Abstract:
:Molecular chaperones are present in the various compartments of the cell and assist the folding of newly synthesized proteins. Compared to wild-type proteins, missense mutant proteins are generally synthesized in a normal fashion, but may be impaired in their folding. A broad array of diseases that are due to misfolding of mutant proteins may be labelled conformational diseases: aggregation diseases, such as Alzheimer disease; diseases caused by negative dominance from misfolded structural proteins, such as hypertrophic cardiomyopathy; and disorders where the misfolded protein is degraded by intracellular proteases. Many metabolic disorders belong to this last category, where the so-called protein quality control systems, comprising chaperones and proteases, attempt to eliminate folding intermediates or misfolded proteins. On the basis of in vitro experiments with a limited number of missense mutations identified in patients with phenylalanine hydroxylase and fatty acid oxidation deficiencies, we discuss the cellular fate of missense mutant proteins. We find that the balance between folding to functional conformers, retention (holding) and degradation of folding intermediates or misfolded proteins is dependent on the nature of the mutation and on the efficiency of the quality control. For example, low temperature may promote formation of functional conformers, while elevated temperature usually promotes retention and degradation. We conclude that disorders caused by many missense mutations are complex diseases in which the mutation itself is a necessary major primary component, but that its effect may be modified by cellular conditions and possibly by genetic variations in the quality control systems. We suggest that this new knowledge about cell handling may open new avenues of understanding of the cell pathology and treatment of patients with metabolic disorders.
journal_name
J Inherit Metab Disjournal_title
Journal of inherited metabolic diseaseauthors
Gregersen N,Bross P,Andrese BS,Pedersen CB,Corydon TJ,Bolund Ldoi
10.1023/a:1010319001722keywords:
subject
Has Abstractpub_date
2001-04-01 00:00:00pages
189-212issue
2eissn
0141-8955issn
1573-2665journal_volume
24pub_type
杂志文章,评审abstract:BACKGROUND:Hearing loss (HL) is a well-known feature of Fabry disease (FD). Its presence and characteristics have mainly been studied in adult patients, while only limited data are available on the presence and degree of HL in children with FD. This prompted us to study hearing sensitivity in pediatric FD patients. ME...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/s10545-017-0051-5
更新日期:2017-09-01 00:00:00
abstract::Tetrahydrobiopterin (BH4) is an essential cofactor for the aromatic amino acid hydroxylases, alkylglycerol monooxygenase, and nitric oxide synthases (NOS). Inborn errors of BH4 metabolism lead to severe insufficiency of brain monoamine neurotransmitters while augmentation of BH4 by supplementation or stimulation of it...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/s10545-015-9909-6
更新日期:2016-03-01 00:00:00
abstract::We describe two patients affected by Barth syndrome. Their symptoms became manifest on respectively the third and first day of their lives. Clinical presentation included poor sucking, lethargy, hypotonia, hypothermia and cardiomyopathy. Laboratory findings such as hypoglycaemia, metabolic acidosis, elevated transamin...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/s10545-006-0388-7
更新日期:2006-10-01 00:00:00
abstract::Untreated pregnancies and their outcomes were studied in 10 women with histidinaemia and their 26 pregnancies. The mean maternal assigned histidine level was 727+/-186 micromol/L (range 484-1,053). Six women had classic histidinaemia (assigned level >700 micromol/L) and the remaining four had mild (atypical) histidina...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1023/B:BOLI.0000028783.35805.dd
更新日期:2004-01-01 00:00:00
abstract::Phosphoglucomutase 1 (PGM1) deficiency is a rare genetic disorder that affects glycogen metabolism, glycolysis, and protein glycosylation. Previously known as GSD XIV, it was recently reclassified as a congenital disorder of glycosylation, PGM1-CDG. PGM1-CDG usually manifests as a multisystem disease. Most patients pr...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章,评审
doi:10.1002/jimd.12286
更新日期:2021-01-01 00:00:00
abstract::Latin America includes more than 40 countries and possessions, and its population of 570 million has an important representation of the three main human races. The area is experiencing an economic improvement, progressively bringing the inborn errors of metabolism (IEM) to a higher level among health priorities. Chall...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/s10545-010-9112-8
更新日期:2010-10-01 00:00:00
