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At least 73 records · Page 4Linked to original sources
PubMed1983

High-resolution proton NMR as indicator of a silent mutation in the haem cavity of a monomeric allosteric haemoglobin.

Comparison of the high-field 1H-NMR spectra of the met-cyano complexes of allosteric haemoglobins III and IV of the insect larva Chironomus thummi thummi (CTT-III and CTT-IV) shows that, in addition to the molecular heterogeneity previously described for both Hbs as due to haem orientational disorder [La Mar et al. (1980) J. Biol. Chem. 255, 66-70], CTT-III but not CTT-IV exhibits a second heterogeneity as evidenced by splitting of numerous signals. Reconstitution of CTT-III with modified haems alters the populations of the two haem rotational isomers but leaves the secondary heterogeneity unaffected. This argues directly for locating this secondary heterogeneity solely within the polypeptide chain rather than the result of protein-haem interaction. We assign this secondary heterogeneity found solely in Hb-III to a point mutation in the haem cavity, 57E6 (Ile/Thr); CTT-IV is chemically homogeneous. The observation of significant hyperfine shift differences for the alternative substitution at 57E6, particularly for non-haem single-proton resonances thought to arise from distal residues, indicates some structural consequences in the haem cavity due to the point mutation. While a difference in the allosteric properties cannot be detected in that the point mutation appears to leave the pK for the allosteric transition unaltered, subtle influences on the function of the protein in both affinity states cannot be ruled out at this time.

Allosteric Regulation↗
PubMed2003

Pharmacologically regulated induction of silent mutations (PRISM): combined pharmacological and genetic approaches for learning and memory.

Mouse transgenic and knock-out approaches have made fundamental contributions to our understanding of the molecular and cellular bases of learning and memory. These approaches have successfully identified a large number of molecules with either a central or modulatory role in learning and memory. However, there are limitations associated with first-generation mutant mice, which include, for example, the lack of temporal control over the mutation. Recent technical developments have started to address some of these shortcomings. Here, the authors review a newly developed inducible approach that takes advantage of synergistic interactions between subthreshold genetic and pharmacological manipulations. This approach is easily set up and can be used to study the functional interactions between molecules in signaling pathways.

Animals↗
PubMed1997

mtDNA analysis shows common ancestry in two kindreds with X-linked recessive hypoparathyroidism and reveals a heteroplasmic silent mutation.

Two kindreds residing in eastern Missouri and exhibiting X-linked recessive idiopathic hypoparathyroidism have been described. Genealogical records extending back five generations revealed no common ancestor. To investigate the possibility of relatedness, the DNA sequence of the mitochondrial D-loop was compared among several individuals in both kindreds. The mtDNA D-loop was amplified from the total DNA of individuals by use of nested PCR reactions, and the resulting 430-bp fragment was sequenced. The mtDNA sequence was identical among affected males and their maternal lineage for individuals in both kindreds. Conversely, the mtDNA sequence of the fathers of the affected males differed from that of the maternal lineage at three to six positions. These results demonstrate that the two kindreds exhibiting X-linked recessive hypoparathyroidism are indeed related and that an identical gene defect is responsible for the disease. A further feature of the inheritance pattern was examined when a unique point mutation was identified in the mtDNA of one branch of one of the kindreds. This mutation appears to be de novo and segregates in subsequent generations without obscuring relatedness. In addition, the results of our study of mtDNA analysis indicate that this approach may be of importance in investigating common ancestry in other X-linked disorders.

Alleles↗
PubMed1999

Analysis of the immunoglobulin heavy chain gene variable region of 101 cases with peripheral B cell neoplasms and B cell chronic lymphocytic leukemia in the japanese population.

We have analyzed the immunoglobulin heavy chain (VH) gene variable regions (CDR2 and FW3) of 101 Japanese cases with peripheral B cell neoplasms. When all except one case with a deletion were graphed by frequency of replacement mutation, the 100 cases could be separated into two groups: 24 cases with zero, one and two mutations (germline or low frequency of somatic mutation); and 76 cases with three or more mutations (medium to high frequency of somatic mutation). While most mantle cell lymphoma cases (11/13) showed germline or low frequency of somatic mutation, all cases of mucosa-associated lymphoid tissue (MALT) lymphoma (11/11), follicular lymphoma (three of three cases), plasma cell myeloma (seven of seven cases) and most cases of diffuse large B cell lymphoma (DLBCL; 42/47) belonged to the latter group. These 76 cases, therefore, may be considered to show somatic hypermutation. More than half of chronic lymphocytic leukemia/small lymphocytic lymphoma cases (CLL/SLL; eight of 13) showed a hypermutated VH gene and the ratio of replacement mutation: silent mutation in CDR2 of CLL/SLL was considerably higher compared with DLBCL and MALT lymphoma, showing somatic hypermutation. When comparing VH gene type of B cell-CLL (B-CLL) among our series and those in the literature, more cases of CD5+ B-CLL in the Western literature have the VH5 and VH6 family types, while more cases in Japan are reported to have VH4 family. The occurrence of VH families in B-CLL between Japanese and Western people seems to be comparable.

