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C Wadelius

Publications and source records attributed to C Wadelius.

At least 37 records · Page 2Linked to original sources
PubMed1997

Identification of mutations in the CACNL1A3 gene in 13 families of Scandinavian origin having hypokalemic periodic paralysis and evidence of a founder effect in Danish families.

Familial hypokalemic periodic paralysis (hypoPP) is an autosomal dominant disorder characterised by episodic attacks of paralysis of varying severity. Recently, linkage was found to markers in 1q31-32 and to the gene encoding the muscle DHP-sensitive calcium channel alpha 1-subunit (CACNL1A3). Subsequently, three mutations in this gene were identified in patients with hypoPP: Arg528His, Arg1239His and Arg1239Gly. In this study, two different mutations were found in the CACNL1A3 gene in 13 Scandinavian families, 10 of whom have the Arg528His mutation while 3 families have the Arg1239His. Furthermore, there is evidence of a founder effect in 8 of the 9 Danish hypoPP families investigated, consisting of haplotypes of microsatellite markers close to and within the CACNL1A3 gene and of the geographic origin of the families. For the first time, reduced penetrance in males with the Arg528His mutation was found in several cases.

Adolescent↗
PubMed1997

Genetic and linkage analysis of familial congenital hypothyroidism: exclusion of linkage to the TSH receptor gene.

Congenital hypothyroidism affects 1/3000-4000 newborns. The causes of this group of disorders are still largely unknown. Although most cases are sporadic some families have several affected children and/or consanguineous parents, suggesting autosomal recessive inheritance. Furthermore, there is a murine strain (hyt) with congenital hypothyroidism and autosomal recessive inheritance, whose phenotype appears to be identical with the corresponding human disease. In the hyt mouse, the disease is caused by a mutation in the thyroid-stimulating hormone receptor (TSHR) gene, making this gene a likely candidate also for the human disease. The human TSHR gene was mapped on radiation hybrid panels and closely linked flanking markers D14S287 and D14S616 were identified. On the Genebridge 4 panel, D14S287 was found to be located 8.5 cR (corresponding to 2.3 cM) proximal to the TSHR gene, and D14S616 was found to be located 4.4 cR (1.2 cM) distal to the TSHR gene. These markers were analyzed in 23 families, most of them with two or more children affected by congenital hypothyroidism and some with appreciable consanguinity of the parents. Assuming homogeneity, the two-point lod score at theta = 0.1 was -4.8 for D14S287 and -5.8 for D14S616, and thus linkage to the TSHR gene was excluded. Even when the data were analyzed with allowance for heterogeneity, there was no evidence of linkage. Our conclusion is that if mutation of the TSHR gene causes familial congenital hypothyroidism in humans, it affects only a small proportion of the cases.

Adult↗
PubMed1997

A missense mutation in the FALDH gene identified in Sjögren-Larsson syndrome patients originating from the northern part of Sweden.

Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by congenital ichthyosis, spastic di- or tetraplegia, and mental retardation. SLS has been reported to occur in many populations but the highest incidence is in the north of Sweden. The gene causing SLS encodes a fatty aldehyde dehydrogenase (FALDH). In the present study, a point mutation in exon 7 of the FALDH gene was found in SLS patients of northern Swedish origin. The mutation consists of a C-to-T exchange at nucleotide position 943 in the cDNA. As a consequence, a highly conserved proline is replaced by a serine. The mutation was found in 49 out of 58 affected chromosomes and could be the most widely spread SLS mutation in the world.

Aldehyde Oxidoreductases↗
PubMed1997

Fine mapping of the gene for autosomal dominant juvenile-onset glaucoma with iridogoniodysgenesis in 6p25-tel.

Glaucoma is a group of ocular disorders leading to reduced visual capabilities and sometimes blindness. The biochemical defect is unknown but it is shown that reduced drainage of the aqueous humour from the anterior chamber may lead to increased intraocular pressure and gradual atrophy of the optic neurons. Families with various forms of autosomal dominant (AD) glaucoma have been linked to 1q21-31, 2cen-q13, 4q25-27, and 13q14 and autosomal recessive congenital glaucoma have been localized to chromosome 1p36 and 2p21. Recently, a locus for AD iridogoniodysgenesis anomaly (IGDA) was mapped to chromosome 6p25. This study refines the localization of IGDA to an approximately 6-cM interval between D6S1600 and D6S1617/D6S1713 at 6p25-tel, based on recombinations in affected individuals with AD juvenile-onset glaucoma and concomitant iridogoniodysgenesis.

