bluuebunny/crossref_metadata_2025_split huggingface dataset:
G‐protein‐coupled receptor domain overexpression in Halobacterium salinarum: Long‐range transmembrane interactions in heptahelical membrane proteins
Authors: Jaakola Veli‐Pekka , Rehn Maria , Moeller Martina , Alexiev Ulrike , Goldman Adrian , Turner George J. 
Published: June 2005

AbstractThe aminergic α2b‐adrenergic receptor (α2b‐AR) third intracellular loop (α2b‐AR 3i) mediates receptor subcellular compartmentalization and signal transduction processes via ligand‐dependent interaction with Gi‐ and Go‐ proteins. To understand the structural origins of these processes we engineered several lengths of α2b‐AR 3i into the third intracellular loop of the proton pump bacteriorhodopsin (bR) and produced the fusion proteins in quantities suitable for physical studies. The fusion proteins were expressed in the Archaeon Halobacterium salinarum and purified. A highly expressed fusion protein was crystallized from bicelles and diffracted to low resolution on an in‐house diffractometer. The bR‐α2b‐AR 3i203–292 protein possessed a photocycle slightly perturbed from that of the wild‐type bR. The first half of the fusion protein photocycle, correlated with proton release, is accelerated by a factor of 3, whereas the second half, correlated with proton uptake, is slightly slower than wild‐type bR. In addition, there is a large decrease in the pKa, (from 9.6 to 8.3) of the terminal proton release group in the unphotolyzed state of bR‐α2b‐AR 3i as deduced from the pH‐dependence of the M‐formation. Perturbation of a cytoplasmic loop has thus resulted in the perturbation of proton release at the extracellular surface. The current work indicates that long‐range and highly coupled intramolecular interactions exist that are capable of “transducing” structural perturbations (e.g., signals) across the cellular membrane. This gene fusion approach may have general applicability for physical studies of G‐protein‐coupled receptor domains in the context of the bR structural scaffold. Proteins 2005. © 2005 Wiley‐Liss, Inc.
Flexibility of prolyl oligopeptidase: Molecular dynamics and molecular framework analysis of the potential substrate pathways
Authors: Fuxreiter Monika , Magyar Csaba , Juhász Tünde , Szeltner Zoltán , Polgár László , Simon István 
Published: June 2005

AbstractThe flexibility of prolyl oligopeptidase has been investigated using molecular dynamics (MD) and molecular framework approaches to delineate the route of the substrate to the active site. The selectivity of the enzyme is mediated by a seven‐bladed β‐propeller that in the crystal structure does not indicate the possible passage for the substrate to the catalytic center. Its open topology however, could allow the blades to move apart and let the substrate into the large central cavity. Flexibility analysis of prolyl oligopeptidase structure using the FIRST (Floppy Inclusion and Rigid Substructure Topology) approach and the atomic fluctuations derived from MD simulations demonstrated the rigidity of the propeller domain, which does not permit the substrate to approach the active site through this domain. Instead, a smaller tunnel at the inter‐domain region comprising the highly flexible N‐terminal segment of the peptidase domain and a facing hydrophilic loop from the propeller (residues 192–205) was identified by cross‐correlation analysis and essential dynamics as the only potential pathway for the substrate. The functional importance of the flexible loop has been also verified by kinetic analysis of the enzyme with a split loop. Catalytic effect of engineered disulfide bridges was rationalized by characterizing the concerted motions of the two domains. Proteins 2005. © 2005 Wiley‐Liss, Inc.
α1‐antitrypsin deficiency and liver disease: Clinical presentation, diagnosis and treatment
Authors: Hussain M. , Mieli‐Vergani G. , Mowat A. P. 
Published: June 2005

SummaryThe α1‐antitrypsin deficient subject (protease inhibitor (PI) phenotype ZZ) has an increased susceptibility to liver disease. The condition is most commonly identified in early infancy as a conjugated hyperbilirubinaemia with hepatitis (11%) or a bleeding state due to vitamin K malabsorption (2%). 50% of cases have cirrhosis and 25% die in the first decade of life. A further 2% present with cirrhosis in later childhood. Adult males are at risk of hepatoma development with or without cirrhosis. Diagnosis is by isoelectric focussing or allele‐specific oligonucleotide hybridization. The treatment is that of cholestasis and cirrhosis including transplantation. The pathobiology of the deficiency state, the mechanism of liver damage and the vulnerability of the newborn liver are discussed in this review. A plea is made for a trial of infusions of α1‐antitrypsin in early infancy, as is used safely but without proven efficacy in the emphysematous PIZZ subject. Prospects of therapy by gene modification are also reviewed.
α1‐antitrypsin deficiency and liver disease
Authors: Birrer P. , McElvaney N. G. , Chang‐Stroman L. M. , Crystal R. G. 
Published: June 2005

