Missense mutation

S Greenland. Probability logic and probability induction. Epidemiology 9 322-332, 1998. GM Petersen, G Parmigiam, D Thomas. Missense mutations in disease genes A Bayesian approach to evaluate causality. Am J Hum Genet. 62 1516-1524, 1998. 

GGM. Several missense mutations in human sodium-dependent glucose transporters (SGLT1) have been described that cause GGM. 

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... 

LRP6 Missense mutation (familial, autosomal dominant) Autosomal dominant early coronary artery disease (hyperlipidemia, hypertension, diabetes)... 

Geisterfer-Lowrance, A.A., Kass, S., Tanigawa, G., Vosberg, H.-P., McKenna, W., Seidman, C.E., Seidman, J.G. (1990). A molecular basis for familial hypertrophic cardiomyopathy a p-cardiac myosin heavy chain gene missense mutation. Cell 62, 999-1006,... 

Dewald G, Bork K Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal Cl inhibitor. Biochem Biophys Res Commun 2006 343 1286-1289. 

Substitution of Amino Acids Causes Missense Mutations... 

Figure 38-4. Examples of three types of missense mutations resulting in abnormal hemoglobin chains. The amino acid alterations and possible alterations in the respective codons are indicated. The hemoglobin Hikari p-chain mutation has apparently normal physiologic properties but is electrophoretically altered. Hemoglobin S has a p-chain mutation and partial function hemoglobin S binds oxygen but precipitates when deoxygenated. Hemoglobin M Boston, an a-chain mutation, permits the oxidation of the heme ferrous iron to the ferric state and so will not bind oxygen at all.

Some cases of famifial hypertrophic cardiomyopathy are due to missense mutations in the gene coding for p-myosin heavy chain. 

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-... 

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... 

GSH-S deficiency is a more frequent cause of GSH deficiency (HI7), and more than 20 families with this enzyme deficiency have been reported since the first report by Oort et al. (05). There are two distinct types of GSH-S deficiency with different clinical pictures. In the red blood cell type, the enzyme defect is limited to red blood cells and the only clinical presentation is mild hemolysis. In the generalized type, the deficiency is also found in tissues other than red blood cells, and the patients show not only chronic hemolytic anemia but also metabolic acidosis with marked 5-oxoprolinuria and neurologic manifestations including mental retardation. The precise mechanism of these two different phenotypes remains to be elucidated, because the existence of tissue-specific isozymes is not clear. Seven mutations at the GSH-S locus on six alleles—four missense mutations, two deletions, and one splice site mutation—have been identified (S14). 

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). 

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... 

H2. Hamaguchi, T., Nakajima, H., Noguchi, T., Nakagawa, C Kuwajima, M., Kono, N., Tarui, S., and Matsuzawa, Y., Novel missense mutation (W686C) of the phosphofructokinase-M gene in a Japanese patient with a mild form of glycogenosis VII. Hum. Mutat. 8,273-275 (1996). 

K9. Kanno, H., Wei, D. C. C., Miwa, S., Chan, L. C., and Fujii, H., Identification of a 5 -splice site mutation and a missense mutation in homozygous pyruvate kinase deficiency cases found in Hong Kong. Blood 82 (Suppl. 1), 97a (1993). 

V16. Vulliamy, T Beutler, E., and Luzzatto, L., Variants of glucose-6-phosphate dehydrogenase are due to missense mutations spread throughout the coding region of the gene. Hum. Mutat. 2,... 

Poort S. R., Landolfi R., Bertina R. M. Compound heterozygosity for two novel missense mutations on the prothrombin gene in a patient with severe bleeding tendency. Thromb Haemost 1997 77,610-5. 

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