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PubMed2001

Mutation detection 2001: Sixth International Symposium on Mutations in the Human Genome, May 3-7, 2001, Bled, Slovenia.

Mutation Detection 2001, an international symposium on human mutations and mutation detection methodologies, was held in Bled, Republic of Slovenia, on May 3-7, 2001. The event was sponsored by the Human Genome Organization (HUGO) and several other co-sponsors. It provided an important forum for not only defining the state-of-the-art in mutation detection methodologies but also a valuable chance for international collaboration. A special issue of Human Mutation with articles derived from the symposium is scheduled for publication in early 2002. Meeting highlights are described at http://www.mutations2001.bled.si.

DNA Mutational Analysis↗
PubMed2005

Mutation analysis of the HOX paralogous 4-13 genes in children with acute lymphoid malignancies: identification of a novel germline mutation of HOXD4 leading to a partial loss-of-function.

The molecular basis of susceptibility to childhood malignant hemopathy remains largely unknown. An excess of skeletal congenital anomalies has been reported among children with hematological malignancy and points towards involvement of developmental genes, like those belonging to the HOX gene family. In addition to their role in embryogenesis, HOX transcription factors are known to be regulators of proliferation and differentiation of hematopoietic cells. We aimed to explore the possibility that germline alterations of HOX genes might be involved in childhood acute lymphoid malignancies. A cohort of 86 children diagnosed with acute lymphoid malignancy was studied, 20 of them concurrently presenting a congenital anomaly of the skeleton. First, we screened for nucleotide changes throughout the HOX genes of paralogous groups 4 to 13 in the 20 patients with skeletal defects, following a skeletal phenotype-based strategy. Subsequently, we extended the HOX mutation screening to the other 66 children having a malignant lymphoproliferative disorder, but without skeletal defects. In total, 16 germline mutations were identified. While 13 changes were also observed in healthy controls, three variants were exclusively found in acute lymphoid malignancy cases. These comprised the germline c.242A>T (p.Glu81Val) missense mutation of HOXD4, detected in two children diagnosed with acute lymphoblastic leukemia (ALL). Furthermore, this mutation was found in association with other specific HOX variants of cluster D (2q31-q37), defining a unique haplotype. Functional analysis of the murine Hoxd4 homolog revealed that mutant Hoxd4 protein had lower transcriptional activity than wild-type protein in vitro. The p.Glu81Val mutation of HOXD4 thus results in a partial loss-of-function, which might be involved in childhood ALL.

Adolescent↗
PubMed2006

A homozygous ZMPSTE24 null mutation in combination with a heterozygous mutation in the LMNA gene causes Hutchinson-Gilford progeria syndrome (HGPS): insights into the pathophysiology of HGPS.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder normally caused by a spontaneous heterozygous mutation in the LMNA gene that codes for the nuclear lamina protein lamin A. Several enzymes are involved in the processing of its precursor, prelamin A, to the mature lamin A. A functional knockout of one of the enzymes involved in prelamin A processing, the zinc metalloprotease ZMPSTE24, causes an even more severe disorder with early neonatal death described as restrictive dermatopathy (RD). This work describes a HGPS patient with a combined defect of a homozygous loss-of-function mutation in the ZMPSTE24 gene and a heterozygous mutation in the LMNA gene that results in a C-terminal elongation of the final lamin A. Whereas the loss of function mutation of ZMPSTE24 normally results in lethal RD, the truncation of LMNA seems to be a salvage alteration alleviating the clinical picture to the HGPS phenotype. The mutations of our patient indicate that farnesylated prelamin A is the deleterious agent leading to the HGPS phenotype, which gives further insights into the pathophysiology of the disorder.

Child, Preschool↗
PubMed2005

Mutation analysis of the MYH gene in an Australian series of colorectal polyposis patients with or without germline APC mutations.

The MYH gene has recently been shown to be associated with a recessive form of colorectal adenomatous polyposis. Two common mutations in the MYH gene have been identified that lend themselves to rapid screening. We have examined a series of 302 individuals comprising 120 control subjects, 120 patients diagnosed with adenomatous polyposis but without germline mutations in the APC gene and 62 patients diagnosed with familial adenomatous polyposis all harbouring confirmed causative APC germline mutations. The results reveal that MYH accounts for 16 percent of polyposis patients without germline mutations in the APC gene and that it does not appear to be a modifier gene in FAP patients diagnosed with APC germline mutations.