abstract::5-Oxoprolinuria is primarily associated with inborn errors of the gamma-glutamyl cycle. In addition, transient 5-oxoprolinuria has been reported to occur in a variety of conditions, such as prematurity and malnutrition, and during medication. We report an unusual case of permanent 5-oxoprolinuria. The patient presente...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/s10545-006-0370-4
更新日期:2006-08-01 00:00:00
abstract::Glycine encephalopathy, or nonketotic hyperglycinaemia (NKH; Mckusick 238300) is a severe autosomal recessive disease due to a defect in the glycine cleavage system (GCS), which is a complex of four subunits: P-, T-, H- and L-proteins. A P-protein (glycine decarboxylase or GLDC) deficiency was reported in about 80% of...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/s10545-006-0202-6
更新日期:2006-02-01 00:00:00
abstract::Twin brothers were born with clinical symptoms indicating that they were suffering from Zellweger syndrome. However, instead of a generalized peroxisomal dysfunction, only very long-chain fatty acids and the pristanic acid/phytanic acid ratio were elevated in plasma and decreased oxidation of very long-chain fatty aci...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1023/a:1005318308422
更新日期:1997-09-01 00:00:00
abstract::Twenty-four pregnancies at risk for Hurler disease (MPS I) were monitored by measurement of alpha-iduronidase in chorionic villi. Adequate samples were obtained for direct assay of the villi in 22 pregnancies. Five were found to be affected and the pregnancies were terminated. In another pregnancy an equivocal result ...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/BF01799636
更新日期:1992-01-01 00:00:00
abstract::The activity (mean +/- SD) of galactose-1-phosphate uridyl transferase in two long-term lymphoid cell lines from Caucasian patients with transferase deficiency galactosaemia, a heterozygote, and eight normal subjects was 0, 78 and 168 +/- 55 nmol UDPG consumed (mg protein)-1h-1, respectively. Also, no activity was fou...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/BF01799977
更新日期:1987-01-01 00:00:00
abstract::We report studies of a Greek boy of gypsy origin that show that he has severe deficiency of glycine N -methyltransferase (GNMT) activity due to apparent homozygosity for a novel mutation in the gene encoding this enzyme that changes asparagine-140 to serine. At age 2 years he was found to have mildly elevated serum li...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1023/B:BOLI.0000009978.17777.33
更新日期:2003-01-01 00:00:00
abstract::The mitochondrial myopathies or encephalomyopathies with known biochemical defects can be divided into 5 groups: (1) defects of mitochondrial transport, such as CPT deficiency or carnitine deficiencies; (2) defects of substrate utilization, such as PDHC deficiency or defects of beta-oxidation; (3) defects of the Krebs...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章,评审
doi:10.1007/BF01812852
更新日期:1987-01-01 00:00:00
abstract::Previous research has documented white matter abnormalities in the brains of individuals with early-treated phenylketonuria (ETPKU). The majority of these past studies have relied on a region-based approach which focused on a limited number of spatially-defined regions within the brain. In the present study, we used d...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/s10545-013-9650-y
更新日期:2014-03-01 00:00:00
abstract::Mixed hyperlipidaemia is a common finding in glycogen storage disease type Ia (GSD Ia). Although cross-sectional studies have demonstrated increases in intermediate-density lipoproteins (IDLs) and reductions in lipoprotein lipase activity, no studies have investigated the dynamics of apolipoprotein B-100 (apo B) metab...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1023/a:1012407609063
更新日期:2001-10-01 00:00:00
abstract::Patients 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 shou...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章,评审
doi:10.1007/BF01799267
更新日期:1996-01-01 00:00:00
abstract::Defects of the mitochondrial oxidative phosphorylation (OXPHOS) system are frequent causes of neurological disorders in children. Linkage analysis and DNA sequencing identified a new founder p.G250V substitution in the C20ORF7 complex I chaperone in five Ashkenazi Jewish patients from two families with a combined OXPH...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/s10545-011-9348-y
更新日期:2012-01-01 00:00:00
abstract:OBJECTIVES:To study the incidence of galactosaemia in the state of São Paulo and the benefit/cost (B/C) ratio of the introduction of neonatal screening for galactosaemia, comparing it with a selective approach. METHODS:An enzymatic-colorimetric assay was used for the screening of total galactose (TG) in a sample of 10...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/s10545-009-1112-1
更新日期:2009-12-01 00:00:00
