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Parkinsonism & Related Disorders Dec 2022Hyperekplexia is a disease that progresses with excessive startle attacks and is included in the differential diagnosis of epilepsy and many movement disorders.
BACKGROUND
Hyperekplexia is a disease that progresses with excessive startle attacks and is included in the differential diagnosis of epilepsy and many movement disorders.
METHODS
The WES results were validated in available family members by Sanger sequencing, or in the case of deletion, PCR followed by agarose gel electrophoresis was performed.
RESULTS
WES analysis revealed the previously reported homozygous c.277C>T p.Arg93Trp variant in the GLRA1 gene (ENST00000455880.2) in Family 1. In all other three families, the previously reported homozygous deletion of exons 1-7 of the GLRA1 gene was identified using CNV analysis based on the WES data.
CONCLUSIONS
The homozygous exon1-7 deletion has been described several times in different populations and may be a founder mutation in the Kurdish people in Turkey. The family with Arg93Trp variant stems from the Black Sea region of Turkey where close consanguinity is common. These analyses are important to provide genetic counseling to families and for a better understanding of the pathophysiology of the disease.
Topics: Humans; Hyperekplexia; Mutation, Missense; Homozygote; Turkey; Sequence Deletion; Exons
PubMed: 36434917
DOI: 10.1016/j.parkreldis.2022.11.011 -
Chemical Communications (Cambridge,... Oct 2022Base excision (BE) is an important yet hard-to-control biological event. Unnatural base pairs are powerful tools to revolutionize biological studies in various areas. In...
Base excision (BE) is an important yet hard-to-control biological event. Unnatural base pairs are powerful tools to revolutionize biological studies in various areas. In this paper, we report a visible-light-induced method to construct site-specific unnatural BE and show the influence of its regulation on transcription and translation levels.
Topics: Base Pairing; Light; Nucleotides; Mutagenesis, Site-Directed; Sequence Deletion
PubMed: 36184910
DOI: 10.1039/d2cc03664a -
BMC Medical Genetics Jan 2019Autosomal recessive nail dysplasia is characterized by thick and hard nails with a very slow growth on the hands and feet. Mutations in FZD6 gene were found to be...
BACKGROUND
Autosomal recessive nail dysplasia is characterized by thick and hard nails with a very slow growth on the hands and feet. Mutations in FZD6 gene were found to be associated with autosomal recessive nail dysplasia in 2011. Presently, only seven mutations have been reported in FZD6 gene; five mutations are clustered in the C-terminus, one is at the seventh transmembrane domain, and another is at the very beginning of third extracellular loop.
METHODS
Whole exome sequencing (WES) was applied to the index case, her one affected sister and her healthy consanguineous parents. The mutation was verified via Sanger sequencing. Molecular dynamics simulations of the predicted structures of native and mutant proteins were compared to gain insight into the pathogenicity mechanism of the mutation.
RESULTS
Here, we report a homozygous 8 bp deletion mutation, p.Gly559Aspfs*16; c.1676_1683delGAACCAGC, in FZD6 gene which causes a frameshift and creates a premature stop codon at position 16 of the new reading frame. Our molecular dynamics calculations predict that the pathogenicity of this frameshift mutation may be caused by the change in entropy of the protein with negative manner, disturbing the C-terminal domain structure, and hence interaction partners of FZD6.
CONCLUSION
We identified a homozygous deletion mutation in FZD6 in a consanguineous Turkish family with nail dysplasia. We also provide a molecular mechanism about the effects of the deletion on the protein structure and its possible motions. This study provides a pathogenicity mechanism for this mutation in nail dysplasia for the first time.