Adenomatous Polyposis Coli↗
PubMed1993

Screening for point mutations in exon 10 of the low density lipoprotein receptor gene by analysis of single-strand conformation polymorphisms: detection of a nonsense mutation-FH469-->Stop.

DNA from 40 unrelated familial hypercholesterolemia (FH) heterozygotes were subjected to analyses of single-strand conformation polymorphisms (SSCPs) of exon 10 of the low density lipoprotein receptor (LDLR) gene. Four different SSCP patterns were observed. The underlying mutations were characterized by DNA sequencing. Three of the patterns represented the three genotypes of a recently described sense mutation in codon 450. A method based upon the polymerase chain reaction (PCR) was developed to analyze this mutation. The frequencies of the wild-type (G at nucleotide 1413) and mutant (A at nucleotide 1413) alleles were 0.56 and 0.44, respectively. The fourth pattern was found in only one FH heterozygote and was caused by heterozygosity at nucleotide 1469 (G/A). Nucleotide 1469 is the second base of codon 469Trp(TGG). The G-->A mutation changes this codon into the amber stop codon, and is referred to as FH469-->Stop. The mutant receptor consists of the amino terminal 468 amino acids. Because the truncated receptor has lost the membrane-spanning domain, it will not be anchored in the cell membrane. FH469-->Stop destroys an AvaII restriction site, and this characteristic was used to develop a PCR method to establish its frequency in Norwegian FH subjects. Two out of 204 (1%) unrelated FH heterozygotes possessed the mutation.

Adult↗
PubMed1996

Phenotypic reversion of the gypsy-induced mutation scD1 of Drosophila melanogaster by replicative transposition of a sc enhancer to the yellow gene and by mutations in the enhancer of yellow and zeste loci.

Both mutations of Drosophila melanogaster in the y2scD1 strain are caused by the insertion of gypsy, but the scD1 mutation contains, in addition, an insertion of the jockey mobile element at a distance of 1.8 kb from gypsy. The su(Hw)-binding region in the copy of gypsy in scD1 inhibits scute expression in several specific areas of the epithelium, and in particular, blocks the formation of anterior notopleural (ANP) bristles. The y2 reversions y+2MC and y2#+9 restore the formation of ANP bristles. Molecular analysis revealed that both revertants were induced by transposition into the gypsy element at the yellow locus of jockey and an adjacent 1.8-kb region of the scute gene which contains an enhancer responsible for the development of ANP bristles. The duplicated enhancer is not insulated by the su(Hw)-binding region and can interact with the scute promoter in spite of the presence of two other promoters between them. Hypomorphic mutation in the e(y)2 gene and zOp6 allele partially inhibit ANP bristle formation in flies with y+2MC and y2+9 mutations. In addition, we found that mutations in the e(y)1, e(y)3 and zeste genes may interfere with transcriptional insulation by the su(Hw)-binding region in the scD1 allele.

Alleles↗
PubMed2003

Characterization of mutations that are synthetic lethal with pol3-13, a mutated allele of DNA polymerase delta in Saccharomyces cerevisiae.

The pol3-13 mutation is located in the C-terminal end of POL3, the gene encoding the catalytic subunit of polymerase delta, and confers thermosensitivity onto the Saccharomyces cerevisiae mutant strain. To get insight about DNA replication control, we performed a genetic screen to identify genes that are synthetic lethal with pol3-13. Mutations in genes encoding the two other subunits of DNA polymerase delta (HYS2, POL32) were identified. Mutations in two recombination genes (RAD50, RAD51) were also identified, confirming that homologous recombination is necessary for pol3-13 mutant strain survival. Other mutations were identified in genes involved in repair and genome stability (MET18/ MMS19), in the control of origin-firing and/or transcription (ABF1, SRB7), in the S/G2 checkpoint (RAD53), in the Ras-cAMP signal transduction pathway (MKS1), in nuclear pore metabolism (SEH1), in protein degradation (DOC1) and in folding (YDJ1). Finally, mutations in three genes of unknown function were isolated (NBP35, DRE2, TAH18). Synthetic lethality between pol3-13 and each of the three mutants pol32, mms19 and doc1 could be suppressed by a rad18 deletion, suggesting an important role of ubiquitination in DNA replication control. We propose that the pol3-13 mutant generates replicative problems that need both homologous recombination and an intact checkpoint machinery to be overcome.

