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PubMed2006

Compound heterozygous mutations including a de novo missense mutation in ABCA12 led to a case of harlequin ichthyosis with moderate clinical severity.

Harlequin ichthyosis (HI) is one of the most devastating genodermatoses. Recently, ABCA12 mutations were identified as the cause of HI. A newborn Japanese male demonstrated the typical features of HI. The patient was treated with oral etretinate and his general condition has been good (now aged 1.5 years). This patient with moderate clinical severity was compound heterozygous for a novel de novo missense mutation 1160G > A (S387N) in exon 10 and a maternal deletion mutation 4158_4160delTAC (T1387del) in exon 28 of ABCA12. T1387del was a deletion of a highly conserved threonine residue within the first adenosine 5' triphosphate-binding domain and is thought to seriously affect the function of the ABCA12 protein. Conversely, the residue 387 is located outside the known active sites of ABCA12 and S387N is predicted not to lead to a serious functional deficiency in ABCA12. Electron microscopy revealed abnormal lamellar granules in the granular layer cells and a moderate number of lipid vacuoles in the cornified cells. Disturbed glucosylceramide transport was confirmed in the cultured keratinocytes from the patient. No de novo mutation in ABCA12 has yet been reported either in HI or lamellar ichthyosis. The present case suggested that a de novo ABCA12 mutation might underlie HI.

ATP-Binding Cassette Transporters↗
PubMed2004

Heterozygous prothrombin 20210G/A mutation, associated with hyperhomocysteinemia, and homozygous methylenetetrahydrofolate reductase 677C/T mutation, in a patient with portal and mesenteric venous thrombosis.

We herein report a 34-year-old man who was investigated for severe abdominal pain. Portal vein thrombosis (PVT) and mesenteric vein thrombosis (MVT) were diagnosed. An association with two predisposing factors for thrombosis was noted: (1) heterozygous factor II 20210G/A mutation and (2) homozygous methylenetetrahydrofolate reductase (MTHFR) 677C/T mutation with hyperhomocysteinemia. Our case is of particular interest because the patient reported herein, is homozygote for the MTHFR 677C/T mutation, while the only two other cases reported in the literature with similar gene mutations, were heterozygotes for the mutation.

Adult↗
PubMed2002

A site-specific plectin mutation causes dominant epidermolysis bullosa simplex Ogna: two identical de novo mutations.

Plectin is one of the largest and most versatile cytolinker proteins known. In basal keratinocytes it links the intermediate filament network to cell membrane-associated hemidesmosomes. Several mutations in its gene have been identified that lead to the recessive disease epidermolysis bullosa with muscular dystrophy. We report here a mutation that leads to a dominant form of the disease, epidermolysis bullosa simplex Ogna. We found that the epidermolysis bullosa simplex Ogna phenotype is due to a site-specific missense mutation within plectin's rod domain. Further, we show that epidermolysis bullosa simplex Ogna is not restricted to a single Norwegian kindred as previously believed. A German family with the phenotypic hallmarks of epidermolysis bullosa simplex Ogna was found to carry an identical de novo mutation. These two mutations arose about 200 y apart in time. Consistent with the absence of muscular symptoms in these patients, muscle biopsies from several epidermolysis bullosa simplex Ogna members of the Norwegian kindred showed normal staining patterns using antibodies to plectin. Skin changes in epidermolysis bullosa simplex Ogna patients are documented on the ultrastructural level.

Adult↗
PubMed1999

An in vitro system for expression analysis of mutations of the beta-globin gene: validation and application to two mutations in the 5' UTR.

We describe the setting up of an in vitro expression system for the analysis of mutations of the beta-globin gene. The system is based on the stable transfection of a normal or mutated beta-globin gene into mouse erythroleukaemia (MEL) cells. The expression construct contains an Agamma gene as an internal control and both globin genes are under the control of the HS2 element of the beta LCR. The system enables analysis of transcription, RNA processing and transport, as well as mRNA stability. With non-mutant genes, high-level expression of both beta and Agamma genes is seen and both mRNAs are stable. The system was validated by comparing the expression of the beta654 thalassaemia splicing mutation in MEL cells with its well-characterized expression in vivo. The level of the initial transcript, the proportion of abnormally spliced mRNA and its instability during erythroid cell maturation were all faithfully reproduced. The system was used to examine the mechanism by which two mutations in the beta-globin 5' untranslated region (5' UTR) result in beta thalassaemia. Surprisingly, the mechanism appeared to differ in the two cases, with the C-G substitution at position +33 affecting transcription, whereas the -T deletion at position +10 resulted in a translational defect. The stably transfected MEL cells, with an internal control and an endogenous enhancer, appear to be a valid and realistic experimental model, superior to transient expression studies. This system should find wide application in the analysis of the effects and mechanisms of gene inactivation in mutations affecting the beta-globin as well as other genes.

