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PubMed1997

A splice-site mutation causing ovine McArdle's disease.

McArdle's disease is an autosomal recessive myopathy with symptoms of exercise intolerance caused by deficiency of the enzyme muscle glycogen phosphorylase which releases glucose for contraction during exercise. The human cDNA has been sequenced and disease-causing mutations identified. An ovine equivalent of McArdle's disease has been diagnosed and the mutation responsible identified by PCR-amplification of the ovine glycogen myophosphorylase cDNA in six overlapping fragments followed by single strand conformation polymorphism (SSCP) analysis. Two fragments showed SSCPs in the glycogen myophosphorylase cDNA from affected sheep. The SSCP in fragment one was a silent polymorphism, while that in fragment six, was an eight base deletion at the 5' end of exon 20. This deletion will cause a frame-shift, a premature stop codon and remove the last 31 amino-acid residues from the protein. The cDNA deletion suggested that the genomic mutation most likely involved a splice-site. Sequencing intron 19 identified the mutation as an adenine for guanine substitution at the intron 19 3' splice-site. This eliminated an XbaI site present in normal sheep allowing diagnosis of normal, affected and carrier sheep. This ovine model of McArdle's disease is now available for therapeutic trials.

Amino Acid Sequence↗

PubMed1991

Analysis of the H-2Kbm8 mutant: correlation of structure with function.

The gene for H-2K class I major histocompatibility antigen on the bm8 variant was cloned and the DNA sequence compared with the parental gene. Sequence analysis demonstrated that seven nucleotides were changed with respect to the parental gene sequence spanning 24 nucleotides. These changes represent an alteration of four amino acids from the parent protein. As this mutation occurred in a single generation, a potential donor gene for such a complex mutation was suggested and identified. The Q4 gene class I-like molecule has a stretch of 95 nucleotides of identity in the region of the bm8 mutation. Genomic Southern analysis of the mutant and parental DNA with a gene-specific oligonucleotide demonstrated that the potential donor gene Q4 is a likely candidate sequence for such an event. The amino acid alterations for the H-2Kbm8 mutation are discussed in consideration of hte three-dimensional structure of the characterized human class I glycoprotein.

Animals↗

PubMed1991

CpG island in the region of an autosomal dominant polycystic kidney disease locus defines the 5' end of a gene encoding a putative proton channel.

In an attempt to isolate candidate genes for autosomal dominant polycystic kidney disease, a number of CpG-rich islands have been identified from a region defined genetically as the site of disease mutations. Genomic fragments adjacent to one of these islands were used to isolate cDNAs from both HeLa cells and cultured cystic epithelium that encode a 155-amino acid peptide having four putative transmembrane domains. The corresponding transcript was found in all tissues tested but was most abundant in brain and kidney. Potential control response elements were identified in the genomic region 5' to the initiation codon. The deduced amino acid sequence has 93% similarity to the 16-kDa proteolipid component that is believed to be part of the proton channel of the vacuolar H(+)-ATPase. Possible roles for a mutated proton channel in the pathogenesis of cystic disease were considered. However, sequencing of cDNAs corresponding to both alleles of an affected individual revealed no differences in the deduced amino acid sequence. Moreover, transcript size and abundance were not altered in cystic kidney.

Amino Acid Sequence↗

PubMed2004

[Proceedings of human mitochondrial DNA study and its applications to forensic medicine].

The mitochondrial DNA (mtDNA) is a small circular genome located within the mitochondria in the cytoplasm of the cell. Evidence of its existence first arose over 30 years ago. Now the field of the mitochondria is one of the fastest growing disciplines in biomedicine which is driven by fundamentally interesting questions. These questions are mainly about the way of mitochondria evolving and energy producing. In addition, what the consequences of mitochondrial genome mutations in diseases are? How program cell death is regulated? What happens to mitochondria when aging? These questions remain to be answered and the basic understanding of them will contribute to anthropological and forensic analysis, as well as therapy of many diseases. The following review has brought this question to notice by summarizing recent mitochondria research.

Aging↗

PubMed2003

Effects of short-term spontaneous mutation accumulation for life history traits in grape phylloxera, Daktulosphaira vitifoliae.

