Frequency and distribution of rare electrophoretic mobility variants in a population of human newborns in Ann Arbor, Michigan

Mohrenweiser, Harvey W.; Wurzinger, K. H.; Neel, James V.

doi:10.1111/j.1469-1809.1987.tb01065.x

Cited by 15 publications

(11 citation statements)

References 29 publications

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“…Several studies demonstrated an allelic frequency from roughly 0.002 (Caucasian and Japanese population) to 0.02 (African American population) [5]–[9]. Indeed this number implies that 1 out of 2000 newborn individuals from the latter population would suffer from this tremendous disorder, but less than 100 individuals have been diagnosed with TPI deficiency worldwide [6]. A mutagenesis screen in mice identified four heterozygous TPI mutations that lead to a 50% reduction in catalytic TPI activity in several tissues examined [12].…”

Section: Discussionmentioning

confidence: 99%

“…These results demonstrated that mutations in the TPI gene resulting in a catalytic inactive TPI enzyme cause homozygote embryonic lethality in mice. The human population studies performed are indicating that this situation is reflected in humans as well [5], [6]. Consequently, the occurring mutations in TPI alleles of TPI deficiency patients cannot encode catalytically inactive TPI enzymes.…”

Section: Discussionmentioning

confidence: 99%

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Triose Phosphate Isomerase Deficiency Is Caused by Altered Dimerization–Not Catalytic Inactivity–of the Mutant Enzymes

et al. 2006

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Triosephosphate isomerase (TPI) deficiency is an autosomal recessive disorder caused by various mutations in the gene encoding the key glycolytic enzyme TPI. A drastic decrease in TPI activity and an increased level of its substrate, dihydroxyacetone phosphate, have been measured in unpurified cell extracts of affected individuals. These observations allowed concluding that the different mutations in the TPI alleles result in catalytically inactive enzymes. However, despite a high occurrence of TPI null alleles within several human populations, the frequency of this disorder is exceptionally rare. In order to address this apparent discrepancy, we generated a yeast model allowing us to perform comparative in vivo analyses of the enzymatic and functional properties of the different enzyme variants. We discovered that the majority of these variants exhibit no reduced catalytic activity per se. Instead, we observed, the dimerization behavior of TPI is influenced by the particular mutations investigated, and by the use of a potential alternative translation initiation site in the TPI gene. Additionally, we demonstrated that the overexpression of the most frequent TPI variant, Glu104Asp, which displays altered dimerization features, results in diminished endogenous TPI levels in mammalian cells. Thus, our results reveal that enzyme deregulation attributable to aberrant dimerization of TPI, rather than direct catalytic inactivation of the enzyme, underlies the pathogenesis of TPI deficiency. Finally, we discovered that yeast cells expressing a TPI variant exhibiting reduced catalytic activity are more resistant against oxidative stress caused by the thiol-oxidizing reagent diamide. This observed advantage might serve to explain the high allelic frequency of TPI null alleles detected among human populations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Triose Phosphate Isomerase Deficiency Is Caused by Altered Dimerization–Not Catalytic Inactivity–of the Mutant Enzymes

et al. 2006

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“…It The reason for the apparent high frequency of vWD, as well as its extensive genetic heterogeneity, is unclear. The vWF gene does represent a large target for mutation, given its size, and such a factor has been postulated to contribute to the high frequency of mutation at other loci (28). Such …”

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confidence: 99%

Molecular basis of human von Willebrand disease: analysis of platelet von Willebrand factor mRNA.

Ginsburg

Konkle

Gill

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

123

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von Willebrand disease (vWD), the most common inherited bleeding disorder in humans, can result from either a quantitative or a qualitative defect in the adhesive glycoprotein, von Willebrand factor (vWF). Molecular studies of vWD have been limited by the large size of the vWF gene and difficulty in obtaining the vWF mRNA from patients. By use of an adaptation of the polymerase chain reaction, vWF mRNA was amplified and sequenced from peripheral blood platelets. A silent vWF allele was identified, resulting from a cis defect in vWF mRNA transcription or processing. In two type IIA vWD patients, two different but adjacent missense mutations were identified, the locations of which may identify an important vWF functional domain. Expression in heterologous cells of recombinant vWF containing one of these latter mutations reproduced the characteristic structural abnormality seen in type IIA vWD plasma.

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“…This notwithstanding, we believe the series reported by Harris (8) to be relatively unbiased, and in our own studies (9,10), oriented toward the detection of mutation, the criterion for selecting a system for study was Marfan syndrome, and epidermalysis bullosa (discussion in refs. 32 and 33).…”

Section: Heterozygosity Indices Of the Proteins Detected In 2-d Page mentioning

confidence: 78%

Average locus differences in mutability related to protein "class": a hypothesis.

Neel

1990

Proc. Natl. Acad. Sci. U.S.A.

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Substantially less genetic variation has been recognized in studies of the proteins of nucleated cells by the technique of two-dimensional polyacrylamide gel electrophoresis than has been encountered in studies of serum transport proteins and erythrocyte enzymes with one-dimensional electrophoresis. Technical factors appear to account for only part of the difference. The two remaining (nonexclusive) explanations are more stringent biological selection against variants of these proteins or lower mutation rates at the loci encoding the proteins visualized with two-dimensional electrophoresis. While the former possibility cannot be rigorously excluded, the evidence suggests the latter hypothesis merits serious consideration. Some consequences of this latter suggestion for genetic monitoring and the interpretation of molecular evolution are mentioned.

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Frequency and distribution of rare electrophoretic mobility variants in a population of human newborns in Ann Arbor, Michigan

Cited by 15 publications

References 29 publications

Triose Phosphate Isomerase Deficiency Is Caused by Altered Dimerization–Not Catalytic Inactivity–of the Mutant Enzymes

Triose Phosphate Isomerase Deficiency Is Caused by Altered Dimerization–Not Catalytic Inactivity–of the Mutant Enzymes

Molecular basis of human von Willebrand disease: analysis of platelet von Willebrand factor mRNA.

Average locus differences in mutability related to protein "class": a hypothesis.

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