The unstable haemoglobins

Williamson, D.

doi:10.1016/0268-960x(93)90002-l

Cited by 77 publications

(43 citation statements)

References 74 publications

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“…This is atypical among the numerous genetic deficiencies for which a three-dimensional structure of the affected protein is known or for which a homology model is available. These include hemoglobin (29), apolipoprotein E (30, 31), factor IX (32-34), antithrombin III (35), ␣ 1 -antitrypsin (36), medium-chain acyl-CoA dehydrogenase (37,38), and myosin (39). Mutations in globular proteins that are associated with genetic diseases are usually found to be distributed into different categories according to how they predominantly affect the function or structure of the protein.…”

Section: Discussionmentioning

confidence: 99%

The atomic model of the human protective protein/cathepsin A suggests a structural basis for galactosialidosis

Rudenko

Bonten

Hól

et al. 1998

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

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Human protective protein͞cathepsin A (PPCA), a serine carboxypeptidase, forms a multienzyme complex with ␤-galactosidase and neuraminidase and is required for the intralysosomal activity and stability of these two glycosidases. Genetic lesions in PPCA lead to a deficiency of ␤-galactosidase and neuraminidase that is manifest as the autosomal recessive lysosomal storage disorder galactosialidosis. Eleven amino acid substitutions identified in mutant PPCAs from clinically different galactosialidosis patients have now been modeled in the three-dimensional structure of the wild-type enzyme. Of these substitutions, 9 are located in positions likely to alter drastically the folding and stability of the variant protein. In contrast, the other 2 mutations that are associated with a more moderate clinical outcome and are characterized by residual mature protein appeared to have a milder effect on protein structure. Remarkably, none of the mutations occurred in the active site or at the protein surface, which would have disrupted the catalytic activity or protective function. Instead, analysis of the 11 mutations revealed a substantive correlation between the effect of the amino acid substitution on the integrity of protein structure and the general severity of the clinical phenotype. The high incidence of PPCA folding mutants in galactosialidosis ref lects the fact that a single point mutation is unlikely to affect both the ␤-galactosidase and the neuraminidase binding sites of PPCA at the same time to produce the double glycosidase deficiency. Mutations in PPCA that result in defective folding, however, disrupt every function of PPCA simultaneously.

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Section: Discussionmentioning

confidence: 99%

The atomic model of the human protective protein/cathepsin A suggests a structural basis for galactosialidosis

Rudenko

Bonten

Hól

et al. 1998

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

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“…Precipitation of denatured hemoglobin in red cells due to mutations in the globin protein or to unbalanced chain synthesis, as in the common alpha thalassaemias, results in the aggregation of hemoglobin as discrete inclusion bodies (9). These inclusions distort the cell and lead to a physical loss of membrane and eventually to lysis.…”

Section: Discussionmentioning

confidence: 98%

What Can Be Found Inside Shunt Catheters

Czernicki

Strzałkowski

Walasek

et al. 2009

Acta Neurochirurgica Supplementum

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Obstruction of shunt catheters is one of the main causes of shunt malfunction. The fragments of shunts removed from five patients were examined using scanning electron microscopy with a (SEM) JEOL JSM-6390 LV microscope. Fifteen catheters from the brain ventricle, lumbar space, and peritoneal space were studied. SEM studies showed that the catheters' surfaces were not sufficiently smooth. The inner surface was often covered by a web of collagen fibrils. Aggregates of red and white blood cells, platelets, lymphocytes, mast cells, and macrophages were trapped in the collagen web. Such cellular aggregates formed a coherent, delicate web mainly consisting of ultrastructurally unchanged cellular elements and were well preserved. Other types of aggregates contained completely destroyed cells that appeared to be submerged in thick collagen web fibrils.We also found a few ultrastructural abnormalities among morphologically unchanged cellular elements. The presence of abnormal red cells showing unusual variability in their shape and size including spherocytosis (thickened, spheroid, and crenate red cells), elliptocytosis (elongated, rod-shaped, or tear-drop red cells), the thalassaemic phenotype of red cells (with inclusion of precipitated unstable hemoglobin in the form of Heinz bodies distorting the red cells, leading to their lysis) was a striking finding. Under scanning electron microscopy, we also recognized swollen or crumpled red cells that looked like potato crisps. Aggregation of thickened blood platelets and white cells was observed frequently. Our study confirmed the importance of the smoothness of the inner surface of the catheter. Smoothness can prevent the formation of cell and protein deposits.

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“…These inclusions are formed in the erythrocyte precursors of the bone marrow, leading to some degree of ineffective erythropoiesis. Usually, these thalassemic Heinz bodies have disappeared from the cytoplasm of the circulating erythrocytes since the protease activity is high in the erythrocyte precursors [22]. By contrast, the Heinz bodies resulting from unstable Hb variants are formed in the blood circulation under various conditions of oxidative stress.…”

Section: Discussionmentioning

confidence: 99%