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C Wadelius

Publications and source records attributed to C Wadelius.

At least 19 recordsLinked to original sources
PubMed2005

Common VKORC1 and GGCX polymorphisms associated with warfarin dose.

We report a novel combination of factors that explains almost 60% of variable response to warfarin. Warfarin is a widely used anticoagulant, which acts through interference with vitamin K epoxide reductase that is encoded by VKORC1. In the next step of the vitamin K cycle, gamma-glutamyl carboxylase encoded by GGCX uses reduced vitamin K to activate clotting factors. We genotyped 201 warfarin-treated patients for common polymorphisms in VKORC1 and GGCX. All the five VKORC1 single-nucleotide polymorphisms covary significantly with warfarin dose, and explain 29-30% of variance in dose. Thus, VKORC1 has a larger impact than cytochrome P450 2C9, which explains 12% of variance in dose. In addition, one GGCX SNP showed a small but significant effect on warfarin dose. Incorrect dosage, especially during the initial phase of treatment, carries a high risk of either severe bleeding or failure to prevent thromboembolism. Genotype-based dose predictions may in future enable personalised drug treatment from the start of warfarin therapy.

Adult↗
PubMed2004

Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors.

The required dose of the oral anticoagulant warfarin varies greatly, and overdosing often leads to bleeding. Warfarin is metabolised by cytochrome P450 enzymes CYP2C9, CYP1A2 and CYP3A. The target cell level of warfarin may be dependent on the efflux pump P-glycoprotein, encoded by the adenosine triphosphate-binding cassette gene ABCB1 (multidrug resistance gene 1). Genetic variability in CYP2C9, CYP3A5 and ABCB1 was analysed in 201 stable warfarin-treated patients using solid-phase minisequencing, pyrosequencing and SNaPshot. CYP2C9 variants, age, weight, concurrent drug treatment and indication for treatment significantly influenced warfarin dosing in these patients, explaining 29% of the variation in dose. CYP3A5 did not affect warfarin dosing. An ABCB1 haplotype containing the exon 26 3435T variant was over-represented among low-dose patients. Thirty-six patients with serious bleeding complications had higher prothrombin time international normalised ratios than 189 warfarin-treated patients without serious bleeding, but there were no significant differences in CYP2C9, CYP3A5 or ABCB1 genotypes and allelic variants.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Best's vitelliform macular dystrophy caused by a new mutation (Val89Ala) in the VMD2 gene.

PURPOSE: To describe the clinical phenotype in a family with Best's vitelliform macular dystrophy (BMD) and a new mutation (Val89Ala) in the VMD2 gene. METHODS: The genotype was determined by direct sequence analysis of the individual exons of VMD2. Nine members of a family with BMD were examined. The examination included best-corrected visual acuity, electro-oculography (EOG), fundus examination, and photography. Four of the patients were also examined with full-field ERG and three with multifocal ERG. RESULTS: A T-to-C substitution was identified at position 370 in the cDNA of VMD2, leading to a Val89Ala change in the protein. Six patients, five with the Val89Ala mutation and a nine-year-old boy without the mutation, presented with a pathological Arden ratio on EOG examination. Most of the patients with BMD in this family had an onset of visual failure by the age of 40-50 years. The older patients in the family demonstrated atrophic macular dystrophy. CONCLUSIONS: Patients with BMD and the Val89Ala mutation in the VMD2 gene can present with a phenotype of a mostly late-onset visual failure. These BMD patients, who present with visual failure and macular degeneration in middle age, can be misdiagnosed as being affected with adult-onset macular dystrophies instead of BMD, because the latter is often regarded as a disease of childhood and adolescence.

Adolescent↗
PubMed1999

The mutation spectrum of the bestrophin protein--functional implications.

Best's macular dystrophy (BMD), also known as vitelliform macular degeneration type 2 (VMD2; OMIM 153700), is an autosomal dominant form of macular degeneration with mainly juvenile onset. BMD is characterized by the accumulation of lipofuscin within and beneath the retinal pigment epithelium. The gene causing the disease has been localized to 11q13 by recombination breakpoint mapping. Recently, we have identified the causative gene encoding a protein named bestrophin, and mutations have been found mainly to affect residues that are conserved from a family of genes in Caenorhabditis elegans. The function of bestrophin is so far unknown, and no reliable predictions can be made from sequence comparisons. We have investigated the bestrophin gene in 14 unrelated Swedish, Dutch, Danish, and Moroccan families affected with BMD and found eight new mutations. Including the previously published mutations, 15 different missense mutations have now been detected in 19 of the 22 families with BMD investigated by our laboratory. Interestingly, the mutations cluster in certain regions, and no nonsense mutations or mutations causing frame-shifts have been identified. Computer simulations of the structural elements in the bestrophin protein show that this protein is probably membrane bound, with four putative transmembrane regions.