Summaryα1‐Antitrypsin (α1AT) deficiency, one of the most common lethal hereditary disorders among Caucasians, is associated with emphysema in adults, while in children it is associated with liver disease. Produced in the liver and released into the plasma, α1AT serves as the body's major inhibitor of neutrophil elastase, a powerful proteolytic enzyme capable of degrading extracellular structural proteins. The pathogenesis of the liver disease associated with α1AT deficiency is not as well understood, but is clearly linked to specific mutations in coding exons of the α1AT gene, and the resulting accumulation of α1AT within hepatocytes. At present, therapy for the liver disease associated with α1AT deficiency is symptomatic, with liver transplantation as a last resort. New strategies are being developed to suppress the accumulation of α1AT by transferring the normal gene into the liver.
Paediatric liver transplantation: Review of current experience
Authors: Buckels J. A. C. 
Published: June 2005

SummaryDuring the 1980s the results of liver replacement in children improved dramatically, with 12‐month survival rates rising from around 20% to over 85% at the most experienced centres. This improvement has been due to several factors, including better patient selection and timing of transplantation, advances in immunosuppressive therapy, and developments in liver preservation. Moreover, the learning curve effect has contributed with advances both in surgical technique and in the rapid diagnosis and treatment of complications, including the need to retransplant patients in whom the first graft has been irreversibly damaged. One major development is the refinement of the anatomically reduced grafts where a larger, usually adult, graft is cut down to fit a child. This has allowed a greater number of children to be grafted, including emergency cases such as fulminant hepatic failure in whom there is insufficient time to wait for a size‐matched donor.
Services for thalassaemia as a model for cost‐benefit analysis of genetics services
Authors: Modell B. , Kuliev A. M. 
Published: June 2005

SummaryEconomic appraisal of genetics services is usually limited to consideration of financial costs and benefits, but this can generate misunder‐standings about the aims of these services. We propose a general framework for economic analysis that includes non‐financial costs and benefits, and the concept of genetic fitness.
β‐Glucuronidase deficiency: Enzyme studies in an affected family and prenatal diagnosis
Authors: Maire I. , Mandon G. , Zabot M. T. , Mathieu M. , Guibaud P. 
Published: June 2005

AbstractAβ‐glucuronidase deficiency found in serum, leukocytes and fibroblasts and an increased [35S]sulphate incorporation in fibroblasts led us to diagnose two cases of type VII mucopolysaccharidosis in one family. In spite of the wide distribution of activities in serum from controls, decreasedβ‐glucuronidase activity allowed us to demonstrate the heterozygous status of the parents and two other children. Following these studies, an antenatal diagnosis was performed when the mother was pregnant again; amniotic fluid and cultured amniotic cells were used for enzyme activity determination. A heterozygous fetus was suspected and confirmed after birth. The reliability of various biological materials for enzymatic diagnosis and existence of genetic variants in the normal population are discussed.
Evolution of the neuroimaging changes in fucosidosis type II
Authors: Terespolsky D. , Clarke J. T. R. , Blaser S. I. 
Published: June 2005

SummaryWe report on clinical and neuroradiological findings in two patients with fucosidosis type II; a 7‐year‐old Jordanian boy and a 3 1/2‐year‐old Anglo‐Canadian girl. This rare, autosomal recessive disorder is caused by deficiency of lysosomalα‐fucosidase and is manifested clinically by progressive mental and motor deterioration, coarse facies, growth retardation, recurrent infections, dysostosis multiplex, angiokeratoma corporis diffusum, visceromegaly and seizures. Cranial CT and magnetic resonance imaging showed density and signal abnormalities in the thalamus, globus pallidus and internal capsules bilaterally, as well as progressive CT density alterations in supratentorial white matter including the internal medullary laminae of the thalami and the internal capsules.
Congenital nephrotic syndrome: A novel phenotype of type I carbohydrate‐deficient glycoprotein syndrome
Authors: van der Knaap M. S. , Wevers R. A. , Monnens L. , Jakobs C. , Jaeken J. , van Wijk J. A. E. 
Published: June 2005