5' Untranslated Regions↗
PubMed2001

Mutation analysis of Crouzon syndrome and identification of one novel mutation in Taiwanese patients.

BACKGROUND: Crouzon syndrome is an autosomal dominant disorder causing premature fusion of the cranial suture. Mutations have been reported in exon IIIa or IIIc of the fibroblast growth factor receptor 2 (FGFR2) gene. METHODS: In the present study, nine unrelated Crouzon syndrome patients were screened for mutations in the two exons of FGFR2 by polymerase chain reaction and direct sequencing. RESULTS: Mutations were detected in 67% (6/9) of all cases. More than half the studied Crouzon patients carried a mutation resulting in either the loss or gain of a cysteine residue. A novel mutation, Tyr281Cys substitution, was discovered at exon IIIa. CONCLUSIONS: The mechanisms by which the same genotypes cause different phenotypes for each type of craniosynostosis syndrome in still uncertain. However, the molecular identification of the FGFR gene has made a great impact on the clinical classification of craniosynostosis syndromes; a new classification based on genotypes seems to be unavoidable.

Asian People↗
PubMed2004

Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes.

Hepatitis C virus (HCV) is a nonretroviral oncogenic RNA virus, which is frequently associated with hepatocellular carcinoma (HCC) and B cell lymphoma. We demonstrated here that acute and chronic HCV infection caused a 5- to 10-fold increase in mutation frequency in Ig heavy chain, BCL-6, p53, and beta-catenin genes of in vitro HCV-infected B cell lines and HCV-associated peripheral blood mononuclear cells, lymphomas, and HCCs. The nucleotide-substitution pattern of p53 and beta-catenin was different from that of Ig heavy chain in HCV-infected cells, suggesting two different mechanisms of mutation. In addition, the mutated protooncogenes were amplified in HCV-associated lymphomas and HCCs, but not in lymphomas of nonviral origin or HBV-associated HCC. HCV induced error-prone DNA polymerase zeta, polymerase iota, and activation-induced cytidine deaminase, which together, contributed to the enhancement of mutation frequency, as demonstrated by the RNA interference experiments. These results indicate that HCV induces a mutator phenotype and may transform cells by a hit-and-run mechanism. This finding provides a mechanism of oncogenesis for an RNA virus.

B-Lymphocytes↗
PubMed2002

A mutation that prevents paramutation in maize also reverses Mutator transposon methylation and silencing.

Both paramutation and Mutator (Mu) transposon inactivation involve heritable changes in gene expression without concomitant changes in DNA sequence. The mechanisms by which these shifts in gene activity are achieved are unknown. Here we present evidence that these two phenomena are linked mechanistically. We show that mutation of a gene, modifier of paramutation 1 (mop1), which prevents paramutation at three different loci in maize, can reverse methylation of Mutator elements reliably. In mop1 mutant backgrounds, methylation of nonautonomous Mu elements can be reversed even in the absence of the regulatory MuDR element. Previously silenced MuDR elements are reactivated sporadically after multiple generations of exposure to mop1 mutations. MuDR methylation is separable from MuDR silencing, because removal of methylation does not cause immediate reactivation. The mop1 mutation does not alter the methylation of certain other transposable elements including those just upstream of a paramutable b1 gene. Our results suggest that the mop1 gene acts on a subset of epigenetically regulated sequences in the maize genome and paramutation and Mu element methylation require a common factor, which we hypothesize influences chromatin structure.

Chromatin↗
PubMed2002

The osteopetrotic mutation toothless (tl) is a loss-of-function frameshift mutation in the rat Csf1 gene: Evidence of a crucial role for CSF-1 in osteoclastogenesis and endochondral ossification.