Topics: Adult; Amino Acid Sequence; Codon, Nonsense; Consanguinity; Female; Frameshift Mutation; Frizzled Receptors; Genetic Association Studies; Genetic Predisposition to Disease; Homozygote; Humans; Models, Molecular; Mutation; Nails, Malformed; Pedigree; Protein Conformation; Sequence Analysis; Sequence Deletion; Turkey
PubMed: 30642273
DOI: 10.1186/s12881-019-0746-6 -
Journal of the Science of Food and... Mar 2016The disordered residues on distal loops affect the molecular structural stability and on some occasions have regulatory roles in catalytic reaction. To increase...
BACKGROUND
The disordered residues on distal loops affect the molecular structural stability and on some occasions have regulatory roles in catalytic reaction. To increase understanding of the influence of distal residue mutation, this study explored the thermostability and enzymatic activity of mannanase Man1312 deletion mutants. The focus was on residues located on the N-terminal region because they are more disordered and changeable. The effects of N-terminal truncation on enzymatic activity and thermal dynamics were investigated by spectrophotometry, circular dichroism and differential scanning calorimetry assays.
RESULTS
The deletion mutants on V3, N7 and Q11 showed a marked increase in stability, while the enzymatic activity was significantly improved when triplet deletion was carried out. Triplet deletion MandVNQ showed around double the stability of its corresponding single-site and double-site deletion mutants. The Tm value of MandVNP was about 8 °C higher than that of Man1312. MandVNP had improved characteristics of Topt by 10 °C, t1/2 by 10 min and catalytic activity by 11% in comparison with Man1312. Analysis of spectra and modeling showed that MandVNQ had increased helix and strand contents.
CONCLUSION
N-terminal truncation had positive effects on the thermostability and activity of mannanase.
Topics: Amino Acid Sequence; Enzyme Stability; Hot Temperature; Models, Molecular; Molecular Structure; Peptide Fragments; Protein Structure, Tertiary; Sequence Deletion; Structure-Activity Relationship; beta-Mannosidase
PubMed: 25930671
DOI: 10.1002/jsfa.7240 -
Animal Biotechnology Apr 2023A-kinase anchoring protein 13 (AKAP13) is one of the AKAP protein family members, which is correlated with estrogen receptors (ERs) and progesterone receptor (PR)...
A-kinase anchoring protein 13 (AKAP13) is one of the AKAP protein family members, which is correlated with estrogen receptors (ERs) and progesterone receptor (PR) activity. Consequently, the gene is considered to be one of the candidate genes for regulating female fertility. Hence, the objectives of this study were to discover the potential insertion/deletion (indel) variants within the gene and evaluate their associations with litter size of Shaanbei white cashmere goats (SBWC) to screen candidate genes for the molecular marker-assisted selection (MAS). Ultimately, we found the 16-bp deletion of gene which displayed three genotypes (II, ID and DD). However, it was not confirmed to Hardy-Weinberg equilibrium (HWE) in the tested population. Statistical analysis demonstrated that this 16-bp indel locus was significantly associated with litter size in goats ( < 0.05), in which the ID genotype was a key genotype for increasing litter size in goats. Besides, independent tests between different genotypes and litter size showed that high-prolific groups had higher frequency of the 'D' allele ( < 0.05). Briefly, gene is a candidate gene for improving fertility, and its 16-bp indel locus can be used as a valid DNA molecular marker for the MAS in goat breeding.
Topics: Pregnancy; Female; Animals; Litter Size; Goats; Genotype; Fertility; Sequence Deletion
PubMed: 34431749
DOI: 10.1080/10495398.2021.1968418 -
BMC Medical Genetics Mar 2019The KMT2A gene encoded lysine methyltransferase plays an essential role in regulating gene expression during early development and hematopoiesis. To date, 92 different...
BACKGROUND
The KMT2A gene encoded lysine methyltransferase plays an essential role in regulating gene expression during early development and hematopoiesis. To date, 92 different mutations of KMT2A have been curated in the human gene mutation database (HGMD), resulting in Wiedemann-Steiner syndrome (WDSTS) and intellectual disability (ID)/developmental delay (DD).