Chromosome Mapping↗
PubMed2002

Episodic ataxia type 2. Three novel truncating mutations and one novel missense mutation in the CACNA1A gene.

We analysed the CACNA1A gene, located on chromosome 19p13, in three unrelated families and one sporadic case with episodic ataxia type 2 (EA-2). In two of the families and the sporadic patient, novel truncating mutations, which disrupt the reading frame and result in a premature stop of the CACNA1A protein, were identified in exons 14, 16 and 26. In the remaining family, a novel missense mutation (H253Y) was found. Of the twenty two EA-2 mutations identified thus far, including those of the present study, seventeen are truncating mutations and five are missense mutations, all resulting in an EA-2 clinical phenotype.

Adult↗
PubMed2004

Mutational analysis of BRAF in gallbladder carcinomas in association with K-ras and p53 mutations and microsatellite instability.

BACKGROUND: Little is known about the genetic changes involved in the pathogenesis of gallbladder cancer. The aim of this study was to examine the presence of mutations in exon 15 of the B-raf gene to investigate its role in gallbladder carcinogenesis. MATERIALS AND METHODS: We examined the mutational status in exon 15 of B-raf gene in 21 gallbladder carcinoma specimens and investigated its association with the presence of K-ras and p53 alterations, microsatellite instability and the clinicopathological features of tumors. RESULTS: B-raf mutations were observed in 7 of 21 (33%) gallbladder carcinomas examined, and all were located at the hot spot codon 599 of exon 15. K-ras and B-raf mutations were never in the same specimens. CONCLUSIONS: B-raf gene mutations seem to be a quite common event in gallbladder carcinomas, implying that B-raf may play an important role in the pathogenesis of this tumor.

Adult↗
PubMed1996

An intron 1 splice mutation and a nonsense mutation (W23X) in CYP21 causing severe congenital adrenal hyperplasia.

Direct DNA sequencing of the steroid 21-hydroxylase gene (CYP21) revealed two novel mutations in two patients with severe congenital adrenal hyperplasia. The nonsense mutation Trp23Stop (TGG --> TGA) was found in a woman with the simple virilizing form of the disease. She was a compound heterozygote, with the previously described Ile173Asn mutation on her other allele. A boy, who developed salt-wasting in the neonatal period, carried an allele with a novel mutation of the canonical splice acceptor site in intron 1 (AG --> GG). He was also a compound heterozygote, with the well-known splice mutation in intron 2 on his other allele.

Adrenal Hyperplasia, Congenital↗
PubMed2003

A common mutation and a novel mutation in Japanese patients with van der Knaap disease.

Van der Knaap disease, or megalencephalic leukoencephalopathy with subcortical cysts (MLC), is an autosomal recessive disorder clinically characterized by macrocephaly, ataxia, spasticity, and mental decline. Magnetic resonance imaging (MRI) shows swollen brain with diffuse white-matter abnormalities and subcortical cysts, particularly in the anterior-temporal region. Recently, the MLC1 gene was identified as the gene responsible for this disorder, and mutations in this gene were described in several patients. We studied three Japanese patients with van der Knaap disease at the molecular genetic level. Two of them were homozygous for a previously-described mutation, S93L, and one was a compound heterozygote for S93L and a novel mutation, 452-468del+g, which leads to frameshift with a premature termination codon. Combining our data with previous reports allowed us to estimate the molecular genetic basis of this disorder in seven Japanese patients. In summary, S93L was observed in six of seven (85.7%) patients at least in one allele, and ten of 14 (71.4%) alleles had this mutation. Therefore, S93L appears to be fairly frequent in Japanese patients with van der Knaap disease, and analysis for this mutation in DNA isolated from leukocytes would provide for an easy and precise diagnosis of this disorder in Japanese patients.