SummaryType I carbohydrate‐deficient glycoprotein (CDG) syndrome is a genetic multisystem disorder generally without overt renal problems. We report a neonate with neurological abnormalities and congenital nephrotic syndrome of diffuse mesangial sclerosis type. Serum transferrin isoelectric focusing showed the typical abnormalities of type I CDG syndrome. Normal transferrin focusing findings in other patients with similar renal problems excluded the possibility of a secondary biochemical phenomenon. The diagnosis of type I CDG syndrome was confirmed by demonstration of a deficiency of phosphomannomutase. No evidence of pontocerebellar atrophy was found in imaging or at autopsy. We conclude that congenital nephrotic syndrome may occur in type I CDG syndrome, and that this diagnosis should be considered in patients with congenital nephrotic syndrome. Absence of pontocerebellar atrophy does not exclude the diagnosis of type I CDG syndrome.
Deficiency of pyrimidine 5′‐nucleotidase in human leukocytes
Authors: de Korte D. , van Doorn C. C. H. , Sijstermans J. M. J. , van Gennip A. H. , Roos D. 
Published: June 2005

SummaryBoth erythrocytes and leukocytes from a patient with erythrocyte pyrimidine 5′‐nucleotidase (P5N) deficiency were shown to contain increased amounts of pyrimidine nucleotides. These findings suggested that the leukocytes were also deficient for P5N. Measurement of the P5N activity in lysates from lymphocytes or granulocytes, in the presence of inhibitors for non‐specific 5′‐nucleotidase or alkaline phosphatase, indeed showed a deficiency for P5N in lymphocytes and granulocytes of the patient with erythrocyte P5N deficiency. However, the P5N deficiency in the leukocytes did not cause clinical disturbances in addition to the weak haemolytic anaemia.
Inheritance and prevalence of von Willebrand's disease severe form in a Brazilian population
Authors: Fischer R. R. , Lerner C. , Bandinelli E. , Fonseca A. S. K. , Roisenberg I. 
Published: June 2005

SummaryReviewed data suggest that the prevalence of severe von Wille‐brand's disease is influenced by ethnic and geographic factors. In the State of Rio Grande do Sul, Brazil, seven genealogies in which 11 individuals had a severe expression of von Willebrand's disease were localized. These affected subjects had similar laboratory results and all of them seemed to have resulted from double genetic defects, but the genealogic examination revealed that four of them probably resulted from combinations of autosomal recessive genes, while in the remaining the presence of dominant genes was likely and the involvement of genes for types I or II of von Willebrand's disease was possible. All of their examined relatives were asymptomatic but some of them presented unusual laboratory results, indicative of heterozygosis. The prevalence of severe cases in the surveyed population was higher than expected even when only the recessive forms were considered. It entered the expected values when it was presumed that these were all the cases currently living in the State. Genetic heterogeneity of the severe form was confirmed and it is suggested that the designations ‘severe von Willebrand's disease’ and ‘type III von Willebrand's disease’ should not be used as synonyms.
Crigler‐Najjar type II disease inheritance: A family study
Authors: Labrune P. , Myara A. , Hennion C. , Gout J. P. , Trivin F. , Odievre M. 
Published: June 2005

SummaryThe inheritance of Crigler‐Najjar type II disease is still contested. Autosomal dominant transmission with incomplete penetrance and autosomal recessive transmission have been proposed. We had the opportunity to study the hepatic activity of bilirubin uridinediphosphate glucuronyltransferase in parents whose first child had been affected by Crigler‐Najjar type II disease. The demonstration of reduced activity of glucuronidation in the liver of both parents suggests autosomal recessive inheritance. The second infant of this couple was affected by the same disease and was treated with success by phenobarbital.
Holocarboxylase synthetase deficiency: 9‐year follow‐up of a patient on chronic biotin therapy and a review of the literature
Authors: Michalski A. J. , Berry G. T. , Segal S. 
Published: June 2005

