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At least 91 records · Page 5Linked to original sources
PubMed1998

alpha-Thalassaemia due to a single codon deletion in the alpha1-globin gene. Computational structural analysis of the new alpha-chain variant. Mutations in brief no. 132. Online.

A new unstable alpha-globin chain associated with alpha-thalassemia phenotype has been found in a Spanish patient. Molecular analysis of the alpha-globin gene complex using PCR and non-radioactive single-strand conformation analysis, allowed to identify a new mutation in the second exon of the alpha-globin gene. Direct sequencing of the abnormal fragment revealed a 3 bp deletion, which led to the loss of a single codon corresponding to a Lys (K) residue at position 60 or 61 DK60 or DK61. Theoretical structural analysis, performed by computational methods, indicated that the loss of an amino acid residue at this position disturbed the contact region between the B and E-helices, affecting the overall stability of the molecule. Therefore, the DK60 and DK61 results in a structurally abnormal alpha-globin chain, not previously described, named Hb Clinic, which leads to the alpha-thalassemia phenotype in the heterozygote patient. No abnormal hemoglobin was detected by standard electrophoretic procedures, suggesting that this alpha-globin chain variant is so unstable that it may be catabolized immediately after its synthesis. This mutation was confirmed by PCR using an allele specific primer.

Codon↗
PubMed1999

A novel 8-bp insertion in codon 281 of p53 in a patient with acute lymphoblastic leukaemia and 2 separate leukaemic clones. Mutations in brief no. 219. Online.

We report a novel p53 insertion in a case of aggressive acute lymphoblastic leukaemia in a 16 year old male, in which 2 separate leukaemic clones were previously identified by T-cell receptor sigma and immunoglobulin heavy chain gene rearrangement studies. Initial p53 mutation screening of blast cells from 29 patients with acute leukaemia by PCR-denaturing gradient gel electrophoresis showed that 2 had a silent codon 213 polymorphism and only the index case had a somatic mutation identified to be an 8 bp insertion in codon 281 (5'CCGGGGGG-3'). This insertion was associated with the second, more aggressive clone which underwent clonal evolution and became resistant to cytotoxic chemotherapy. With an allele-specific primer in PCR, we were able to demonstrate the presence of this clone as a minority at disease presentation, and in 2 of 3 collections of peripheral blood progenitor cells.

Adolescent↗
PubMed1992

Identification of splicing mutations of the last nucleotides of exons, a nonsense mutation, and a missense mutation of the XPAC gene as causes of group A xeroderma pigmentosum.

Four mutations of the XPAC gene were identified as molecular bases of different UV-sensitive subgroups of xeroderma pigmentosum (XP) group A. One was a G to C transversion at the last nucleotide of exon 4 in GM1630/GM2062, a little less hypersensitive subgroup than the most sensitive XP2OS/XP12RO. The second mutation was a G to A transition at the last nucleotide of exon 3 in GM2033/GM2090, an intermediate subgroup. Both mutations caused almost complete inactivation of the canonical 5' splice donor site and aberrant RNA splicing. The third mutation was a nucleotide transition altering the Arg-211 codon (CGA) to a nonsense codon (TGA) in another allele of GM2062. The fourth mutation was a nucleotide transversion altering the His-244 codon (CAT) to an Arg codon (CGT) in XP8LO, an intermediate subgroup. Our results strongly suggest that the clinical heterogeneity in XP-A is due to different mutations in the XPAC gene.

Adolescent↗
PubMed1999

ATP2A2 mutations in Darier's disease: variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class.