Age of Onset↗
PubMed1997

Refined genetic localization of the Best disease gene in 11q13 and physical mapping of linked markers on radiation hybrids.

Best's macular dystrophy, also known as vitelliform macular degeneration type 2 (VMD-2), is an autosomal dominant eye disorder that causes reduced visual acuity. It generally manifests itself in the teenage years. The gene mutated in VMD-2 patients may provide valuable insight into the biological mechanisms of the far more common disorder age-related macular degeneration. The VMD-2 gene has been localized to 11q13 between UGB and Fc epsilon RI. In order to clone the gene positionally, a large Swedish VMD-2 family dating back to the 17th century was studied for recombinations. Since the last study, another 40 microsatellite markers have been analyzed in the family; the closest centromeric flanking marker, D11S4076, revealed two recombinations and the closest telomeric flanking marker, UGB, revealed one recombination. The recombinations have occurred in affected individuals, which eliminates the potential problem of reduced penetrance. The order and physical distance between 22 markers located at proximal 11q13 were analyzed on the G3 Stanford radiation-reduced cell hybrids. The data suggest that the VMD-2 region flanked by the microsatellite markers D11S4076 and UGB is approximately 980 kb.

Centromere↗
PubMed1997

Genetic mapping using fluorescent quantification of allele frequencies in pooled DNA loaded by solid support.

An efficient and labour-saving method for fragment analysis in linkage studies using biotinylated primers and streptavidin-coated combs is presented. The level of streptavidin attached to the combs was used to control the amount of immobilised material. Thus, the need for titration of PCR products to fit the dynamic range of the sequencer was reduced. The method was used to investigate the possibility of quantitating allele frequencies in pools of DNA from family members with the autosomal dominant eye disorder Best's macular dystrophy. The method allowed the detection of one unique allele in a background of 39 other alleles. Using independent datasets, it was further found that the method was able to detect distorted allele frequencies in affected individuals of one family as compared to reference individuals, for markers located more than 30 cM from the disease locus. It was found that this procedure is a powerful alternative to conventional linkage analysis and the method may prove useful in a genome scan for genes involved in complex disorders.

Alleles↗
PubMed1997

Venous thrombosis: factor V G1691A genotyping related to APC resistance as measured by 2 methods.

Blood samples were collected from consecutive unrelated patients with venous thrombosis. The patients originate from the middle part of Sweden. We investigated the presence of the reported point mutation at nt 1691 of factor V which renders the protein resistant to cleavage by activated protein C (APC). Thirty-seven per cent of the patients were heterozygote carriers, and 4.5% were homozygotes for a mutated factor V gene. In addition, resistance to coagulation induced by APC was measured, both by the conventional APTT assay and by a modified APTT assay which has been reported to have an increased resolution. Compared to a control group of healthy people, the mean value was significantly lower in the patient group. A strong correlation between low APC ratio and presence of the factor V mutation was found. By using the modified method, a complete resolution of carriers of the factor V mutation and people with normal factor V alleles was found. However, there was still an overlap between heterozygote carriers and people homozygous for the mutation. The modified method was also found useful in patients treated with warfarin. Among 40 healthy blood donors 7% were found to be heterozygous.

Adolescent↗
PubMed1997

First prenatal diagnosis by mutation analysis in a family with Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS) is a rare, autosomal recessive disorder characterized by congenital ichthyosis, mental retardation, and spastic diplegia or tetraplegia. The disorder has the highest incidence in the north of Sweden and most of the cases are caused by a C943T mutation in the FALDH gene. Prenatal diagnosis and PCR-based mutation analysis was performed in a pregnancy where the parents are heterozygous carriers for this mutation. The fetus was found to be homozygous for the mutation and thus affected by SLS.

Abortion, Induced↗
PubMed1996

Molecular analysis of chromosome 21 in a patient with a phenotype of Down syndrome and apparently normal karyotype.

Down syndrome (DS) is caused in most cases by the presence of an extra chromosome 21. It has been shown that the DS phenotype is produced by duplication of only a small part of the long arm of chromosome 21, the 21q22 region, including and distal to locus D21S55. We present molecular investigations on a woman with clinically typical DS but apparently normal chromosomes. Her parents were consanguineous and she had a sister with a DS phenotype, who died at the age of 15 days. Repeated cytogenetic investigations (G-banding and high resolution banding) on the patient and her parents showed apparently normal chromosomes. Autoradiographs of quantitative Southern blots of DNAs from the patient, her parents, trisomy 21 patients, and normal controls were analyzed after hybridization with unique DNA sequences regionally mapped on chromosome 21. Sequences D21S59, D21S1, D21S11, D21S8, D21S17, D21S55, ERG, D21S15, D21S112, and COL6A1 were all found in two copies. Fluorescent in situ hybridization with a chromosome 21-specific genomic library showed no abnormalities and only two copies of chromosome 21 were detected. Nineteen markers from the critical region studied with polymerase chain reaction amplification of di- and tetranucleotide repeats did not indicate any partial trisomy 21. From this study we conclude that the patient does not have any partial submicroscopic trisomy for any segment of chromosome 21. It seems reasonable to assume that she suffers from an autosomal recessive disorder which is phenotypically indistinguishable from DS.