abstract::A 13.5-year-old boy with biotinidase deficiency was studied 8 days before and 5 months after biotin treatment by positron emission tomography (PET) and computerized electroencephalographic topography (CET). With biotin treatment there was a marked improvement in the presenting symptom of loss of visual acuity and a mo...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/BF00710288
更新日期:1993-01-01 00:00:00
abstract::Congenital disorders of glycosylation (CDG) are one group among the disorders of glycosylation. The latter comprise defects associated with hypoglycosylation but also defects with hyperglycosylation. Genetic diseases with hypoglycosylation can be divided in primary congenital disorders of glycosylation (CDG) and in ge...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章,评审
doi:10.1007/s10545-017-0050-6
更新日期:2017-07-01 00:00:00
abstract::In addition to systemic manifestations with skeletal, pulmonary, renal, and haematological signs, lysinuric protein intolerance (LPI), a membrane transport defect of cationic amino acids, is often complicated by severe life-threatening immunological manifestations. A 10-year-old boy with LPI who exhibited a severe sys...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1023/a:1005383307100
更新日期:1998-04-01 00:00:00
abstract::Glutaric aciduria type I (GA1) is a preventable cause of acute brain damage in early childhood, leading to a severe dystonic-dyskinetic disorder that is similar to cerebral palsy and ranges from extreme hypotonia to choreoathetosis to rigidity with spasticity. Degeneration of the putamen and caudate typically occurs b...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章,评审
doi:10.1023/a:1005390105171
更新日期:1998-06-01 00:00:00
abstract::In three untreated patients with phenylketonuria (PKU), three PKU and six hyperphenylalaninaemic (HPA) patients in good metabolic control, the kinetic constants of platelet in vitro uptake of [14C]serotonin (5HT) did not significantly differ from those in 12 control subjects matched for age. The platelet concentration...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/BF01800371
更新日期:1988-01-01 00:00:00
abstract::We measured the activities of two major forms of alpha-glucosidase in lymphocytes and cultured fibroblasts from normal healthy controls and patients with Pompe's disease by using 4-methylumbelliferyl-alpha-D-glucoside as substrate. We found (1) enzyme activity of the pH 4 and pH 6 forms varied with age, and (2) patien...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/BF01799482
更新日期:1987-01-01 00:00:00
abstract::6-Methyluracil (6MU) has been identified in urine collected during acute illness in two children with beta-ketothiolase deficiency (approximately 1 mmol/L) and in two children with recurrent infection-related ketoacidaemia of unknown aetiology (levels of 6.3 and 7.1 mmol/mmol creatinine). Significant amounts of 6MU we...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/BF00735400
更新日期:1994-01-01 00:00:00
abstract:BACKGROUND:Hearing loss and tinnitus are common symptoms in Fabry disease and increase in prevalence with age. This study aimed to provide an epidemiological description of hearing impairment and tinnitus in children with Fabry disease in the Fabry Outcome Survey (FOS), an international database to assess the natural h...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章,多中心研究
doi:10.1007/s10545-009-1290-x
更新日期:2009-12-01 00:00:00
abstract:OBJECTIVE:To assess clinical features and general health status of adult patients with mucopolysaccharidosis (MPS) VI. METHODS:This report includes the clinical history of patients older than 18 years with slowly progressing MPS VI and the retrospective analysis of the outcomes of available data collected between Sept...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/s10545-012-9474-1
更新日期:2012-11-01 00:00:00
abstract::The 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 chi...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/BF01799221
更新日期:1989-01-01 00:00:00
abstract::Plasmalogens are a special class of ether-phospholipids, best recognized by their vinyl-ether bond at the sn-1 position of the glycerobackbone and by the observation that their deficiency causes rhizomelic chondrodysplasia punctata (RCDP). The complex plasmalogen biosynthetic pathway involves multiple enzymatic steps ...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章,评审
doi:10.1007/s10545-014-9795-3
更新日期:2015-01-01 00:00:00
abstract::We report a 31 year old woman who had prenatal carrier screening for Ashkenazi Jewish (AJ) genetic diseases and was found to have two acid ß-glucosidase (GBA) mutations, c.1226A>G(p.N370S) and c.1448T>C(p.L444P), consistent with the diagnosis of Type 1 Gaucher disease (GD1). This genotype typically manifests in late-a...
journal_title:Journal of inherited metabolic disease
pub_type: 杂志文章
doi:10.1007/s10545-011-9307-7
更新日期:2011-06-01 00:00:00