Mutation is the source of all genetic variation, but rate of input and effects of new mutations for phenotypic traits related to fitness and the role they play in the maintenance of genetic variation are still subject to controversy. These parameters are important in models of the evolution of sex and recombination, the persistence of asexual populations, and the extinction of small populations. Most estimates have come from a few model organisms. Here, mutation accumulation experiments were conducted with three clones of grape phylloxera, Daktulosphaira vitifoliae Fitch, a gall forming herbivore and pest of grapes, to estimate the rate of input and effects of spontaneous mutation on life history traits. This is perhaps the first such experiment using a non-model organism of economic importance. Significant heritable genetic variation accrued in one of three sets of lines for one of four traits measured, and deleterious effects of mutation were found for two of four traits in two of the three sets of lines. Estimates of the parameters by the Bateman-Mukai (BM) method were within the range found in previous studies but at the lower end for genomic mutation rate, U approximately 0.023 and mutational variance, V(M) approximately 0.0003, the upper end for average heterozygous effect, alpha, of approximately -0.11, and on the order of previous estimates for mutational heritability, hM approximately 0.007. Under a model of equal effects of mutations, maximum likelihood (ML) estimates of U were slightly higher, and of alpha lower, than the BM estimates. Support limits were too large to provide much confidence in the ML estimates, however, and models of mutational effects assuming a gamma distribution of effects under different values of the shape parameter, beta, could not be distinguished though likelihoods tended to be lower at lower values of beta (more leptokurtic). Rapid accumulation of deleterious mutations suggest that for many pest species, adaptive response under agricultural conditions may depend more on the standing variation derived from introductions than new mutation.

Adaptation, Physiological↗

PubMed1988

Biased hypermutation and other genetic changes in defective measles viruses in human brain infections.

We assessed the alterations of viral gene expression occurring during persistent infections by cloning full-length transcripts of measles virus (MV) genes from brain autopsies of two subacute sclerosing panencephalitis patients and one measles inclusion body encephalitis (MIBE) patient. the sequence of these MV genes revealed that, most likely, almost 2% of the nucleotides were mutated during persistence, and 35% of these differences resulted in amino acid changes. One of these nucleotide substitutions and one deletion resulted in alteration of the reading frames of two fusion genes, as confirmed by in vitro translation of synthetic mRNAs. One cluster of mutations was exceptional; in the matrix gene of the MIBE case, 50% of the U residues were changed to C, which might result from a highly biased copying event exclusively affecting this gene. We propose that the cluster of mutations in the MIBE case, and other combinations of mutations in other cases, favored propagation of MV infections in brain cells by conferring a selective advantage to the mutated genomes.

Child↗

PubMed1995

A mutation in either dsbA or dsbB, a gene encoding a component of a periplasmic disulfide bond-catalyzing system, is required for high-level expression of the Bacteroides fragilis metallo-beta-lactamase, CcrA, in Escherichia coli.

The metallo-beta-lactamase gene, ccrA, from Bacteroides fragilis is functionally expressed in Escherichia coli only in the presence of a genomic mutation in iarA or iarB (increased ampicillin resistance), identified in this study as dsbA or dsbB, respectively. DsbA and DsbB are components of a periplasmic protein disulfide bond-catalyzing system. Data indicated that DsbA interacted with CcrA, creating aberrant disulfide bond linkages that render CcrA proteolytically unstable. Mutations in dsbA or dsbB permissive for CcrA expression eliminated or greatly reduced DsbA activity, allowing CcrA to assume a disulfide bond-free and proteolytically stable conformation.

Ampicillin Resistance↗

PubMed1996

p53 expression in odontogenic keratocyst epithelium.