Aged↗
PubMed1996

p16/CDKN2 gene and p53 gene alterations in Japanese non-smoking female lung adenocarcinoma.

Primary lung adenocarcinomas in non-smoking females are increasing in the USA and Japan. Environmental factors such as passive smoking, asbestos, domestic radon, and hormonal effects have been implicated, but the etiology is still uncertain. We therefore analyzed point mutations of p16 gene, a newly characterized tumor suppressor gene, and compared the results with alterations of p53 gene in 28 primary lung adenocarcinomas in non-smoking Japanese females. There were no cases with somatic point mutation of p16 gene, except for one case with two germline mutations (silent mutations). In contrast, six out of 16 informative cases showed loss of heterozygosity of p53 gene using a TP53 microsatellite marker and 19 out of 28 cases showed expression of oncoprotein using DO-7 immunohistochemistry. These findings suggest that p16 gene alteration is a rare event in primary lung adenocarcinomas in Japanese non-smoking females, compared with alterations of the p53 gene.

Adenocarcinoma↗
PubMed2002

[Relationship between core gene mutations of hepatitis B virus and response to alpha interferon therapy in chronic hepatitis B].

BACKGROUND/AIMS: Treatment of chronic hepatitis B with interferon results in a sustained loss of hepatitis B virus DNA and hepatitis B e antigen (HBeAg) and remission of liver disease only in a proportion of cases. Recently, mutations of hepatitis B virus (HBV) core gene have been reported as being related to the failure of interferon treatment in chronic hepatitis B. This study investigated whether core gene mutations of HBV are related to non-response to interferon therapy and whether the recurrence of HBeAg and HBV DNA in initial responders to interferon therapy is associated with the emergence of HBV core gene mutants. METHODS: The precore/core gene sequence was determined by polymerase chain reaction (PCR) and direct sequencing of PCR product in serum samples obtained before interferon treatment from 10 responders and 10 non-responders to interferon therapy. In addition, precore/core gene sequence was determined in serum samples obtained before interferon treatment and after recurrence from 10 patients who showed recurrence of HBeAg and HBV DNA after initial response to interferon therapy. RESULTS: In samples from 10 responders, there were 7 missense mutations and 71 silent mutations. However, there were 43 missense mutations and 109 silent mutations in samples from 10 non-responders. In samples obtained before interferon treatment from the 10 patients who showed recurrence after initial response, 8 missense mutations and 74 silents mutations were found. The nucleotide sequences from the samples obtained after the recurrence showed 6 silent nucleotide substitutions compared with the sequences from the samples obtained before interferon treatment. CONCLUSIONS: Mutations in the core protein of HBV occur more frequently in non-responders than responders to interferon therapy of chronic hepatitis B and may be a factor responsible for the failure of interferon treatment. The recurrence of HBeAg and HBV-DNA in initial responders to interferon therapy is not associated with the emergence of the HBV core gene mutants.

Adolescent↗
PubMed1999

Low incidence of p53 mutations in betel quid and tobacco chewing-associated oral squamous carcinoma from India.

Mutations of the p53 tumor suppressor gene have been found to be the single most frequent event in human cancers. In India and other southeast Asian countries tobacco chewing with betel quid was attributed to be the major factor in oral carcinogenesis. We have analyzed 72 untreated primary oral squamous cell carcinomas (SCCs) for mutations in the tumor suppressor gene p53 exons 4-9 by PCR-SSCP and DNA sequencing. Sequencing analysis revealed 16 missense mutations, one silent mutation in codon 307 and four A to G substitution polymorphism in codon 213. The incidence of p53 mutation was 21% (15 of 72) excluding the polymorphism and the silent mutation. Eight mutations were clustered in codons 266-282 of exon 8. Of the total mutation events 37.5% were G to A transitions and 31.3% were G to T transversions. These results indicate the possible involvement of tobacco derived nitrosamines and their adducts in the genesis of oral cancer among Indians.