Adult↗
PubMed1993

Large-scale mutational analysis of EMS-induced mutation in the lacI gene of Escherichia coli.

Mutational spectra produced by mutagens in various repair backgrounds can provide important information about the roles of different repair systems in the mutagenic process. Until recently, such studies have been restricted to the characterisation of comparatively small numbers of mutants or reversion analysis at relatively few sites. The colony hybridisation method used in this study in conjunction with DNA sequencing allows the characterisation of large numbers of mutants and therefore allows analysis of resultant mutational distributions to be made with confidence. We have determined the DNA alterations recovered after treatment with EMS in the N-terminal region of the lacI gene of E. coli. A total of 1138 and 1102 independent lacI-d mutants were characterised in Uvr+ and UvrB-, respectively. Consistent with the known ethylating ability of this compound, the predominant mutation was G:C-->A:T transitions, which accounted for 97% and 93% in Uvr+ and UvrB- strains, respectively. An analysis of the DNA context of mutation induction indicates differential reparability by the Uvr repair pathway. Excision repair appears to more efficiently counter EMS-induced G:C-->A:T transitions at sites flanked by A:T base pairs. However, the influence of excision repair on the ultimate distribution of mutation can not be easily defined with respect to neighbouring sequence.

DNA Mutational Analysis↗
PubMed2005

Novel TBX3 mutation data in families with ulnar-mammary syndrome indicate a genotype-phenotype relationship: mutations that do not disrupt the T-domain are associated with less severe limb defects.

We describe a family affected by Ulnar-Mammary syndrome (UMS) in which typical UMS traits (hypoplasia of the breast and axillary hair, upper limbs and genital defects) are present together with cardiac malformations and pulmonary stenosis. Sequence analysis of TBX3 shows a new heterozygous mutation that causes a frame-shift (Nt.1586-1587-insC) in exon 6, resulting in a truncated ORF. Recently the expression of Tbx3 has been described also in the septal region of the embryonic murine heart. This observation may establish a link between the congenital heart defects and the TBX3 mutation in this family. Combining the TBX3 mutation data in the literature with this novel mutation we find an association between mutations that disrupt the DNA-binding domain and a higher frequency of severe upper limb malformations and teeth defects. A possible explanation is that mutant TBX3 proteins that retain the T-domain, if translated, might be minimally active in promoting/repressing transcription of target genes in the limbs and in other embryonic tissues.

DNA Mutational Analysis↗
PubMed2004

Mutation analysis of the MMAA and MMAB genes in Japanese patients with vitamin B(12)-responsive methylmalonic acidemia: identification of a prevalent MMAA mutation.

Methylmalonic acidemia (MMA) is caused by the deficient activity of l-methylmalonyl-CoA mutase, which is a vitamin B(12) (or cobalamin, Cbl)-dependent enzyme. MMA due to the effect of insufficient Cbl metabolism is classified into three forms (cblA, cblB, and cblH). Recently, the genes responsible for cblA and cblB were identified as MMAA and MMAB, respectively. The MMAA protein likely transports Cbl into the mitochondria for adenosylcobalamin synthesis, while the MMAB protein appears to be an adenosyltransferase. We performed a mutation analysis of 10 unrelated Japanese patients with vitamin B(12)-responsive MMA. Seven patients had mutations in MMAA, whereas the other three patients showed no disease-causing substitutions in either MMAA or MMAB. Five novel mutations were identified in MMAA (R22X, R145X, L217X, R359G, and 503delC). The 503delC mutation was observed in five of the seven MMAA patients, suggesting that the mutation is prevalent in Japanese patients. This finding may facilitate the DNA diagnosis of vitamin B(12)-responsive MMA within the Japanese population.

Acidosis↗
PubMed2006

Mutation and biochemical analysis of 19 probands with mut0 and 13 with mut- methylmalonic aciduria: identification of seven novel mutations.