CASE PRESENTATION
In this report, we present a de novo heterozygous deletion mutation [c.74delG; p. (Gly26Alafs*2)] in the KMT2A gene, which was identified by trio-based whole exome sequencing from a 5.5-year-old boy with ID/DD, stereotypic hand movements and blood eosinophilia. Many deleterious germline mutations of KMT2A have been documented to affect development of central nervous system, oral and craniofacial tissues, but not blood eosinophils.
CONCLUSIONS
This is the first report of a rare case with ID/DD as well as eosinophilia, resulting from a previously undescribed null mutation of KMT2A. Our findings expand the phenotypical spectrum in affected individuals with KMT2A mutations, and may shed some insight into the role of KMT2A in eosinophil metabolism.
Topics: Child; Developmental Disabilities; Eosinophilia; Heterozygote; Histone-Lysine N-Methyltransferase; Humans; Intellectual Disability; Loss of Function Mutation; Male; Myeloid-Lymphoid Leukemia Protein; Pedigree; Sequence Deletion; Exome Sequencing
PubMed: 30841869
DOI: 10.1186/s12881-019-0776-0 -
Human Mutation Mar 2022Microdeletions and gross deletions are important causes (~20%) of human inherited disease and their genomic locations are strongly influenced by the local DNA sequence...
Microdeletions and gross deletions are important causes (~20%) of human inherited disease and their genomic locations are strongly influenced by the local DNA sequence environment. This notwithstanding, no study has systematically examined their underlying generative mechanisms. Here, we obtained 42,098 pathogenic microdeletions and gross deletions from the Human Gene Mutation Database (HGMD) that together form a continuum of germline deletions ranging in size from 1 to 28,394,429 bp. We analyzed the DNA sequence within 1 kb of the breakpoint junctions and found that the frequencies of non-B DNA-forming repeats, GC-content, and the presence of seven of 78 specific sequence motifs in the vicinity of pathogenic deletions correlated with deletion length for deletions of length ≤30 bp. Further, we found that the presence of DR, GQ, and STR repeats is important for the formation of longer deletions (>30 bp) but not for the formation of shorter deletions (≤30 bp) while significantly (χ , p < 2E-16) more microhomologies were identified flanking short deletions than long deletions (length >30 bp). We provide evidence to support a functional distinction between microdeletions and gross deletions. Finally, we propose that a deletion length cut-off of 25-30 bp may serve as an objective means to functionally distinguish microdeletions from gross deletions.
Topics: Base Composition; Base Sequence; DNA; Genome, Human; Humans; Mutation; Sequence Deletion
PubMed: 34918412
DOI: 10.1002/humu.24314 -
Nucleic Acids Research Oct 2016The accumulation of somatic mitochondrial DNA (mtDNA) mutations contributes to the pathogenesis of human disease. Currently, mitochondrial mutations are largely...
The accumulation of somatic mitochondrial DNA (mtDNA) mutations contributes to the pathogenesis of human disease. Currently, mitochondrial mutations are largely considered results of inaccurate processing of its heavily damaged genome. However, mainly from a lack of methods to monitor mtDNA mutations with sufficient sensitivity and accuracy, a link between mtDNA damage and mutation has not been established. To test the hypothesis that mtDNA-damaging agents induce mtDNA mutations, we exposed MutaMouse mice to benzo[a]pyrene (B[a]P) or N-ethyl-N-nitrosourea (ENU), daily for 28 consecutive days, and quantified mtDNA point and deletion mutations in bone marrow and liver using our newly developed Digital Random Mutation Capture (dRMC) and Digital Deletion Detection (3D) assays. Surprisingly, our results demonstrate mutagen treatment did not increase mitochondrial point or deletion mutation frequencies, despite evidence both compounds increase nuclear DNA mutations and demonstrated B[a]P adduct formation in mtDNA. These findings contradict models of mtDNA mutagenesis that assert the elevated rate of mtDNA mutation stems from damage sensitivity and abridged repair capacity. Rather, our results demonstrate induced mtDNA damage does not readily convert into mutation. These findings suggest robust mitochondrial damage responses repress induced mutations after mutagen exposure.