The expression of p53 protein was studied in odontogenic keratocysts (OKC, 11 solitary, 5 recurrent and 6 NBCCS cysts), radicular (RC, n = 5) and dentigerous (DC, n = 5) cysts, using a panel of antibodies to p53 (clone BP53-12, clone 1801 and polyclonal CM1) and a sensitive biotin-streptavidin method on paraffin embedded sections. Of the three antibodies tested, clone BP53-12 gave the most intense and consistent nuclear staining pattern. Clone 1801 and polyclonal CM1 stained only 38% and 71% OKC linings, respectively, but not RC and DC linings. However, BP53-12+ cells were detected in the epithelial linings of all cyst types. Quantification of BP53-12+ cells was performed by manual counting and by relating cell number to unit length of basement membrane as determined by TV image analysis. BP53-12+ cell counts in solitary OKC linings (25.5 +/- 11.0 cells/mmBM) were significantly greater than those in DC (9.3 +/- 4.9 cells/mmBM, P < 0.01) and RC (6.7 +/- 2.6 cells/mmBM, P < 0.01) linings. The epithelial distribution of positive cells in OKC was predominantly suprabasal, which also varied from that of DC and RC linings (P < 0.005). There were no detectable differences in BP53-12 reactivity between the different subtypes of OKC (i.e., solitary, recurrent and NBCCS-associated OKC; P > 0.1). When data for the NBCCS-related OKC group were excluded, there was a significant correlation (r = 0.55, P < 0.01) between p53 and Ki67 labelling. To detect the presence of p53 gene mutations, genomic DNA, extracted from paraffin sections of OKC (4 solitary, 2 recurrent and 4 NBCCS cysts), RC (n = 3) and normal oral mucosa (n = 1), was subjected to a combination of polymerase chain reaction and single-stranded conformation polymorphism (PCR-SSCP) analysis for exons 5-10 of the p53 gene. Exon 4 was not analysed because of compromised DNA quality. No abnormality in banding patterns was found and all samples gave results similar to DNA from known, sequenced, normal p53 gene controls. Absence of p53 mutations within exons 5-9 was confirmed by the direct sequencing of 2 fresh frozen OKC samples (1 solitary and 1 NBCCS cyst). These results suggest that overexpression of p53 protein in OKC epithelium, detected by immunocytochemistry, is not reflected by alteration of the p53 gene and presumably reflects overproduction and/or stabilisation of normal p53 protein.

Antibodies↗

PubMed2026

Homology-directed CRISPR-Cas9 correction of the KRT5 p.E475G mutation in human iPSC line from a patient with severe epidermolysis bullosa simplex.

Severe epidermolysis bullosa simplex is a skin fragility disorder characterized by blistering caused by cytolysis within basal keratinocytes, resulting in compromised epidermal integrity. Here we report the generation of the human induced pluripotent stem cell (hiPSC) line MLi002-A-1, an isogenic control derived from patient-specific MLi002-A line carrying the KRT5 c.1424A > G (p.E475G) mutation. Genome editing restored the wild-type sequence without detectable changes at top-predicted off-target sites. The edited line exhibits a normal karyotype, typical pluripotent morphology, robust pluripotency marker expression, and trilineage differentiation potential. This genetically matched control enables mutation-specific studies and in vitro modeling of epidermolysis bullosa simplex.

CRISPR-Cas9↗

PubMed2005

Mutations in the transketolase-like gene TKTL1: clinical implications for neurodegenerative diseases, diabetes and cancer.

Transketolase proteins or transketolase enzyme activities have been related to neurodegenerative diseases, diabetes, and cancer. Transketolase enzyme variants and reduced transketolase enzyme activities are present in patients with the neurodegenerative disease Wernicke-Korsakoff syndrome. In Alzheimer's disease patients transketolase protein variants with different isoelectric points or a proteolytic cleavage leading to small transketolase protein isoforms have been identified. In diabetes mellitus patients reduced transketolase enzyme activities have been detected and the lipid-soluble thiamine derivative benfotiamine activates transketolase enzyme reactions, thereby blocking three major pathways of hyperglycemic damage and preventing diabetic retinopathy. In cancer inhibition of transketolase enzyme reactions suppresses tumor growth and metastasis. All the observed phenomena have been interpreted solely on the basis of a single transketolase gene (TKT) encoding a single transketolase enzyme. No mutations have been identified so far in TKT transketolase explaining the altered transketolase proteins or transketolase enzyme activities found in neurodegenerative diseases, diabetes and cancer. We demonstrate the presence of a second transketolase enzyme (TKTL1) in humans. During the evolution of the vertebrate genome, mutations in this transketolase gene (TKTL1) have led to tissue-specific transcripts different in size, which encode an enzymatically active transketolase protein as well as different smaller protein isoforms. The mutations within the TKTL1 gene caused a mutant transketolase enzyme with an altered substrate specificity and reaction modus. Here we characterize the TKTL1 gene and its encoded TKTL1 protein(s) and discuss the medical and clinical implications of this mutated transketolase. We furthermore postulate a novel metabolic concept for the understanding, prevention and therapy of neurodegenerative diseases, diabetes and cancer.