SummaryWe report on the long‐term medical and neurodevelopmental follow‐up of a patient with the rare and potentially lethal disease, holocarboxylase synthetase deficiency. He was originally treated prenatally with biotin megatherapy and for 9 years with 6 mg/day since his only episode of fulminant acidosis at 3 months of age. While growth and general health have been normal, the patient has exhibited signs of minimal brain dysfunction. However, evaluation of unaffected siblings suggests that this may be unrelated to his metabolic disease. A review of the literature and recommendations for optimal treatment are provided.
Association of hyperprolinaemia type I and heparin cofactor II deficiency with CATCH 22 syndrome: evidence for a contiguous gene syndrome locating the proline oxidase gene
Authors: Jaeken J. , Goemans N. , Fryns J. ‐P. , François I. , de Zegher F. 
Published: June 2005

SummaryIncreased proline levels were found in plasma of a girl with slight psychomotor retardation, epilepsy, obesity, scoliosis, hypocalcaemia, variable lymphocytopenia and facial dysmorphy suggestive of CATCH 22 syndrome. Fluorescencein situ hybridization indicated the presence of a submicroscopic 22q11 deletion, confirming this diagnosis. Further investigation showed evidence that the patient was heterozygous for heparin cofactor II deficiency and for hyperprolinaemia type I, a proline catabolic disorder due to proline oxidase deficiency. This association extends the CATCH 22 syndrome and suggests that expression of the proline oxidase gene depends on the chromosome 22q11 region.
Mucopolysaccharidosis IVA: a comparative study of polymorphic DNA haplotypes in the Caucasian and Japanese populations
Authors: Rezvi G. M. M. , Tomatsu S. , Fukuda S. , Yamagishi A. , Cooper A. , Wraith J. E. , Iwata H. , Kato Z. , Yamada N. , Sukegawa K. , Shimozawa N. , Suzuki Y. , Kondo N. , Orii T. 
Published: June 2005

SummaryMucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder caused by deficiency of the lysosomal enzymeN‐acetylgalactosamine‐6‐sulphate sulphatase (GALNS). The genetic heterogeneity at the GALNS locus was studied in 62 mutant alleles and 376 normal alleles in the Caucasian population and also in 40 mutant and 100 normal alleles in the Japanese population. For this study, six different restriction fragment length polymorphisms (RFLPs) at the GALNS locus were analysed to search for the frequency of each RFLP produced byStyI,SphI,RsaI,HaeIII,StuI andHapII restriction endonucleases. We detected a total of 27 haplotypes in the Caucasian and Japanese population. Of these 27 haplotypes, 18 haplotypes were present in the Caucasian population and the most common of these was haplotype 1 (ABHcde) in both mutant and normal alleles. In contrast, in the Japanese population we found 20 of the 27 haplotypes and the most common in mutant and normal alleles was haplotype 2 (abhcDE). Within these two populations a parent in the MPS IVA family has an average probability of greater than 77% (in the Caucasian population 77.27% and in the Japanese population 78.26%) of being heterozygous, and hence informative for linkage, at one or more GALNS RFLP sites. Our results delineate the molecular heterogeneity of MPS IVA haplotypes, as well as their significant interpopulation variation, and make prenatal diagnosis and carrier detection possible in the majority of families with one affected child.
Seizures in a boy with succinic semialdehyde dehydrogenase deficiency treated with vigabatrin (γ‐vinyl‐GABA)
Authors: Matern D. , Lehnert W. , Gibson K. M. , Korinthenberg R. 
Published: June 2005

SummarySuccinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disease involving the catabolism of the neurotransmitter γ‐amino‐butyric acid (GABA). The main symptoms include retardation of psychomotor and language development, muscle hypotonia and non‐progressive ataxia. Therapy consisting of approximately 75 mg/kg per day of vigabatrin, an irreversible inhibitor of GABA‐transaminase, is reported to lead to some improvement of the clinical condition in affected patients. We report on a 12‐year‐old boy with SSADH deficiency who, when treated with 75 mg/kg per day of vigabatrin, showed marked amelioration of symptoms but also EEG changes and two generalized seizures. On discontinuing vigabatrin therapy, the seizures resolved and the EEG improved, but the patient's clinical condition deteriorated to its pre‐treatment state. A stable EEG without the recurrence of seizures as well as renewed improvement of cognitive and behavioural functions was achieved with a reduced vigabatrin dose of 25 mg/kg per day. We conclude that vigabatrin in SSADH deficiency should be administered in a gradually increasing dosage combined with frequent evaluation of the clinical condition and the EEG.
Homocysteine response to methionine challenge in four obligate heterozygotes for homocystinuria and relationship with cystathionineβ‐synthase mutations
Authors: Sperandeo M. P. , Candito M. , Sebastio G. , Rolland M. O. , Turc‐Carel C. , Giudicelli H. , Dellamonica P. , Andria G. 
Published: June 2005