The toothless (tl) mutation in the rat is a naturally occurring, autosomal recessive mutation resulting in a profound deficiency of bone-resorbing osteoclasts and peritoneal macrophages. The failure to resorb bone produces severe, unrelenting osteopetrosis, with a highly sclerotic skeleton, lack of marrow spaces, failure of tooth eruption, and other pathologies. Injections of CSF-1 improve some, but not all, of these. In this report we have used polymorphism mapping, sequencing, and expression studies to identify the genetic lesion in the tl rat. We found a 10-base insertion near the beginning of the open reading of the Csf1 gene that yields a truncated, nonfunctional protein and an early stop codon, thus rendering the tl rat CSF-1(null). All mutants were homozygous for the mutation and all carriers were heterozygous. No CSF-1 transcripts were identified in rat mRNA that would avoid the mutation via alternative splicing. The biology and actions of CSF-1 have been elucidated by many studies that use another naturally occurring mutation, the op mouse, in which a single base insertion also disrupts the reading frame. The op mouse has milder osteoclastopenia and osteopetrosis than the tl rat and recovers spontaneously over the first few months of life. Thus, the tl rat provides a second model in which the functions of CSF-1 can be studied. Understanding the similarities and differences in the phenotypes of these two models will be important to advancing our knowledge of the many actions of CSF-1.

Alternative Splicing↗
PubMed1996

Transcription-induced mutations: increase in C to T mutations in the nontranscribed strand during transcription in Escherichia coli.

Cytosines in single-stranded DNA deaminate to uracils at 140 times the rate for cytosines in double-stranded DNA. If resulting uracils are not replaced with cytosine, C to T mutations occur. These facts suggest that cellular processes such as transcription that create single-stranded DNA should promote C to T mutations. We tested this hypothesis with the Escherichia coli tac promoter and found that induction of transcription causes approximately 4-fold increase in the frequency of C to U or 5-methylcytosine to T deaminations in the nontranscribed strand. Excess mutations caused by C to U deaminations were reduced, but not eliminated, by uracil-DNA glycosylase. Similarly, mutations caused by 5-methylcytosine to T deaminations were only partially reduced by the very short-patch repair process in E.coli. These effects are unlikely to be caused by differential repair of the two strands, and our results suggest that all actively transcribed genes in E. coli should acquire more C to T mutations in the nontranscribed strand.

Base Sequence↗
PubMed2003

Differing effects of breast cancer 1, early onset (BRCA1) and ataxia-telangiectasia mutated (ATM) mutations on cellular responses to ionizing radiation.

PURPOSE: The ataxia-telangiectasia mutated (ATM) gene encodes a protein kinase, the activation of which is an early event in the cellular response to ionizing radiation. One of the many substrates of ATM is BRCA1 (breast cancer 1, early onset gene), which has been associated with susceptibility to breast and ovarian cancer, and has been implicated in DNA repair processes. Various cellular responses to radiation were analysed in cells with mutations in ATM or BRCA1 in an attempt to clarify which effects of ATM can be mediated through BRCA1. MATERIALS AND METHODS: The response to radiation of cells with mutations in ATM or BRCA1 was examined, as were BRCA1-mutant tumour cells transfected with an exogenous wild-type BRCA1 allele. Assays included cell-survival curves, studies of potentially lethal damage repair, measurement of chromosomal aberrations and of G1 arrest, and Western blot analysis of lysates of irradiated cells to determine the phosphorylation of the product of the human Mdm2 gene (HDM2). RESULTS: Both ATM and BRCA1 mutations were associated with sensitivity to ionizing radiation, deficient repair of potentially lethal damage and markedly increased chromosomal aberrations. A BRCA1-mutated tumour cell line HCC1937, like ATM mutant cells, did not exhibit a normal G1 arrest but, unlike ATM mutant cells, did exhibit phosphorylation of HDM2. Expression of wild-type BRCA1 in HCC1937 cells partially restored radioresistance, restored repair of potentially lethal damage and markedly reduced radiation-induced chromosomal aberrations. G1 arrest, however, was not restored by expression of BRCA1. CONCLUSIONS: The results are consistent with a model in which ATM phosphorylation of BRCA1 regulates DNA repair functions, particularly those involved in potentially lethal damage repair and chromosomal integrity, but not other aspects of the cellular response to radiation such as G1 cell cycle arrest. To the authors' knowledge, this is the first demonstration of the ability of exogenously expressed BRCA1 to restore the ability to perform potentially lethal damage repair and maintain chromosomal integrity in irradiated cells.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1998

HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q.

The hereditary deficiency of 3-hydroxy-3-methylglutaryl (HMG) CoA lyase (HL; OMIM 246450 [http://www3.ncbi.nlm.nih. gov:80/htbin-post/Omim/dispmim?246450]) results in episodes of hypoketotic hypoglycemia and coma and is reported to be frequent and clinically severe in Saudi Arabia. We found genetic diversity among nine Saudi HL-deficient probands: six were homozygous for the missense mutation R41Q, and two were homozygous for the frameshift mutation F305fs(-2). In 32 non-Saudi HL-deficient probands, we found three R41Q alleles and also discovered four other deleterious point mutations in codons 41 and 42: R41X, D42E, D42G, and D42H. In purified mutant recombinant HL, all four missense mutations in codons 41 and 42 cause a marked decrease in HL activity. We developed a screening procedure for HL missense mutations that yields residual activity at levels comparable to those obtained using purified HL peptides. Codons 41 and 42 are important for normal HL catalysis and account for a disproportionate 21 (26%) of 82 of mutant alleles in our group of HL-deficient probands.