Diabetes Mellitus↗

PubMed1994

Similar origins of two mouse minisatellites within transposon-like LTRs.

Tandem arrays of simple sequence repeat units are among the most unstable regions of mammalian genomes. Mutational instability at such loci depends on both repeat unit sequence and DNA sequences external to the tandem array, which have been recently implicated in polarized variability at human minisatellites. The characteristics of DNA sequences flanking the mouse minisatellite Ms6-hm have been investigated. This locus has a high mutation rate both in the germline and during early somatic development and is composed of a hypervariable tandem array of 500-2000 pentanucleotide repeat units flanked by a transposon-like long terminal repeat sequence of the mouse transcript (MT) family. A subpopulation of MT elements in the mouse genome are shown to flank a 1.1-kb internal sequence, consistent with their classification within a newly defined mammalian retrotransposon-like superfamily (MaLR). A second mouse minisatellite, Hm-2, also originates from within a MaLR LTR. Hm-2 is related to Ms6-hm in repeat unit sequence and profiles of germline and somatic instability; at both loci the tandem array has amplified from precisely the same point within the LTR. The similar origins of Ms6-hm and Hm-2 suggest that flanking MaLR sequences may be involved in mutational processes at these loci.

Animals↗

PubMed2000

High direct estimate of the mutation rate in the mitochondrial genome of Caenorhabditis elegans.

Mutations in the mitochondrial genome have been implicated in numerous human genetic disorders and offer important data for phylogenetic, forensic, and population genetic studies. Using a long-term series of Caenorhabditis elegans mutation accumulation lines, we performed a wide-scale screen for mutations in the mitochondrial genome that revealed a mutation rate that is two orders of magnitude higher than previous indirect estimates, a highly biased mutational spectrum, multiple mutations affecting coding function, as well as mutational hotspots at homopolymeric nucleotide stretches.

Amino Acid Substitution↗

PubMed2004

The basal layer in human squamous tumors harbors more UVA than UVB fingerprint mutations: a role for UVA in human skin carcinogenesis.

We hypothesized that a substantial portion of the mutagenic alterations produced in the basal layer of human skin by sunlight are induced by wavelengths in the UVA range. Using laser capture microdissection we examined separately basal and suprabasal keratinocytes from human skin squamous cell carcinomas and premalignant solar keratosis for both UVA- and UVB-induced adduct formation and signature mutations. We found that UVA fingerprint mutations were detectable in human skin squamous cell carcinomas and solar keratosis, mostly in the basal germinative layer, which contrasted with a predominantly suprabasal localization of UVB fingerprint mutations in these lesions. The epidermal layer bias was confirmed by immunohistochemical analyses with a superficial localization of cyclobutane thymine dimers contrasting with the localization of 8-hydroxy-2'-deoxyguanine adducts to the basal epithelial layers. If unrepaired, these adducts may lead to fixed genomic mutations. The basal location of UVA-rather than UVB-induced DNA damage suggests that longer-wavelength UVR is an important carcinogen in the stem cell compartment of the skin. Given the traditional emphasis on UVB, these results may have profound implications for future public health initiatives for skin cancer prevention.

Carcinoma, Squamous Cell↗

PubMed1989

Increased cancer risk as a genetic effect of ionizing radiation.