Amino Acid Sequence↗
PubMed1999

Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies.

Vitelliform macular dystrophy (VMD2, Best disease, MIM153700) is an early onset, autosomal, dominant macular degeneration characterized by the deposition of lipofuscin-like material within and below the retinal pigment epithelium (RPE); it is associated with degeneration of the RPE and overlying photoreceptors. Recently, we cloned the gene bestrophin, which is responsible for the disease, and identified a number of causative mutations in families with VMD2. Here, we report that the analysis of bestrophin in a collection of 259 age-related macular degeneration (AMD) patients provides evidence that mutations in the Best disease gene do not play a significant role in the predisposition of individuals to AMD. However, our results suggest that, in addition to Best disease, mutations within the bestrophin gene could be responsible for other forms of maculopathy with phenotypic characteristics similar to Best disease and for other diseases not included in the VMD category.

Adult↗
PubMed1999

Properdin deficiency in a large Swiss family: identification of a stop codon in the properdin gene, and association of meningococcal disease with lack of the IgG2 allotype marker G2m(n).

Properdin deficiency was demonstrated in three generations of a large Swiss family. The concentration of circulating properdin in affected males was < 0.1 mg/l, indicating properdin deficiency type I. Two of the nine properdin-deficient males in the family had survived meningitis caused by Neisseria meningitidis serogroup B without sequel. Two point mutations were identified when the properdin gene in one of the properdin-deficient individuals was investigated by direct solid-phase sequencing of overlapping polymerase chain reaction (PCR) products. The critical mutation was found at base 2061 in exon 4, where the change of cytosine to thymine had generated the stop codon TGA. The other mutation was positioned at base 827 in intron 3. The stop codon in exon 4 was also demonstrated by standard dideoxy sequencing in three additional family members. The question was asked if genetic factors such as partial C4 deficiency and IgG allotypes could have influenced susceptibility to meningococcal disease in the family. No relationship was found between C4 phenotypes and infection. Interestingly, the two properdin-deficient males with meningitis differed from the other properdin-deficient persons in that they lacked the G2m(n) allotype, a marker known to be associated with poor antibody responses to T-independent antigens. This implies that the consequences of properdin deficiency might partly be determined by independent factors influencing the immune response.

Adolescent↗
PubMed1999

Clinical expression of Best's vitelliform macular dystrophy in Swedish families with mutations in the bestrophin gene.

OBJECTIVE: To examine the clinical phenotype of three Swedish families with Best's vitelliform macular dystrophy (BMD) and three different mutations in the recently identified bestrophin gene. METHODS: Three families, including 13 patients, were examined clinically using visual acuity testing, electro-oculography, fundus inspection, and fundus photography. The mutations were previously determined by direct sequence analysis of the individual exons in the bestrophin gene. RESULTS: The largest family (SL76), with the Y85K (T357C) mutation in the bestrophin gene, demonstrated a clinical phenotype characterized by a variable degree of visual acuity reduction and a marked intrafamilial variability in macular pathology. The electro-oculograms, however, demonstrated similar results in all patients regardless of the severity of the macular dysfunction. The smallest family (SL3), with the mutation V9A (T130C) in the bestrophin gene, and the family (SL2) with the mutation D104E (C416A) demonstrated a similar clinical phenotype. The majority of patients (11/13 examined subjects) had a binocular visual acuity of 20/63 or better at a late stage of the disease course, indicating a relatively good prognosis for visual acuity in this specific phenotype. The ophthalmoscopic changes were followed in one of the patients for 38 years and in three of the patients for 19 years and showed that the macular appearance seems to be stable after adolescence. CONCLUSIONS: Patients with BMD and mutations in the bestrophin gene have a similar clinical phenotype characterized by a variable, but relatively moderate visual acuity reduction, atrophic changes in the macula, and pathological results of the electro-oculograms. The macular appearance remains essentially unchanged through the atrophic stage (stage IV) in the majority of patients, indicating a stationary disease course associated with this specific genotype.

Adolescent↗
PubMed1999

Further evidence of genetic homogeneity in Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome is an autosomal recessive disorder characterized by congenital ichthyosis, spastic di- or tetraplegia and mental retardation. In 1994 Sjögren-Larsson syndrome was mapped to chromosome 17, close to the genetic marker D17S805 in a study of 24 Swedish families. We have analysed 12 microsatellite markers in 10 additional non-Swedish families with Sjögren-Larsson syndrome originating from Germany, Lebanon, Spain and Canada. The results are consistent with earlier data and give further evidence of Sjogren-Larsson syndrome being a homogeneous disorder. Swedish soldiers were bivouacking in Germany during the 30-year war in the 17th century and it has been suggested that they could have introduced the Sjögren-Larsson syndrome gene to the German population. Haplotypes from 7 German families with Sjögren-Larsson syndrome were compared with earlier analysed Swedish haplotypes. No evidence of all German patients carrying the same mutation or the major "Swedish Sjögren-Larsson syndrome gene" was found.

