Nonsense mutation

Low levels or absence of adenosine deaminase (ADA) is associated with one form of severe combined immunodeficiency disease (SCID) characterized by B-andT-lymphocyte dysfunction due to toxic effects of deoxyadenosine (HI9). Most patients present as infants with failure to thrive, repeated infections, severe lymphopenia, and defective cellular and humoral immunity. Disease severity is correlated with the degree of deoxyadenosine nucleotide pool expansion and inactivation of S-adenosylhomocysteine hydrolase in red blood cells. Up to now, more than 40 mutations have been identified (A4, H20, S5, S6). The majority of the basic molecular defects underlying ADA deficiency of all clinical phenotypes are missense mutations. Nonsense mutations, deletions ranging from very large to single nucleotides, and splicing mutations have also been reported. It is likely that severe... 

Carbonic anhydrase (CA) exists in three known soluble forms in humans. All three isozymes (CA I, CA II, and CA III) are monomeric, zinc metalloenzymes with a molecular weight of approximately 29,000. The enzymes catalyze the reaction for the reversible hydration of C02. The CA I deficiency is known to cause renal tubular acidosis and nerve deafness. Deficiency of CA II produces osteopetrosis, renal tubular acidosis, and cerebral calcification. More than 40 CA II-defi-cient patients with a wide variety of ethnic origins have been reported. Both syndromes are autosomal recessive disorders. Enzymatic confirmation can be made by quantitating the CA I and CA II levels in red blood cells. Normally, CA I and CAII each contribute about 50% of the total activity, and the CAI activity is completely abolished by the addition of sodium iodide in the assay system (S22). The cDNA and genomic DNA for human CA I and II have been isolated and sequenced (B34, M33, V9). Structural gene mutations, such as missense mutation, nonsense... 

Missense mutant proteins/enzymes may have full, partially impaired, or null (biological) activities depending on the location of the mutation. When the functional impairment manifests itself only at a higher or lower than normal temperature that is considered optimal for the wild-type enzyme, the mutation is called temperature sensitive (ts). Although most ts mutants are sensitive to higher than normal temperatures, some ts mutants are cold sensitive. When an amino acid codon is changed to a termination codon, it is called a nonsense mutation. Nonsense mutations result in incomplete or truncated polypeptides of varying sizes and functional profiles. 

Genetic disorders of HDL metabolism have also resulted in greater understanding of the molecular regulation of HDL metabolism. Nonsense or missense mutations in apoA-I can result in substantially reduced HDL-C levels due to rapid catabolism of structurally abnormal or truncated apoA-I proteins. Tangier disease is a rare autosomal codominant disorder characterized by markedly low HDL-C and apoA-I levels and caused... 

Point mutations Protein folding Transcriptional control Frameshiftand nonsense mutations RNA processing Sickle cell disease P-Thalassemia P-Thalassemia P-Thalassemia... 

P-Thalassemla (MIM 141900) A very wide variety of mutations in the p-globin gene, including deletions, nonsense and frameshift mutations, and others affecting every aspect of its structure (eg, splice sites, promoter mutants)... 

To date, 15 GPI variants have been analyzed at the molecular level, and 16 mis-sense mutations, 1 nonsense mutation, and 1 splicing mutation due to a four-nucleotide deletion have been reported (Fig. 7) (B9, F13, K14, Wl, XI). The GPI gene mutations were heterogeneous, although most GPI variants had common biochemical characteristics such as heat instability and normal kinetic properties. We have determined the molecular abnormalities of four homozygous variants, GPI Matsumoto, GPI Iwate, GPI Narita, and GPI Fukuoka (K14). GPI Narita has a homozygous mutation from A to G at position 1028 (343 Gin to Arg), and the same mutation was reported in an Italian patient, GPI Moscone (B9). The substituted Gin is adjacent to the reported active site residue, 341 Asp. Homozygous missense mutations, C to T at position 14 (5 Thr to lie) and C to T at position 671 (224 Thr to Met) have been identified in GPI Matsumoto and GPI Iwate, respectively. GPI... 

Studies have led to the identification of 14 alleles associated with PFK deficiency. Eight missense mutations, one nonsense mutation, one frameshift muta-... 

