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Biomedical subjects

G de Haas

Publications and source records attributed to G de Haas.

17 recordsLinked to original sources
PubMed2004

Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients.

Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is an autosomal dominant disorder characterized by an aberrant vascular development. The resulting vascular lesions range from smaller mucocutaneous telangiectases to large visceral arteriovenous malformations, especially in the skin, lung, gastrointestinal tract and the brain. Mutations in the genes encoding endoglin (ENG, chromosome 9q34) and activin A receptor type-like kinase 1 (ALK-1, also named ACVRL1, chromosome 12q13) are associated with HHT1 and HHT2, respectively. We report here on the genetic and molecular heterogeneity found in the HHT population in the Netherlands. Probands of 104 apparently unrelated families were studied and we performed sequence analysis on both the ENG gene and ALK-1 gene. In most of the probands, we found a mutation in one of the two genes: 53% in the ENG gene and 40% in the ALK-1 gene. In 7% of the families no ENG or ALK1 mutation was found. The mutations detected were deletions, insertions, nonsense, missense and splice site mutations. The majority were novel mutations.

Activin Receptors, Type I↗
PubMed1991

Two-dimensional 1H-NMR studies of phospholipase-A2-inhibitor complexes bound to a micellar lipid-water interface.

One- and two-dimensional NMR studies were performed on the complexes of porcine pancreatic phospholipase A2 with substrate analogs bound to a micellar lipid-water interface of fully deuterated dodecylphosphocholine. The interactions between the inhibitor and the enzyme were localized by comparison of the two-dimensional NOE spectra recorded for the enzyme-inhibitor complex using both protonated and selectively deuterated inhibitors. These experiments led us to the following conclusions for the phospholipase-A2-micelle complex: (i) the 38-kDa phospholipase A2 complex gives NMR spectra with relatively narrow lines, which is indicative of high mobility of the enzyme; (ii) the residues Ala1, Trp3, Phe63 and Tyr69 located in the interface recognition site, as well as Phe22, Tyr75, Phe106 and Tyr111 are involved in the micelle-binding process; (iii) when present on the micelle, phospholipase A2 is stereospecific for the inhibitor binding; (iv) the inhibitor, (R)-dodecyl-2-aminohexanol-1-phosphoglycol, binds stoichiometrically to phospholipase A2 with high affinity (Kd less than or equal to 10 microM); (v) the inhibitor binds in the active site of the enzyme, which is evidenced by large chemical-shift differences for Phe5, Ile9, Phe22, His48, Tyr52 and Phe106; (vi) the acyl chain of the inhibitor makes hydrophobic contacts (less than 0.4 nm) near Phe5, Ile9, Phe22 and Phe106. Comparison of our results on the enzyme-inhibitor-micelle ternary complex with the crystal structure of the enzyme-inhibitor complex [Thunnissen, M. M. G. M., AB, E., Kalk, K. H., Drenth, J., Dijkstra, B. W., Kuipers, O. P., Dijkman, R., de Haas, G. H. & Verheij, H. M. (1990) Nature 347, 689-691] shows that the mode of inhibitor binding is similar.

Animals↗
PubMed1991

Porcine pancreatic phospholipase A2: sequence-specific 1H and 15N NMR assignments and secondary structure.

The solution structure of porcine pancreatic phospholipase A2 (124 residues, 14 kDa) has been studied by two-dimensional homonuclear 1H and two- and three-dimensional heteronuclear 15N-1H nuclear magnetic resonance spectroscopy. Backbone assignments were made for 117 of the 124 amino acids. Short-range nuclear Overhauser effect (NOE) data show three alpha-helices from residues 1-13, 40-58, and 90-109, an antiparallel beta-sheet for residues 74-85, and a small antiparallel beta-sheet between residues 25-26 and 115-116. A 15N-1H heteronuclear multiple-quantum correlation experiment was used to monitor amide proton exchange over a period of 22 h. In total, 61 amide protons showed slow or intermediate exchange, 46 of which are located in the three large helices. Helix 90-109 was found to be considerably more stable than the other helices. For the beta-sheets, four hydrogen bonds could be identified. The secondary structure of porcine PLA in solution, as deduced from NMR, is basically the same as the structure of porcine PLA in the crystalline state. Differences were found in the following regions, however. Residues 1-6 in the first alpha-helix are less structured in solution than in the crystal structure. Whereas in the crystal structure residues 24-29 are involved both in a beta-sheet with residues 115-117 and in a hairpin turn, the expected hydrogen bonds between residues 24-117 and 25-29 do not show slow exchange behavior. This and the absence of several expected NOEs imply that this region has a less well defined structure in solution. Finally, the hydrogen bond between residues 78-81, which is part of a beta-sheet, does not show slow exchange behavior.

Amino Acid Sequence↗
PubMed1986

Generalized soft tissue calcification in children and adolescents with end stage renal failure.

Sixteen children and adolescents undergoing regular haemodialysis treatment were studied for the occurrence of metastatic calcifications. By the use of diphosphonate bone-scanning, roentgenography of the chest and skull and ocular slit lamp examination, generalized visceral calcification was diagnosed in two patients. No relationship between visceral calcification and biochemical, radiological or histological abnormalities of renal osteodystrophy was found. Our study demonstrates that visceral calcification also occurs in children with chronic renal failure and may be detected by scintigraphy.

Adolescent↗
PubMed1983

Molecular cloning of pldA, the structural gene for outer membrane phospholipase of E. coli K12.