Darier's disease (DD) is an autosomal dominant skin disorder characterized clinically by multiple keratotic papules, and histologically by focal loss of adhesion between epidermal cells (acantholysis) and by abnormal keratinization. Variant forms of cutaneous phenotype, sometimes familial, have been described. Associated neuropsychiatric features, including mental handicap, schizophrenia, bipolar disorder and epilepsy, have also been reported. The cause of DD was shown recently to be mutation in the ATP2A2 gene at 12q24.1, which encodes the sarco-endoplasmic reticulum calcium ATPase type 2 (SERCA2). Here, we show that while both common isoforms of SERCA2 are expressed in the cytoplasm of cultured keratinocytes and fibroblasts, in adult skin sections only the longer isoform, SERCA2b, was expressed abundantly in epidermal structures. Extended mutation analysis in European DD patients using single-strand conformation polymorphism and/or direct sequencing identified 40 different patient-specific mutations in 47 families. The majority (23/40) were likely to result in nonsense-mediated RNA decay. The remaining 17 were missense mutations distributed throughout the protein and were associated significantly with atypical clinical features. The clearest association was with the familial haemorrhagic variant where all four families tested had a missense mutation. Three of the families (one Scottish family and two unrelated Italian families) exhibited the same N767S substitution in the M5 transmembrane domain, and a fourth family, from Sweden, had a C268F substitution in the M3 transmembrane domain. Neuropsychiatric features did not appear to be associated with a specific class of mutation and may be an intrinsic, but inconsistent, effect of defective ATP2A2 expression.

Calcium-Transporting ATPases↗
PubMed1999

Identification of a D579G homozygote cystic fibrosis patient with pancreatic sufficiency and minor lung involvement. Mutations in brief no. 221. Online.

Here we describe the identification of an italian patient homozygote for the D579G mutation affected by a mild form of Cystic Fibrosis with pancreatic sufficiency, minor lung involvement and marked viscosity of the cervical mucous. The D579G mutation causes an A1868G transition, a substitution of an aspartic acid to a glycine residue, generating an important amino acid change (charged to hydrophobic) in the nucleotide-binding domain (NBD). The mutation was first described by Brancolini et al. (1995) on two pancreatic sufficient CF patients, compound heterozygotes for delta508F. Patients were from Southern Italy (Puglia) as the D579G homozygote one, who is a 30 years old woman from Taranto (Puglia), daughter of second cousins born in Bari (Puglia). The identification of a homozygote D579G patient might confirm that this mutation does correlate with pancreatic sufficiency and a mild pulmonary phenotype.

Adult↗
PubMed1985

Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins: XIV. Mutational and non-mutational mechanisms as subsets of a more general mechanism. Part C. A defined cancer mutation.

The results of applying a mechanism of ethionine-induced embryonic gene derepressions to explain similar features found in hereditary tyrosinemia have been extended to a well defined cancer mutation. In all three cases, the described mechanism is compatible with the explanation for the etiology of embryonic like phenotypic expressions in cells and potentially for the carcinogenic process. The essence of the formulated process for a human bladder carcinoma mutation in the ras gene for a protein phosphokinase states that a specific proto-oncogene is mutated to an oncogene by various known processes. The protein phosphokinase that has an altered specificity resulting in anomalous phosphorylation of important regulating proteins by a non-mutation mechanism, i.e. by ethionine, would produce the same effect in a hypomethylated state of deoxyribonucleic acid causing an embryonic type protein phosphokinase gene to become activated. These embryonic oncogenes are supersensitive to methylation control mechanisms--thus the link between non-mutation and mutation type mechanisms.

Carcinogens↗
PubMed2005

The T12I mutation within the SP1 region of Gag restricts packaging of spliced viral RNA into human immunodeficiency virus type 1 with mutated RNA packaging signals and mutated nucleocapsid sequence.

Specific packaging of human immunodeficiency virus type 1 (HIV-1) RNA is attributable to the high affinity of nucleocapsid (NC) sequence of Gag for the cis-acting RNA packaging signals located within the 5' un-translated region (5' UTR). Interestingly, we have previously reported that the T12I mutation (named MP2) within SP1 of Gag prevented incorporation of spliced viral RNA into mutated viruses that lacked the stem-loop 1 (SL1) RNA element (also named dimerization initiation site, DIS), suggesting a role for the SP1 sequence in viral RNA packaging. In this study, we have further tested this activity of MP2 in the context of a variety of mutations that affect viral RNA incorporation. The results showed that MP2 was able to effectively restrict packaging of spliced viral RNA into viruses containing either NC mutations R10A and K11A or mutated 5' UTR sequence, such as DeltaGU3 that lacked the 112-GUCUGUUGUGUG-123 sequence of U5, D1 that was deleted of a 27 nt fragment immediately downstream of the primer binding site (PBS), Delta(306-325) that had the SL3 RNA element removed and MD2 that was missing the 328-GGAG-331 sequence. As a result, MP2 contributed increased infectivity to the related viruses. Therefore, the MP2 mutation demonstrates a distinct role in HIV-1 RNA packaging that is neither pertained to the specific viral RNA packaging signal nor to the NC sequence.