DNA↗
PubMed1999

Polymorphisms in NAT2, CYP2D6, CYP2C19 and GSTP1 and their association with prostate cancer.

The development of prostate cancer is dependent on heredity, androgenic influences, and exposure to environmental agents. A high intake of dietary fat is associated with an increased risk of prostate cancer, either through influence on steroid hormone profiles or through production of carcinogenic compounds that require biotransformation by enzymes. The polymorphic glutathione S-transferase (GST), N-acetyltransferase (NAT), and cytochrome P450 (CYP) enzymes are of particular interest in prostate cancer susceptibility because of their ability to metabolize both endogenous and exogenous compounds, including dietary constituents. Association between different NAT2, CYP2D6, CYP2C19 and GSTP1 genotypes and prostate cancer was studied in a Swedish and Danish case-control study comprising 850 individuals. The combined Swedish and Danish study population was analysed by polymerase chain reaction for the NAT2 alleles *4, *5A, *5B, *5C, *6 and *7, and for the CYP2D6 alleles *l, *3 and *4. The Swedish subjects were also analysed for the CYP2C19 alleles *1 and *2, and the GSTP1 alleles *A, *B and *C. No association was found between prostate cancer and polymorphisms in NAT2, CYP2D6, CYP2C19 or GSTP1. An association between CYP2D6 poor metabolism and prostate cancer was seen among smoking Danes; odds ratio 3.10 (95% confidence interval 1.07; 8.93), P = 0.03, but not among smoking Swedes; odds ratio 1.19 (95% confidence interval 0.41; 3.42), P = 0.75. Smoking is not a known risk factor for prostate cancer, and the association between CYP2D6 poor metabolism and prostate cancer in Danish smokers may have arisen by chance.

Acetylation↗
PubMed1999

Prostate cancer associated with CYP17 genotype.

Androgens play an important role in the development of prostate cancer. Androgen regulating genes that show allelic variation may be susceptibility factors for the disease. One of these genes, CYP17, encodes the cytochrome P450c17alpha enzyme. It catalyses steroid 17alpha-hydroxylase/17,20 lyase activities at key points in testosterone biosynthesis. We investigated the association between a polymorphism in the CYP17 gene and prostate cancer in a population-based case-control study. All individuals studied were Caucasians born in Sweden, 178 were consecutive clinical prostate cancer patients, and 160 were age-matched control individuals randomly selected from the same catchment area. DNA was extracted from blood samples. A CYP17 gene fragment was amplified by polymerase chain reaction. The MspA1I restriction enzyme, which recognizes the base pair substitution, was used to identify the allelic variants CYP17A1 and CYP17A2. Significantly more men homozygous for the CYP17A1 allele were found among prostate cancer patients compared with control individuals; odds ratio 1.61 (95% confidence interval 1.02; 2.53), P = 0.04. According to a preliminary report, the CYP17A1/A1 genotype leads to higher circulating androgen levels, possibly by encoding for a more active androgen synthesizing CYP17 enzyme. Consequently, the CYP17A1/A1 genotype, which was found in a higher frequency among prostate cancer patients, may prove to be one of the important susceptibility factors for prostate cancer. If verified, this genotype is likely to convey a larger risk on a population basis, than the rare hereditary prostate cancer genes do.

Aged↗
PubMed1998

Boy with an interstitial 1q (q31q41) duplication confirmed by fluorescent in situ hybridisation.

A 20-year-old man with multiple anomalies caused by a de novo duplication of the long arm of chromosome 1 is presented. The patient suffers from severe mental retardation, epilepsy, bronchial stenosis, and minor anomalies (e.g., hirsutism, midface dysplasia, and beaked nose). A G-banding analysis of the patient's chromosomes showed additional segments in chromosome 1. Fluorescent in situ hybridisation analysis with a chromosome 1 painting probe showed that the extra material originated from chromosome 1. Further analysis with cosmid probes demonstrated that the region involving chromosome bands 1q31 to q41 is present in a tandem duplication.

Abnormalities, Multiple↗
PubMed1998

Spectrum of mutations and sequence variants in the FALDH gene in patients with Sjögren-Larsson syndrome.

