Missense mutations caused

Donger, C., Denjoy, I., Berthet, M., Neyroud, N., Cruaud, C., Bennaceur, M., Chivoret, G., Schwartz, K., Coumel, P. and Guicheney, P. (1997) KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation, 96, 2778-2781. 

In most countries, about one third of the mutations that are identified wfll not have been reported previously in AIP and may represent rare polymorphisms rather than disease-specific mutations. Criteria that suggest that such novel mutations cause disease include production of a frameshift or stop codon, the absence of any other sequence abnormality in the gene, segregation with disease, and nonconservative change of an amino acid residue that is conserved between species and/or known to have a functional role in catalysis. Mutations of consensus bases in splice sites are also likely to be disease specific, but ideally all putative splicing defects should be confirmed by analysis of mRNA. Proof that a missense mutation causes disease may require expression and characterization of the mutant enzyme in a prokaryotic or eukaryotic vector. 

Viola, R.E., Yerman, L., Fowler, J.M., Arvidson, C.G., Brubaker, R.R. 2008. A missense mutation causes aspartase deficiency in Yersiniapestis. Microbiology 154 1271-1280. 

Vastardis, H., Karimbux, N., Guthua, S.W., Seidman, J.G., Seidman, C.E. 1996. A human MSX1 homeodomain missense mutation causes selective tooth agenesis. Nat. Genet. 13, 417-421. 

The genetic defect in patients with a-mannosidosis generally do not appear to involve the alterations in the transcription or translation of the mannosidase polypeptide [162], but recent data indicate that a human mutations can include splicing, missense, or nonsense mutations, as well as small insertions or deletions [177-179], Animal models for the enzyme deficiency have also been identified in Persian cats [158] and in Angus and Galloway cattle [159]. The defect in the feline disease results from a 4 bp deletion resulting in a frame shift at codon 583 and a premature termination at codon 645 [158], Each of the bovine mutations involve different missense mutations causing amino acid substitutions that influence the either the level of protein expression or enzyme stability [159],... 

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... 

Substitution of Amino Acids Causes Missense Mutations... 

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). 

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... 

Maruo Y, Sato H, Yamano T et al. Gilbert syndrome caused by a homozygous missense mutation (Tyr486Asp) of bilirubin UDP-glucuronosyltransferase gene. 

Martin, N., Jaubert, J., Gounon, P. et al. A missense mutation in Tbce causes progressive motor neuronopathy in mice. Nat. Genet. 32 443-447, 2002. 

FIGURE 45-2 Missense mutations in the a-synuclein gene and multiplication of the chromosomal region containing the a-synuclein gene cause autosomal-dominantly inherited forms of Parkinson s disease and dementia with Lewy bodies. The a-synuclein gene is shown schematically in green. 

Sickle cell anemia is caused by a missense mutation in codon 6 of the P- obin gene. 

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