SummaryFasting and post‐methionine load plasma total homocysteine concentrations were investigated in the parents of two homocystinuric patients. Three genetic mutations in the cystathionineβ‐synthase gene were found. In the patient of family 1, a frequent Caucasian mutation, T833C, was found on one allele, while the mutation on the other allele has not yet been defined. In the patient of family 2, a mutation C569T, recently described by Sperandeo and colleagues, was found on one allele, while a novel mutation, G346A, was characterized on the other allele. The frequent gene mutation T833C was detected in a heterozygous mother who, surprisingly, exhibited strictly normal fasting and post‐methionine load homocysteinaemia. In contrast, in the other family, we found a novel mutation (G346A) in the mother located near Lys 119, the putative binding site of phosphopyridoxal phosphate. This mother exhibited increased fasting and post‐methionine load homocysteinaemia. These observations could explain the conflicting results reported for vascular pathologies in parents of homocystinuric patients and direct the search for genetic mutations in these vascular pathologies.
Mucopolysaccharidosis type IVA (morquio syndrome): A clinical review
Authors: Northover H. , Cowie R. A. , Wraith J. E. 
Published: June 2005

SummaryPatients with MPS IV have a clinical disorder quite different from other MPS conditions. The major treatment issue revolves around the prevention of cervical myelopathy, although the other aspects of this multisystem disease should not be forgotten. Management is inevitably multidisciplinary and the paediatrician should play a lead role in the coordination of services for affected patients.The timing of occipito‐cervical fusion and the selection of patients for this procedure remain unclear. A prophylactic approach to surgery is suggested in this review, although it is by no means clear that all patients will invariably develop cervical myelopathy if left untreated.Parents of affected children need considerable support in dealing with the affected child and the children themselves need help to try to come to terms with their severe physical disabilities. The Society for Mucopolysaccharide Diseases (55 Hill Avenue, Amersham, Bucks HP6 5BX, UK) has offered many parents and affected individuals considerable help as well as raising significant sums for research.Finally, it is important to remember the genetic nature of the disease and the possibility of prenatal diagnosis in subsequent pregnancies.
The salience of Garrod's ‘molecular groupings’ and ‘Inborn Factors in Disease’
Authors: Scriver C. R. 
Published: June 2005

SummaryGarrod's important second book,Inborn Factors in Disease (1931), was about inherited predisposition to disease. Chemical and metabolic individuality, which are the modalities of predisposition, originated in ‘molecular groupings’ (proteins) in Garrod's view of life. Such ‘groupings’ as interlocus molecular hybrids, allelic complementation and expressions of modifier genes, can assume variant expression in heterozygotes. Here, it is shown that genetic variation in such ‘molecular groupings’ has clinical relevance, for example (1) in reproductive counselling for thalassaemia; (2) in heterozygosity where the affected enzymes are normally homopolymeric; (3) in clinical severity of ‘monogenic’ disease (e.g. familial hypercholesterolaemia and muscular dystrophy) when variation is not explained by allelic heterogeneity. The associated chemical individuality in each case can be used to identify risk and thus as a mode of predictive medicine.
Acute metabolic encephalopathy: A review of causes, mechanisms and treatment
Authors: Surtees R. , Leonard J. V. 
Published: June 2005

SummaryAcute encephalopathy is a relatively common problem: one of the causes is metabolic disorders. A detailed history, examination and investigations performed during the acute illness (blood sugar, blood gases, plasma ammonia, blood lactate, plasma ketones, plasma amino acids, liver function tests, and urinary organic acids) should identify those patients in whom a metabolic disorder is likely. More detailed studies may be needed to establish a precise diagnosis.The mechanism of the acute brain dysfunction is multifactorial. Factors that contribute include changes in blood flow and, initially, a disturbance in neurotransmitter function followed by failure of energy metabolism and cellular depolarization. Treatment of these conditions is largely supportive, with especial attention to the management of cerebral perfusion pressure.