Adult↗
PubMed1996

Chromosome-specific panels of tri- and tetranucleotide microsatellite markers for multiplex fluorescent detection and automated genotyping: evaluation of their utility in pathology and forensics.

A set of 391 microsatellite markers (Weber set 6), 85% of which consist of tri- and tetranucleotide repeat markers, were used to design chromosome-specific panels that allowed for a high degree of multiplexing with respect to the fragment size range and fluorophore (FAM, HEX, TET). This marker set has an average coverage of 10.5 cM, with the largest gap being 28.1 cM. The markers were divided into 49 panels, with a maximum degree of multiplexing of 15 markers per panel. The utility of the markers for analysis of DNA from blood, hair, and formalin-fixed archival tissue biopsies was evaluated with respect to amplification efficiency, product yield, and degree of preferential amplification of the shorter allele in heterozygotes. The amplification efficiency was inversely related to repeat length and amplicon length. Based on the analysis of DNA from formalin-fixed biopsies, 51 markers suitable for loss of heterozygosity (LOH) studies were identified. The utility of the marker set for genome scanning, LOH, and forensic analyses is discussed.

Chromosomes↗
PubMed1996

Achondroplasia in Sweden caused by the G1138A mutation in FGFR3.

Achondroplasia, an autosomal dominant inherited disorder, is one of the most common forms of skeletal dysplasia resulting in disproportionate extreme shortness. Recently, two point mutations, both affecting nucleotide 1138 in the fibroblast growth factor receptor type 3 (FGFR3) gene, were found to be the cause of the disorder. We investigated DNA from 16 Swedish patients with achondroplasia for the presence of these mutations. All patients were found to be heterozygous for the G to A transition at nucleotide 1138. Our data thus support previous reports showing a striking genetic homogeneity, in that almost all achondroplasia patients have the FGFR3 G380R mutation at the protein level.

Achondroplasia↗
PubMed1996

Hyperkalemic periodic paralysis caused by recurring mutation in the adult muscle sodium channel alpha-subunit gene.

Linkage studies and mutation analysis were performed in two Swedish families with hyperkalemic periodic paralysis (HYPP), an autosomal dominant inherited disorder characterized by episodic muscle weakness associated with increasing or high levels of serum potassium. The gene for HYPP is the gene encoding the alpha-subunit of the sodium channel of adult human skeletal muscle (SCN4A). SCN4A has been localized on chromosome 17 q closely linked to the human growth hormone gene. Linkage between a microsatellite polymorphism in the SCN4A gene and the disease was shown in two Swedish families (Z = 12.10 theta = 0). Sequence analysis revealed that the two Swedish families have got a C to T transition at position 2188 in the cDNA. At the protein level this Thr 704 to Met mutation is located in the fifth membrane spanning segment of domain II of the protein, as previously described (28). The mutation was linked to different microsatellite alleles regarding both a (GT)n and a (GA)n repeat in the gene. Either the families are related and new mutations have occurred in both microsatellites when the pedigrees were separated or the mutation has arisen independently in the two families analysed. From the mutant alleles characterized so far it seems as if a limited number of mutations is present in this gene.

Adult↗
PubMed1995

Confirmation of linkage to 1q21-31 in a Danish autosomal dominant juvenile-onset glaucoma family and evidence of genetic heterogeneity.

Autosomal dominant juvenile-onset open-angle glaucoma has been mapped to 1q21-31 in a number of American families. Our study confirms linkage in a Danish five-generation dominant juvenile-onset glaucoma family with a maximum two-point lod score of 6.67 at the D1S210 locus. Multipoint linkage analysis in a nine-generation Swedish family with dominant juvenile-onset glaucoma and iris hypoplasia excludes linkage to the region of approximately 18 cM between loci D1S104 and D1S218, shown to contain the previously mapped glaucoma gene. This study thus provides support for genetic heterogeneity with respect to dominant juvenile-onset glaucoma.

Adolescent↗