Base Sequence↗
PubMed1988

Adaptive evolution that requires multiple spontaneous mutations. I. Mutations involving an insertion sequence.

Escherichia coli K12 strain chi 342LD requires two mutations in the bgl (beta-glucosidase) operon, bglR0----bglR+ and excision of IS103 from within bglF, in order to utilize salicin. In growing cells the two mutations occur at rates of 4 x 10(-8) per cell division and less than 2 x 10(-12) per cell division, respectively. In 2-3-week-old colonies on MacConkey salicin plates the double mutants occur at frequencies of 10(-8) per cell, yet the rate of an unselected mutation, resistance to valine, is unaffected. The two mutations occur sequentially. Colonies that are 8-12 days old contain from 1% to about 10% IS103 excision mutants, from which the Sal+ secondary bglR0----bglR+ mutants arise. It is shown that the excision mutants are not advantageous within colonies; thus, they must result from a burst of independent excisions late in the life of the colony. Excision of IS103 occurs only on medium containing salicin, despite the fact that the excision itself confers no detectable selective advantage and serves only to create the potential for a secondary selectively advantageous mutation.

Adaptation, Physiological↗
PubMed1993

Mutations at the Darkener of apricot locus modulate transcript levels of copia and copia-induced mutations in Drosophila melanogaster.

Mutations of the Doa locus of Drosophila melanogaster darken the eye color of the copia-induced white(apricot) (wa) allele and increase the accumulation of white promoter-initiated transcripts encoding functional mRNA. We show here that quantities of transcripts initiated in both long terminal repeats (LTRs) of the specific wa-copia element are increased, and those initiating in the 5' LTR of the element are structurally altered, yielding a slightly shortened transcript. Accumulation of host-initiated transcripts of a copia-induced mutation within the achaete-scute complex, Hairy-wing Ua (HwUa), are reduced by Doa mutations. Finally, we show that homozygosity for Doa mutations increases the accumulation of copia transcripts from the population of elements in the genome. These results suggest that Doa modulates the severity of copia-induced mutations while functioning as a dosage-sensitive modulator of copia transcription.

Alleles↗
PubMed1994

The axr2-1 mutation of Arabidopsis thaliana is a gain-of-function mutation that disrupts an early step in auxin response.

The dominant axr2-1 mutation of Arabidopsis thaliana confers resistance to the plant hormones auxin, ethylene, and abscisic acid. In addition, axr2-1 has pleiotropic effects on plant morphology which include gravitropic defects in roots, hypocotyls and inflorescences of axr2-1 plants. Two genetic screens were conducted to isolate new mutations at the AXR2 locus. First, axr2-1 pollen was gamma-irradiated, crossed onto wild-type plants, and the M1 progeny screened for loss of the axr2-1 phenotype. Large deletions of the axr2-1 region on chromosome 3 resulted; however, none of these deletions appeared to be heritable. In the second, M2 seed obtained from axr2-1 gl-1 plants was screened for reversion of the axr2-1 phenotype. One revertant line, axr2-r3, has a distinctive phenotype caused by a second mutation at the axr2 locus. To learn more about the nature of the axr2-1 mutation, the effects of varying the ratio of wild-type to mutant copies of the AXR2 gene were examined by comparing plants of the following genotypes: +/+, +/+/+, axr2-1/axr2-1, axr2-1/+ and axr2-1/+/+. Additionally, accumulation of transcripts from the auxin-inducible SAUR-AC1 gene was examined to determine the response of wild-type and mutant plants to auxin. Wild-type seedlings and mature plants accumulate transcripts with auxin treatment. In contrast, axr2-1 tissue does not accumulate SAUR-AC1 transcripts in response to auxin. Taken together, these results indicate that axr2-1 is a neomorphic or hypermorphic mutation that disrupts an early step in an auxin response pathway.

Arabidopsis↗
PubMed1996

Interaction between mutations in the suppressor of Hairy wing and modifier of mdg4 genes of Drosophila melanogaster affecting the phenotype of gypsy-induced mutations.