Isolated methylmalonic acidurias (MMA-urias) comprise a group of rare autosomal recessively inherited disorders characterised by accumulation of MMA in urine and other body fluids, resulting from deficient activity of the mitochondrial enzyme methylmalonyl-CoA mutase (MCM). Isolated MMA-uria results from either MCM apoenzyme defects (mut(0) and mut(-)) or defects in synthesis of its cofactor 5-deoxyadenosylcobalamin, i.e. cblA, cblB and cblD-variant 2. To date various studies have identified 171 disease-causing mutations in the MCM gene (MUT). We report mutation analysis in 32 probands with mut MMA-uria including 13 probands with a mut(-) defect. Sixty two of 64 possible mutant alleles were identified, seven of which were novel missense alleles. We found three novel mutations (c.427C>T/p.H143Y; c.862T>C/p.S288P; c.1361G>A/p.G454E) among 19 probands with a mut(0) defect and four novel mutations (c.299A>G/p.Y100C; c.1031C>T/p.S344F; c.1097A>G/p.N366S; c.2081G>T/p.R694L) among 13 probands with a mut(-) defect. Our study provides evidence that the p.Y100C, p.R108H, p.N366S, p.V633G, p.R694W, p.R694L and p.M700K mutations are associated with a mut(-) phenotype.

Adolescent↗
PubMed2002

Identification of G6PD Mediterranean mutation by amplification refractory mutation system.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common X chromosome-linked hereditary enzymopathy in humans. The authors have developed an amplification refractory mutation system (ARMS) to detect the G6PD Mediterranean mutation (nt. 563 C-->T) that is the most frequent among Caucasian population. METHODS: Specific forward polymerase chain reaction (PCR) primers, within exon 6 of the G6PD gene, were designed: ARMS M complementary to the mutated DNA sequence and ARMS N complementary to the wild-type DNA. They were paired with a common reverse primer. The new method was validated using known DNA samples from 72 G6PD-deficient patients carrying the G6PD Mediterranean mutation ascertained by the restriction enzyme analysis. The ARMS test was performed on DNA extracted both from blood or saliva samples. RESULTS: The ARMS test showed an excellent reproducibility and a complete concordance with the endonuclease cleavage reference method. At the same time, it is more rapid and less expensive. CONCLUSIONS: The described molecular test may be a method of choice to identify the G6PD Mediterranean mutation. It could also be helpful to obtain a definite diagnosis of G6PD Mediterranean heterozygotes, which is not feasible by using red blood cell enzyme activity measurements.

DNA Mutational Analysis↗
PubMed2001

Temporal delineation of sequential HPRT mutations arising in vivo in a T-cell clone with a mutator phenotype.

Recurrent mutations in vivo in T-lymphocytes identify clonally restricted genomic instabilities in some individuals. Cell-based assays allow initial recognition of clones with mutator phenotypes, but genotypic selection is required to determine frequencies and temporal sequences of potentially independent mutational events isolated only as complex changes in the same allele. The present work illustrates how two single-base insertions in the HPRT gene recovered only as a double event in a cell-based assay were shown to arise as separate in vivo mutations, being individually present at frequencies of < or =10(-4) and < or =10(-5), respectively, in peripheral blood. Full characterizations of mutator clones will allow elucidation of the earliest events in the emergence of genomic instability in human somatic cells.

Adult↗
PubMed1999

Detection of tandem CC-->TT mutations induced by oxygen radicals using mutation-specific PCR.

DNA lesions caused by reactive oxygen species (ROS) are considered to be one of the major contributors to DNA damage and mutagenesis. In this study, we developed a modification of allele-specific PCR to detect CC-->TT mutations caused by oxidative damage. These tandem mutations have been previously demonstrated to be indicative of oxygen damage in the absence of UV-irradiation. Using a CC target site in the rat DNA polymerase beta (pol beta) gene and a thermostable restriction enzyme that cuts the wild type sequence but not the TT mutation, we demonstrate that the TT mutation can be preferentially amplified from plasmid DNA damaged by oxygen radicals but not other DNA-damaging agents. We evaluated the potential utility of this assay in screening for mutations in cells and in analyzing those that arise during clonal proliferation in carcinogenesis.

DNA Damage↗