Animals↗
PubMed2002

K-ras mutations in sporadic colorectal tumors in Israel: unusual high frequency of codon 13 mutations and evidence for nonhomogeneous representation of mutation subtypes.

Colorectal cancer is one of the most common malignancies in the western world, including Israel. An important step in progression includes induction of activating mutations in the protooncogene K-ras. This event is very frequent and is detected in about 40% of colorectal carcinomas. Previous studies of a variety of genetic disorders revealed unique gene mutation prevalence in Jewish populations, attributed both to differences in genetic background and to variability in environmental exposure. To determine the incidence and molecular subtypes of K-ras mutations in colorectal cancer in Israel, compared with other countries, DNA was isolated from a random collection of 105 colorectal carcinoma samples, and K-ras mutations were detected by an improved designed RFLP and direct sequencing. K-ras sporadic mutations in colorectal cancer in Israel are relatively frequent, with a higher fraction in codon 13 than reported thus far. Comparison with other countries shows a vast heterogeneity in terms of the relative abundance of the affected K-ras codon and in type and representation of specific mutations. The heterogeneous distribution found may be due to a variable genetic background and different environmental factors involved in the initiation and propagation of sporadic colorectal cancer.

Adult↗
PubMed1998

A mutation screen of the TSC1 gene reveals 26 protein truncating mutations and 1 splice site mutation in a panel of 79 tuberous sclerosis patients.

The entire coding region of the TSC1 gene has been screened for mutations in 79 unrelated patients with tuberous sclerosis. Causative mutations have been found in 27 of these patients and five other variations in the gene have been identified. 26 of the mutations are predicted to cause premature truncation of the protein product of the gene and one mutation is in a splice site. The mutation screen has revealed that TSC1 mutations are rarer in sporadic tuberous sclerosis patients than in familial cases. We have also found that the only previously described case of non-penetrance can no longer be described as such, and that a single ungual fibroma is not necessarily diagnostic of tuberous sclerosis, important findings for the genetic counselling of tuberous sclerosis patients.

Blotting, Southern↗
PubMed1995

A mutation in yeast TOP2 homologous to a quinolone-resistant mutation in bacteria. Mutation of the amino acid homologous to Ser83 of Escherichia coli gyrA alters sensitivity to eukaryotic topoisomerase inhibitors.

In prokaryotic type II topoisomerases (DNA gyrases), mutations that result in resistance to quinolones frequently occur at Ser83 or Ser84 of the gyrA subunit. Mutations to Trp, Ala, and Leu have been identified, all of which confer high levels of quinolone resistance. Extensive segments of DNA gyrase are homologous to eukaryotic topoisomerase II, and Ser741 of yeast TOP2 is homologous to Ser83 of prokaryotic DNA gyrA. Introduction of the Ser741-->Trp mutation into yeast TOP2 confers resistance to 6,8-difluoro-7-(4'-hydroxyphenyl)-1-cyclopropyl- 4-quinolone-3-carboxylic acid (CP-115,953), a fluoroquinolone with substantial activity against eukaryotic topoisomerase II, whereas changing Ser741 to either Leu or Ala does not change sensitivity to quinolones. Interestingly, Ser741-->Trp in the yeast TOP2 also confers hypersensitivity to etoposide. Sensitivity to intercalating anti-topoisomerase II agents such as amsacrine is not changed by any of the three mutations. The topoisomerase II protein carrying the Ser741-->Trp mutation was overexpressed and purified. The purified mutant enzyme had enhanced levels of etoposide stabilized covalent complex as compared with the wild type enzyme and reduced cleavage with CP-115,953. Unlike the wild type enzyme, etoposide-stabilized cleavage is not readily reversible by heat. We suggest that Ser741 is near a binding site for both quinolones and etoposide and that the Ser741-->Trp mutation leads to a more stable ternary complex between etoposide, DNA, and the mutant enzyme.