The pldA gene of Escherichia coli K12, which is involved in the synthesis of an outer membrane (OM) phospholipase, has been cloned using a cosmid cloning system. For detection of the cloned gene a newly developed, in vivo phospholipase assay was used. Subsequent cloning of the pldA gene was performed into the multicopy plasmid vectors pBR322 and pACYC184. The gene was localised on these hybrid plasmids by the analysis of in vitro-constructed deletion plasmids and mutant plasmids generated by transposon gamma delta-insertions. Analysis of plasmid-encoded proteins in a minicell system showed that the pldA gene product is a polypeptide with apparent molecular weight of 29,000. This apparent molecular weight changes from 29,000 to 26,000 when the denaturing temperature is changed from 95 degrees C to 37 degrees C. These data are in agreement with those on purified OM phospholipase (Nishijima et al. 1977), and therefore strongly suggest that pldA is the structural gene for this phospholipase. From the minicell experiments the direction of transcription of pldA could be established relative to the metE gene, which is also cloned on the same hybrid plasmids. Strains carrying the pldA gene on these high copy vectors do not appear to be affected by the product with respect to cell growth in any way. However they do harbour increased amounts of 29 K protein in cell envelope fractions, indicating that gene expression and product translocation to the OM are proportional to the increased gene copy number. We therefore conclude that phospholipase enzymatic activity is strictly regulated at the protein level.

Chromosome Mapping↗
PubMed1980

Mechanism of action of milk lipoprotein lipase at substrate interfaces: effects of apolipoproteins.

The mechanism of action of bovine milk lipoprotein lipase was studied by using a monomolecular film of 1,2-didecanoylglycerol. The apparent rate of hydrolysis of diglyceride increased with increasing surface pressures above 12 mN/m; the enzyme was inactive at pressures less than 12 mN/m. We have measured the effects of four plasma apolipoproteins (apoC-II, apoC-III, apo-I, and apoE), bovine serum albumin, porcine pancreatic colipase, heparin, and NaCl on the kinetics of lipid hydrolysis. At a surface pressure of 15 mN/m, all of the proteins, with the exception of colipase, gave increased enzyme activity compared to lipase alone; apoC-II gave maximal activation. At 25 mN/m, apoC-II at concentrations of less than 0.25 microgram/mL showed a specific activation, whereas the other proteins had no effect. Heparin activated at both high and low surface pressures; NaCl had little or no effect in this system. At a higher concentration of apoC-II (0.50 microgram/mL), the apoprotein inhibited the enzyme. The addition of apoC-III, apoA-I, or apoE (final concentration 0.25 microgram/mL), but not albumin or colipase, to apoC-II (0.25 microgram/mL) caused an increase in surface pressure of 5-6 mN/m and an apparent rate which was less than half that found for lipase alone, suggesting that all of the apoproteins inhibit the apoC-II specific activation.

Animals↗
PubMed1980

Early detection of asymptomatic hereditary chemodectoma with radionuclide scintiangiography. A possibility for family screening and surveillance.

A large family with a history of hereditary chemodectoma has been successfully screened by means of radionuclide scintiangiography. This procedure could restrict selective and more invasive roentgenangiography only to those cases in which flow patterns are abnormal. Three asymptomatic cases of chemodectoma were revealed by this method. Early therapeutic measures may now be feasible. We discuss the possibilities for surveillance of these families without causing discomfort to the group involved.

Adolescent↗
PubMed1978

Computerized axial tomography and cerebral scintigraphy in leukodystrophy. A study of two boys presumably suffering from lysosomal disease.

Two unrelated boys, 12 and 9 years old, suffered from a diffuse cerebral disease that followed a parallel, subacute course. Mental regression, loss of hearing and vision, spastic-ataxic and pseudobulbar disturbances, and atrophy of the optic nerves occurred in both. Enzyme studies and the liver biopsy of one of the patients suggest a "lysosomal disease." The hallmark of both patients is the striking similarity of the cerebral scintigraphy and the computerized axial tomography (CT). Cerebral scintigraphy showed annular and crescent-shaped areas of increased radioactivity in the parietoccipital region. The CT indicated bilateral, symmetric bands of elevated density after contrast enhancement in the paraventricular white matter in the same region. These findings and the neurologic symptoms are compatible with leukodystrophy. Thus cerebral scintigraphy and CT appear to be useful aids in the diagnosis of metabolic brain disease. Computerized axial tomography is preferred for distinguishing whether lesions are in white or gray matter.

Brain↗
PubMed1978

Screening of a family for chemodectoma.

59 relatives with a family history of hereditary chemodectoma have been successfully screened by means of radionuclide scintiangiography. The findings showed a close correlation with selective roentgenangiography. 3 asymptomatic patients with chemodectoma were revealed by these methods without causing discomfort to the group involved.

Adolescent↗
PubMed1978

Selective scintiangiography of the kidney with xenon-133.

Measurement of the spatial distribution of the clearance rate of xenon-133 from the kidney after its injection into the renal artery for estimating intrarenal blood flow can easily be combined with selective X-ray angiography as a routine method. Using a gamma camera as detection equipment anand applying a special computer analysis technique, 'functional images' can be obtained, by which the spatial distribution of the blood flow in the kidney is quantitatively mapped. Experiments with a rather heterogenous group of 12 patients suggest that in at least one type of renal pathology the xenon-133 flow study is more indicative for clinical evaluation than the X-ray angiography

Adult↗