A naturally occurring animal model of PFK-M deficiency has been reported in English springer spaniels. Molecular analysis of this canine PFK-M deficiency disclosed that the enzyme deficiency was caused by a nonsense mutation in the penultimate exon of the PFK-M gene, leading to rapid degradation of a truncated (40 amino acid residues) and therefore unstable enzyme protein (SI8). 

Up to now, 101 different mutations have been identified (Fig. 11) (B29, H18). Most of the variant enzymes are produced by one or two missense mutations in the structural gene. G6PD Vancouver is caused by three nucleotide substitutions (M4). Although nucleotide deletions or nonsense mutations are common molecular abnormalities that may cause a variety of genetic disorders, they are rare in G6PD deficiency cases. Nucleotide deletions have been found in only five variants... 

Hereditary deficiency of LDH-B was first reported by Kitamura et al. in 1970 (K21). Since then, this enzyme deficiency has been discovered in at least five families in Japan. There were no clinical symptoms in these cases. On the other hand, LDH-A deficiency was associated with an exertional rhabdomyolysis and myoglobinuria after severe exercise (K15). One Japanese and one Italian with LDH-A deficiency showed the typical skin rash. To date, nine LDH-A variants have been analyzed at the molecular level, and four missense mutations, one nonsense mutation, one frameshift mutation due to a single base insertion, and three gene deletions have been elucidated (K16, M5). Missense mutations have also been identified in LDH-B deficiency (M6). 

Hereditary methemoglobinemia is classified into three types a red blood cell type (type I), a generalized type (type II), and a blood cell type (type HI). Enzyme deficiency of type I is limited to red blood cells, and these patients show only the diffuse, persistent, slate-gray cyanosis not associated with cardiac or pulmonary disease. In type II, the enzyme deficiency occurs in all cells, and patients of this type have a severe neurological disorder with mental retardation that predisposes them to early death. Patients with type III show symptoms similar to those of patients with type I. The precise nature of type III is not clear, but decreased enzyme activity is observed in all cells (M9). It is considered that uncomplicated hereditary methemoglobinemia without neurological involvement arises from a defect limited to the soluble cytochrome b5 reductase and that a combined deficiency of both the cytosolic and the microsomal cytochrome b5 reductase occurs in subjects with mental retardation. Up to now, three missense mutations in type I and three missense mutations, two nonsense mutations, two in-frame 3-bp deletions, and one splicing mutation in type n have been identified (M3, M8, M31). 

V8. Vasconcelos, O., Sivakumar, K., Dalakas, M. C., Quezado, M., Nagle, J., Leon-Monzon, M., Dubnick, M., Gajdusek, C., and Goldfarb, L. G., Nonsense mutation in the phosphofructokinase muscle subunit gene associated with retention of intron 10 in one of the isolated transcripts in Ashkenzai Jewish patients with Tarui disease. Proc. Natl Acad. Sci. U.S.A. 92, 10322-10326 (1995). 

Ware J., Russell S. R., Vicente V., et al. Nonsense mutation in the glycoprotein Iba coding sequence associated with Bemard-Soulier syndrome. Proc Natl Acad Sci USA 1990 87,2026-30. 

Mutations Much of our knowledge of viral reproduction and how it is regulated has depended on the isolation and characterization of virus mutants. Several kinds of mutants have been studied in viruses host-range mutants, plaque-type mutants, temperature-sensitive mutants, nonsense mutants, transposons, and inversions. 

Nonsense mutations change normal codons into nonsense codons. In viruses, nonsense mutations are recognized because hosts are available that contain suppressors able to read nonsense codons. The virus mutant will be able to grow in the host containing the suppressor, but not in the normal host. 

Three Japanese patients with Crigler-Naj-jar syndrome type I carry an identical nonsense mutation in the gene for UDP-glucuronosyltransferase. Jpn J Hum Genet 1995 40 253-257. 

The lacl system for analyzing nonsense mutations in E. coli... 

We have not directly determined the relative frequencies of frameshift mutations and other mutational events in comparison to the base substitution mutations. However, based on the high frequency of nonsense mutations (11%) among all lacl mutants induced by BPDE and because nonsense mutations are monitorable at less than one-fifth of the lacl codons and, even then, only via certain base pair substitutions, we believe that base substitutions account for a major fraction of mutations induced by BPDE. 

Table II. Distribution of lacl Nonsense Mutations Induced by BPDE...

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