The well known genetic effects of ionizing radiation include severe developmental disorders in the progeny of irradiated parents resulting in embryonic death, stillbirth and early postnatal mortality, congenital abnormalities, malformations and fertility disturbances in live-born organisms. These effects are considered to be due to gross mutations (genomic, chromosomal and those of essential genes). Physiological inferiority and an increased cancer risk in phenotypically normal offspring of irradiated parents appear to be two further types of genetic effect of radiation. The genetic background of these effects is suggested to be induced recessive polygene mutations and regulatory DNA alterations, which may lead to instability of the hereditary apparatus of cells, activation of protooncogenes and other inducible processes. A comparison of somatic and genetic effects of radiation shows certain similarities, not only in phenomenology, but probably also in pathogenetic mechanisms.

Animals↗

PubMed2003

Novel single nucleotide polymorphisms of the cytokeratin 19 pseudogene are associated with primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is characterized by chronic inflammation and destruction of intra-hepatic bile ducts. However, the pathogenesis of PBC has not been fully delineated. We examined whether patients with PBC harbor genomic mutations of the cytokeratin 19 (CK19) gene since that gene is specifically expressed in biliary epithelial cells. Thirty-six patients with PBC, 26 patients with other liver diseases, and 36 healthy volunteers were enrolled in this study, but there were no significant differences in the genomic sequence of the CK19 gene between those groups. On the other hand, novel single nucleotide polymorphisms (SNPs) of the CK19 pseudogene, C341T, T524G and A754G, were frequently detected in PBC patients. These results suggest that those novel SNPs of the CK19 pseudogene may be associated with PBC and may prove useful for predicting susceptibility to PBC.

Journal Article↗

PubMed1993

The advance of Muller's ratchet in a haploid asexual population: approximate solutions based on diffusion theory.

Asexual populations experiencing random genetic drift can accumulate an increasing number of deleterious mutations, a process called Muller's ratchet. We present here diffusion approximations for the rate at which Muller's ratchet advances in asexual haploid populations. The most important parameter of this process is n0 = N e-U/s, where N is population size, U the genomic mutation rate and s the selection coefficient. In a very large population, n0 is the equilibrium size of the mutation-free class. We examined the case n0 > 1 and developed one approximation for intermediate values of N and s and one for large values of N and s. For intermediate values, the expected time at which the ratchet advances increases linearly with n0. For large values, the time increases in a more or less exponential fashion with n0. In addition to n0, s is also an important determinant of the speed of the ratchet. If N and s are intermediate and n0 is fixed, we find that increasing s accelerates the ratchet. In contrast, for a given n0, but large N and s, increasing s slows the ratchet. Except when s is small, results based on our approximations fit well those from computer simulations.

Computer Simulation↗

PubMed2001

Alu-mediated inactivation of the human CMP- N-acetylneuraminic acid hydroxylase gene.

Inactivation of the CMP-N-acetylneuraminic acid hydroxylase gene has provided an example of human-specific genomic mutation that results in a widespread biochemical difference between human and nonhuman primates. We have found that, although a region containing a 92-bp exon and an AluSq element in the hydroxylase gene is intact in all nonhuman primates examined, the same region in the human genome is replaced by an AluY element that was disseminated at least one million years ago. We propose a mechanistic model for this Alu-mediated replacement event, which deleted the 92-bp exon and thus inactivated the human hydroxylase gene. It is suggested that Alu elements have played potentially important roles in genotypic and phenotypic evolution in the hominid lineage.

Alu Elements↗

PubMed1992

Dynamic changes in HIV-1 quasispecies from azidothymidine (AZT)-treated patients.

The emergence of azidothymidine (AZT)-resistant human immunodeficiency virus (HIV) variants in clinical samples was studied by a direct genomic sequencing method. Sequential lymphocyte samples from four patients, who had been treated with AZT for up to 27 months, were shown to gradually accumulate multiple nucleotide changes, some of which are known to be associated with AZT resistance. Several samples were shown to contain mixtures of wild-type and mutated genomes, indicating gradual rather than sudden changes in the HIV-1 quasispecies. These results demonstrate for the first time that automated solid-phase DNA sequencing is a rapid and useful tool for investigation of antiviral drug resistance and suggest that DNA sequencing may be important in routine clinical diagnostics in the future.

Acquired Immunodeficiency Syndrome↗