typing. Allele Cw*0612 showed one nucleotide difference with Cw*0602 at codon 153 (GCG-->ACG) resulting in an amino acid change from alanine to threonine.
Subject(s)
Alleles , Amino Acid Substitution/genetics , HLA-C Antigens/genetics , Point Mutation/genetics , Amino Acid Substitution/immunology , Base Sequence , HLA-C Antigens/chemistry , HLA-C Antigens/immunology , Humans , Molecular Sequence Data , Point Mutation/immunology , Protein Structure, Tertiary/geneticsABSTRACT
In this report, we describe the identification of an human leucocyte antigen-Cw*0102 (HLA-Cw*0102) nucleotide sequence variant, a new HLA-Cw*010203, in a case - control study by using sequence-based typing. Allele HLA-Cw*010203 showed one nucleotide difference with HLA-Cw*010201 by a silent substitution at codon 130 (CTG-->CTA).
Subject(s)
Alleles , HLA-C Antigens/genetics , Base Sequence , Case-Control Studies , Codon , Exons , Female , Histocompatibility Testing , Humans , Introns , Leucine/genetics , Middle Aged , Molecular Sequence Data , Peptides/chemistry , Sequence Analysis, DNA , Sequence Homology, Nucleic AcidABSTRACT
In this report, we describe the identification of a human leucocyte antigen-A*11 (HLA-A*11) nucleotide sequence variant, a new HLA-A*1120 by using sequence-based typing (SBT). The new allele was detected during routine HLA typing by high-resolution SBT. Allele A*1120 showed one nucleotide difference with A*110101 at codon 152 (GCG-->GAG) resulting in an amino acid change from alanine to glutamate. Residue 152 is located on alpha(2)-helix of HLA class I molecule and involved in peptide binding by constructing E pocket of peptide-binding groove, implying that the change of the residue 152 would affect the binding affinity of peptides to A*1120 allele.
Subject(s)
Alleles , Base Sequence , HLA-A Antigens/genetics , HLA-A Antigens/immunology , Asian People/genetics , Exons , Histocompatibility Testing/methods , Humans , Korea/ethnology , Models, Biological , Molecular Sequence Data , Polymorphism, Single Nucleotide , Protein Binding , Sequence AlignmentABSTRACT
In this report, we describe the identification of an HLA-A*31 nucleotide sequence variant, a new HLA-A*3111, in three members of a Korean family by using sequence-based typing (SBT). The new allele was detected during routine HLA typing by high-resolution SBT. Allele A*3111 showed one nucleotide difference with A*310102 at codon 165 (GTG-->CTG) resulting in an amino acid change from valine to leucine (V165L). Serologic reactivity was shorter than normally expected.
Subject(s)
Alleles , HLA-A Antigens/genetics , HLA-A Antigens/immunology , Asian People/genetics , Base Sequence , Codon/genetics , Histocompatibility Testing/methods , Humans , Korea/ethnology , Molecular Sequence Data , Polymorphism, Single Nucleotide , Sequence AlignmentABSTRACT
We report here a new HLA-B*56 allele, B*560502, identified by sequencing-based typing in the Korean population. HLA-B*560502 differs from B*560501 by a single nucleotide at position 141 in exon 2 (T(r)C). This single nucleotide substitution may not result in an amino acid difference in the alpha1 domain at residue 23. The putative haplotype involving B*560502 may be A*24-DRB1*1201-DQA1*0503-DQB1*0304-DPB1*0202.