Topics: Animals; Benzo(a)pyrene; Bone Marrow; Cell Nucleus; DNA Adducts; DNA, Mitochondrial; Ethylnitrosourea; Liver; Male; Mice; Mutagenesis; Mutagens; Point Mutation; Sequence Deletion
PubMed: 27550180
DOI: 10.1093/nar/gkw716 -
Clinical Genetics Nov 2023Knudson's "two hit" hypothesis, mostly associated with cancer, relates to a primary heterozygous germline mutation complemented by a somatic mutation in the second...
Knudson's "two hit" hypothesis, mostly associated with cancer, relates to a primary heterozygous germline mutation complemented by a somatic mutation in the second allele. When the somatic "second hit" is a deletion mutation, the heterozygosity due to the first hit is lost ("loss of heterozygosity"). As the rate of germline mutations is almost two orders of magnitude lower than that of somatic mutations, de-novo germline mutations causing autosomal recessive diseases in carriers of inherited heterozygous mutations are not common. We delineate a case of high myopia presenting at infancy with mild diminution of retinal responses. Exome sequencing identified a paternally inherited apparently homozygous missense mutation in RBP3. Chromosomal microarrays delineated a de-novo germline heterozygous deletion encompassing RBP3, verified through revision of WES data. Thus, we demonstrate an inherited RBP3 missense mutation complemented by a de-novo germline RBP3 deletion, causing loss of heterozygosity of the inherited mutation. We describe a novel RBP3 missense mutation, report the first isolated RBP3 deletion, and demonstrate infantile high myopia as an initial presentation of RBP3 disease. Notably, we highlight de-novo germline deletion mutations causing "loss of heterozygosity" of inherited heterozygous mutations, culminating in autosomal recessive diseases, and discuss the scarce literature.
Topics: Humans; Germ-Line Mutation; Heterozygote; Mutation; Myopia; Sequence Deletion
PubMed: 37308324
DOI: 10.1111/cge.14384 -
Genetics and Molecular Research : GMR Nov 2015The aim of this study is to investigate the ability to prenatally diagnose phenylketonuria (PKU) by using phenylalanine hydroxylase (PAH) gene mutation analysis combined...
The aim of this study is to investigate the ability to prenatally diagnose phenylketonuria (PKU) by using phenylalanine hydroxylase (PAH) gene mutation analysis combined with short tandem repeat (STR) linkage analysis in 118 fetuses from 112 Chinese families. Genomic DNA was extracted from the peripheral blood from members of 112 families and the exons and exon-intron boundaries of the PAH gene were amplified by PCR. PCR products were analyzed by bi-directional Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). The three variable number of tandem repeat (VNTR) markers PAH-1, PAH-26, PAH-32 were used in the prenatal diagnosis for the PKU families. We identified a spectrum of 63 different mutations, including 61 point mutations and indels, two large exon deletion mutations, and five novel mutations. A substantial proportion of mutant alleles were accounted for by p.R243Q (15.62%), EX6-96AG (9.82%), p.V399V (7.59%), p.Y356X (6.70%), and p.R413P (5.36%). The same mutations were identified in 31 prenatally genotyped fetuses. We identified 58 fetuses that carried only one mutant allele and 29 fetuses that carried no mutations of PAH and were presumed normal. PAH gene mutation analysis combined with STR linkage analysis can provide rapid and accurate prenatal diagnosis for PKU families.
Topics: Alleles; Asian People; Exons; Female; Genetic Linkage; Genotype; Humans; Introns; Microsatellite Repeats; Phenylalanine Hydroxylase; Phenylketonurias; Point Mutation; Pregnancy; Prenatal Diagnosis; Sequence Deletion
PubMed: 26600521
DOI: 10.4238/2015.November.18.25