Adult↗
PubMed2001

Scanning of estrogen receptor alpha (ERalpha) and thyroid hormone receptor alpha (TRalpha) genes in patients with psychiatric diseases: four missense mutations identified in ERalpha gene.

Estrogen and thyroid hormones exert effects on growth, development, and differentiation of the nervous system. Hormone administration can lead to changes in behavior, suggesting that genetic variants of the estrogen receptor alpha (ERalpha) and the thyroid hormone receptor alpha (TRalpha) genes may predispose to psychiatric diseases. To investigate this possibility, regions of likely functional significance (all coding exons and flanking splice junctions) of the ERalpha and TRalpha genes were scanned in patients with schizophrenia (113), along with pilot studies in patients with bipolar illness (BPI), puerperal psychosis, autism, attention-deficit hyperactivity disorder (ADHD), and alcoholism. A total of 1.18 megabases of the ERalpha gene and 1.16 megabases of the TRalpha gene were scanned with Detection of Virtually All Mutations-SSCP (DOVAM-S), a method that detects virtually all mutations. Four missense mutations, seven silent mutations and one deletion were identified in the ERalpha gene, while only four silent mutations were present in the TRalpha gene. Two of the missense mutations in ERalpha are conserved in the six available mammalian and bird species (H6Y, K299R) and a third sequence variant (P146Q) is conserved in mammals, birds, and Xenopus laevis, hinting that these sequence changes will be of functional significance. These changes were found in one patient each with BPI, puerperal psychosis, and alcoholism, respectively. Analysis of the ERalpha and TRalpha genes in 240 subjects reveals that missense changes and splice site variants are uncommon (1.7% and 0%, respectively). Further analyses are necessary to determine if the missense mutations identified in this study are associated with predisposition or outcome for either psychiatric or nonpsychiatric diseases.

Alleles↗
PubMed1993

Precise missense and silent point mutations are fixed in the genomes of poliovirus mutants from persistently infected cells.

Poliovirus mutants selected in persistently infected human neuroblastoma cells have a modified cell tropism and can establish a secondary persistent infection in nonneural cells, such as HEp-2c cells. Nucleotide sequence analysis revealed that the genome of a persistent mutant, S11, differed from that of the parental lytic Sabin 1 poliovirus strain by 31 point mutations. Three mutations occurred in the noncoding regions. The other mutations resulted in 12 amino acid substitutions; 1 substitution occurred in a nonstructural protein (3A), while the other 11 substitutions were clustered in the capsid proteins VP2 and VP1. The same missense mutations, as well as many of the silent mutations that we observed in mutant S11, also accumulated in the genome of two other persistent viruses isolated from independent infections. This finding indicates that both missense and silent mutations are selected during the persistent infection of neuroblastoma cells and suggests that the secondary structure of RNA in the coding region may play a role in viral infection.

Capsid↗
PubMed2001

Ankyrin gene mutations in japanese patients with hereditary spherocytosis.

We studied mutations of the ankyrin-1 (ANK-1) gene of genomic DNA from Japanese patients with hereditary spherocytosis (HS). Forty-nine patients from 46 unrelated families were included in this study. Of these patients, 19 cases from 16 unrelated families had HS of autosomal-dominant inheritance, and 30 patients had non-autosomal-dominant HS. Fifteen mutations of the ANK-1 gene pathognomonic for HS were identified: 4 nonsense mutations, 7 frameshift mutations, and 4 abnormal splicing mutations. These 15 mutations have not been previously reported. The frameshift mutations were found from exon 1 to exon 26, corresponding particularly to the band 3-binding domain of ankyrin. The nonsense mutations, on the contrary, were present mostly at the 3'-terminal side, especially in the spectrin-binding domain and the regulatory domain. The patients with ankyrin gene mutations tended to be more anemic with a higher level of reticulocytosis than those without these mutations. Fifteen silent mutations of the ANK-1 gene, most of which have previously been detected in HS patients in Western populations, were also found. The allele frequency of these silent mutations in the HS patients was nearly identical to that in normal subjects. There was no difference between the Japanese and Western populations in the allele frequency of these gene polymorphisms in healthy subjects or HS patients.

Alleles↗