The suppressor of Hairy-wing [su(Hw)] protein mediates the mutagenic effect of the gypsy retrotransposon by repressing the function of transcriptional enhancers located distally from the promoter with respect to the position of the su(Hw)-binding region. Mutations in a second gene, modifier of mdg4, also affect the gypsy-induced phenotype. Two major effects of the mod(mdg4)1u1 mutation can be distinguished: the interference with insulation by the su(Hw)-binding region and direct inhibition of gene expression that is not dependent on the su(Hw)-binding region position. The mod(mdg4)1u1 mutation partially suppresses ct6, scD1 and Hw1 mutations, possibly by interfering with the insulation effect of the su(Hw)-binding region. An example of the second effect of mod(mdg4)1u1 is a complete inactivation of yellow expression in combination with the y2 allele. Phenotypic analyses of flies with combinations of mod(mdg4)1u1 and different su(Hw) mutations, or with constructions carrying deletions of the acidic domains of the su(Hw) protein, suggest that the carboxy-terminal acidic domain is important for direct inhibition of yellow transcription in bristles, while the amino-terminal acidic domain is more essential for insulation.

Animals↗
PubMed1999

A mutation in a methionine tRNA gene suppresses the prp2-1 Ts mutation and causes a pre-mRNA splicing defect in Saccharomyces cerevisiae.

The PRP2 gene in Saccharomyces cerevisiae encodes an RNA-dependent ATPase that activates spliceosomes for the first transesterification reaction in pre-mRNA splicing. We have identified a mutation in the elongation methionine tRNA gene EMT1 as a dominant, allele-specific suppressor of the temperature-sensitive prp2-1 mutation. The EMT1-201 mutant suppressed prp2-1 by relieving the splicing block at high temperature. Furthermore, EMT1-201 single mutant cells displayed pre-mRNA splicing and cold-sensitive growth defects at 18 degrees. The mutation in EMT1-201 is located in the anticodon, changing CAT to CAG, which presumably allowed EMT1-201 suppressor tRNA to recognize CUG leucine codons instead of AUG methionine codons. Interestingly, the prp2-1 allele contains a point mutation that changes glycine to aspartate, indicating that EMT1-201 does not act by classical missense suppression. Extra copies of the tRNA(Leu)(UAG) gene rescued the cold sensitivity and in vitro splicing defect of EMT1-201. This study provides the first example in which a mutation in a tRNA gene confers a pre-mRNA processing (prp) phenotype.

Amino Acid Substitution↗
PubMed2001

Dynamics of microsatellite divergence under stepwise mutation and proportional slippage/point mutation models.

Recently Kruglyak, Durrett, Schug, and Aquadro showed that microsatellite equilibrium distributions can result from a balance between polymerase slippage and point mutations. Here, we introduce an elaboration of their model that keeps track of all parts of a perfect repeat and a simplification that ignores point mutations. We develop a detailed mathematical theory for these models that exhibits properties of microsatellite distributions, such as positive skewness of allele lengths, that are consistent with data but are inconsistent with the predictions of the stepwise mutation model. We use our theoretical results to analyze the successes and failures of the genetic distances (delta(mu))(2) and D(SW) when used to date four divergences: African vs. non-African human populations, humans vs. chimpanzees, Drosophila melanogaster vs. D. simulans, and sheep vs. cattle. The influence of point mutations explains some of the problems with the last two examples, as does the fact that these genetic distances have large stochastic variance. However, we find that these two features are not enough to explain the problems of dating the human-chimpanzee split. One possible explanation of this phenomenon is that long microsatellites have a mutational bias that favors contractions over expansions.

Animals↗
PubMed2002

An allelic series of mutations in the kit ligand gene of mice. I. Identification of point mutations in seven ethylnitrosourea-induced Kitl(Steel) alleles.

An allelic series of mutations is an extremely valuable genetic resource for understanding gene function. Here we describe eight mutant alleles at the Steel (Sl) locus of mice that were induced with N-ethyl-N-nitrosourea (ENU). The product of the Sl locus is Kit ligand (or Kitl; also known as mast cell growth factor, stem cell factor, and Steel factor), which is a member of the helical cytokine superfamily and is the ligand for the Kit receptor tyrosine kinase. Seven of the eight ENU-induced Kitl(Sl) alleles, of which five cause missense mutations, one causes a nonsense mutation and exon skipping, and one affects a splice site, were found to contain point mutations in Kitl. Interestingly, each of the five missense mutations affects residues that are within, or very near, conserved alpha-helical domains of Kitl. These ENU-induced mutants should provide important information on structural requirements for function of Kitl and other helical cytokines.

Alleles↗