Anti-Infective Agents↗
PubMed1999

Mutation screening of neurofibromatosis type 1 (NF1) exons 28 and 29 with single strand conformation polymorphism (SSCP): five novel mutations, one recurrent transition and two polymorphisms in a panel of 118 unrelated NF1 patients. Mutations in brief no. 229. Online.

Neurofibromatosis type 1 is a clinically variable disorder caused mostly by small mutations within the NF1 gene on chromosome 17q11.2. We used Single Strand Conformation Polymorphism (SSCP) and radioactive sequencing to screen NF1 exons 28 and 29 from 118 unrelated patients, diagnosed with NF1 according to the NIH criteria, identifying five novel and one recurrent germline mutations, two novel polymorphisms and a variant base exchange. All but one cause protein truncation and represent typical NF1 mutations. There are reports that NF1 patients with mutations in exons 28 and 29 could be at greater risk of developing myeloid leukemia. This question was given consideration in this investigation, but none of the children involved have yet shown any symptoms of myeloid leukemia. 4 out of the 6 mutations were de novo.

Codon, Terminator↗
PubMed1995

Mutation analysis of the BRCA1 gene in 76 Japanese ovarian cancer patients: four germline mutations, but no evidence of somatic mutation.

To investigate the putative role of BRCA1, a gene involved in hereditary breast and ovarian cancer, in sporadic ovarian tumors among Japanese women, we examined 76 unselected primary ovarian cancers for mutations in the coding region of BRCA1 using the single-strand conformation polymorphism technique. Although no somatic mutations were detected in any of the tumors, constitutional mutations were identified in four cases: two frameshifts, one nonsense mutation and one intronic base substitution 32 bp downstream of exon 22; RT-PCR experiments revealed that the single-base substitution in the intron seemed to increase the transcript lacking exon 22. All four cases were judged to involve truncation of the gene product. The evidence reported here supports a rather limited role of BRCA1 in ovarian carcinogenesis in the Japanese population.

BRCA1 Protein↗
PubMed1999

Mutation analysis in patients with Wilson disease: identification of 4 novel mutations. Mutation in brief no. 250. Online.

In order to obtain novel mutations in the recently discovered Wilson disease gene, we screened 5 unrelated German individuals for mutations in the 21 exons and their flanking intronic sequences. We detected 9 mutations affecting the Wilson disease gene. Four of those, designated 802-808delTGTAAGT, 2008-2013delTATATG, Cys985Thr, and Ile1148Thr have not yet been reported. One patient had a homozygous mutation whereas the remaining four subjects were compound heterozygous. Therefore these data confirm, that mutations causing Wilson disease are frequently found in affected subjects and they are very heterogenous.

Adenosine Triphosphatases↗
PubMed1995

A splicing mutation, a nonsense mutation (Y167X) and two missense mutations (I159T and A209V) in Spanish patients with ornithine transcarbamylase deficiency.

Four novel mutations are identified in the ornithine transcarbamylase (OTC) gene, in four patients with OTC deficiency (an X-linked disorder). The mutations represent three different categories: missense (Ile159Thr and Ala209Val), nonsense (Tyr167Stop), and causing inefficient splicing (G-->A in the first intronic base) with associated aberrant splicing. They are located in exons 5, and 6, and in intron 3. Two of the mutations arose de novo in the patients, and only one mutation occurs at a CpG site. The nonsense and the splicing mutation cause, respectively, lethal early onset and non-lethal, delayed early onset clinical presentations in males. Our results confirm for Spain the high genotypic heterogeneity of OTC deficiency.