The gene encoding the human fatty aldehyde dehydrogenase (FALDH) is located on 17p11.2, causing Sjögren-Larsson syndrome (SLS) when mutated. SLS is an autosomal recessive disorder characterized by a combination of mental retardation, congenital ichthyosis, and spastic di- or tetraplegia. We report here on studies of 16 SLS families from Europe and the Middle East, which resulted in identification of 11 different mutations. The spectrum of mutations characterized in the present study are five nucleotide substitutions resulting in amino acid changes, five frameshift mutations introducing a stop codon, and one in-frame deletion with insertion at the same position. We also observed silent sequence variants in the FALDH gene and a base pair substitution in exon 5 that alters aspartic acid to asparagine, all of which are considered polymorphisms.

Aldehyde Oxidoreductases↗
PubMed1998

Identification of the gene responsible for Best macular dystrophy.

Best macular dystrophy (BMD), also known as vitelliform macular dystrophy (VMD2; OMIM 153700), is an autosomal dominant form of macular degeneration characterized by an abnormal accumulation of lipofuscin within and beneath the retinal pigment epithelium cells. In pursuit of the disease gene, we limited the minimum genetic region by recombination breakpoint analysis and mapped to this region a novel retina-specific gene (VMD2). Genetic mapping data, identification of five independent disease-specific mutations and expression studies provide evidence that mutations within the candidate gene are a cause of BMD. The 3' UTR of the candidate gene contains a region of antisense complementarity to the 3' UTR of the ferritin heavy-chain gene (FTH1), indicating the possibility of antisense interaction between VMD2 and FTH1 transcripts.

Amino Acid Sequence↗
PubMed1998

Detailed genetic and physical mapping in the Sjögren-Larsson syndrome gene region in 17p11.2.

Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterised by mental retardation, spasticity, and ichthyosis. In 1994, SLS was linked to chromosome 17 and the gene causing the disorder was recently identified as fatty aldehyde dehydrogenase (FALDH) located in 17p11.2. In this paper we present a detailed genetic and physical map of the region surrounding the SLS/FALDH locus, produced by using new microsatellite markers analysed on the extensive Swedish family material, a radiation hybrid panel, and yeast artificial chromosomes (YACs).

Chromosome Mapping↗
PubMed1998

Centrotemporal spikes in families with rolandic epilepsy: linkage to chromosome 15q14.

OBJECTIVE: To localize a gene predisposing to benign epilepsy of childhood with centrotemporal spikes (BECTS). BACKGROUND: BECTS, or rolandic epilepsy, is the most prevalent idiopathic epilepsy syndrome in childhood. Functional relevant defects in the alpha 4 subunit of the neuronal nicotinic acetylcholine receptor (AChR) have been demonstrated in autosomal dominant nocturnal frontal lobe epilepsy, which, like BECTS, is an idiopathic partial epilepsy. METHODS: A DNA linkage study was conducted screening all chromosomal regions known to harbor neuronal nicotinic AChR subunit genes. Twenty-two nuclear families with BECTS were analyzed. RESULTS: In an "affected-only" study, best p values and lod scores were reached between D15S165 and D15S1010 on chromosome 15q14. In multipoint nonparametric linkage analysis a nominal p value of 0.000494 was calculated by GENEHUNTER. Best parametric results were obtained under an autosomal recessive model with heterogeneity (multipoint lod score 3.56 with 70% of families linked to the locus). These markers are localized in direct vicinity to the alpha 7 subunit gene of the AChR. CONCLUSIONS: We found evidence for linkage of BECTS to a region on chromosome 15q14. Either the alpha 7 AChR subunit gene or a closely linked gene are implicated in pedigrees with BECTS. The disorder is genetically heterogeneous. Surprisingly, the same chromosomal area has been reported to be linked to the phenotype in families with an auditory neurophysiologic deficit as well as in families with juvenile myoclonic epilepsy, another idiopathic but generalized epilepsy syndrome.

Adolescent↗
PubMed1998

Linkage analysis excludes familial congenital hypothyroidism from chromosome 21.

Congenital hypothyroidism (CH) is a heterogeneous disorder with largely unknown causes, affecting 1/3000-1/4000 new-borns. Individuals with Down syndrome have a much higher incidence of CH than the normal population, probably due to the extra copy of chromosome 21. Moreover, a girl has recently been described with CH and an interstitial deletion of proximal 21q, possibly revealing a recessive disease allele on the undeleted chromosome. To establish whether chromosome 21 is also involved in the etiology of familial cases of presumably autosomal recessive CH, we investigated 22 families with recessive CH, using 10 microsatellite markers from 21q. Linkage analysis allowing for heterogeneity revealed no signs of linkage even in a small proportion of the families, and two-point analysis of the markers made it possible to exclude the long arm of chromosome 21 from containing any major disease-causing gene.

Adult↗