Base Sequence↗
PubMed2004

OCTN2 mutation (R254X) found in Saudi Arabian kindred: recurrent mutation or ancient founder mutation?

The truncating R254X mutation in the OCTN2 gene results in defective high-affinity carnitine transport and has been previously described as a founder mutation in the Chinese population. We now report a Saudi Arabian kindred with this same mutation, suggesting that it may be a recurrent mutation or a very ancient founder mutation. Western blot analysis of skin fibroblast lysates from the proband with our specific anti-murine OCTN2 antibody revealed the absence of the OCTN2 protein.

Blotting, Western↗
PubMed2005

Mutation screening of EXT1 and EXT2 by direct sequence analysis and MLPA in patients with multiple osteochondromas: splice site mutations and exonic deletions account for more than half of the mutations.

Multiple osteochondromas (MO) is an autosomal dominant condition, caused by mutations in either the EXT1 or the EXT2 gene. The DNA of a cohort of 35 patients, clinically suspected to be affected with MO, was screened for mutations by a combination of direct sequence analysis and multiplex ligation-dependent probe amplification (MLPA). In this cohort, 26 pathogenic gene alterations were found (74%). With sequence analysis mutations were detected in 22 patients (63%). In total, 10 mutations were detected in the EXT1 and 12 in the EXT2 gene. The number of the splice site mutations detected was larger than expected from the literature. In addition, with the MLPA four deletions of one or more exons were found in this cohort. Two patients, of whom one had a negative family history, showed deletions of exon 1 of the EXT1 gene, which is possibly a deletion hot spot. In patients suspected to be affected by MO, we recommend a quantitative analysis such as MLPA, followed by direct sequence analysis for the screening of the EXT1 and EXT2 genes.

Cohort Studies↗
PubMed2005

Lymphoedema-distichiasis and FOXC2: unreported mutations, de novo mutation estimate, families without coding mutations.

Lymphoedema-distichiasis (LD) is a syndromic form of primary lymphoedema, where mutations in the gene for the developmental transcription factor FOXC2 have been shown to be causative. The disorder has been considered very rare, but our group has now ascertained 34 families and 11 sporadic cases in the UK. Two families with LD have no mutation in the coding region of FOXC2, although both are consistent with linkage to the FOXC2 locus. A deletion has been ruled out as a possible cause of LD in these families, leaving promoter mutations as the most likely cause. Sixteen previously unpublished mutations are reported, plus an estimate of the frequency of new mutations in this disorder.

Amino Acid Sequence↗
PubMed2007

Autosomal recessive von Willebrand disease associated with compound heterozygosity for a novel nonsense mutation (2908 del C) and the missense mutation C2362F: definite evidence for the non-penetrance of the C2362F mutation.

A novel null mutation (2908del C in exon 22) of the von Willebrand factor (VWF) gene was identified in compound heterozygosity with the missense mutation G7335T (C2362F) in exon 42 in a propositus from a new family with autosomal recessive von Willebrand disease (VWD). The propositus, referred at age 2 for severe epistaxis and prolonged bleeding after a tongue bite, had factor VIII:C 14-21 IU/dL, VWF Antigen 3-8 IU/dL and Ristocetin Cofactor activity < 3 IU/dL. Multimeric pattern showed the lack of triplet pattern and a faster mobility of central band, while heterozygotes for C2362F showed intermediate mobility compared to normal plasma and plasma from the propositus. In the propositus' family 5 subjects were heterozygotes for the C2362F mutation and 5 were heterozygotes for the cytosine deletion. Bleeding score was assessed with a detailed questionnaire in 28 heterozygotes for C2362F, 23 of whom identified in 5 previously reported families and 5 in the present one, and found to be similar to what is observed in normal controls and heterozygotes for null allele. In conclusion, the mutation C2362F is frequently observed in compound heterozygosity with null alleles in patients with recessive VWD in the Veneto region and cause bleeding only in the compound heterozygous or homozygous state.

Alleles↗