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H Eiberg

Publications and source records attributed to H Eiberg.

At least 55 records · Page 3Linked to original sources
PubMed1997

Structural organization of the human short-chain acyl-CoA dehydrogenase gene.

Short-chain acyl-CoA dehydrogenase (SCAD) is a homotetrameric mitochondrial flavoenzyme that catalyzes the initial reaction in short-chain fatty acid beta-oxidation. Defects in the SCAD enzyme are associated with failure to thrive, often with neuromuscular dysfunction and elevated urinary excretion of ethylmalonic acid (EMA). To define the genetic basis of SCAD deficiency and ethylmalonic aciduria in patients, we have determined the sequence of the complete coding portion of the human SCAD gene (ACADS) and all of the intron-exon boundaries. The SCAD gene is approximately 13 kb in length and consists of 10 exons. Four polymorphic sites have previously been detected by sequencing of cDNA from fibroblasts of patients excreting elevated amounts of EMA. Three of these polymorphisms (321T/C, 990C/T, 1260G/C) are silent variants, while a 625G/A polymorphism results in an amino acid replacement and has been shown to be associated with ethylmalonic aciduria. From analysis of 18 unrelated Danish families, we show that the four SCAD gene polymorphisms constitute five allelic variants of the SCAD gene, and that the 625A variant together with the less frequent variant form of the three other polymorphisms (321C, 990T, 1260C) constitutes an allelic variant with a frequency of 22% in the general Danish population. Using fluorescence in-situ hybridization, we confirm the localization of the human SCAD gene to the distal part of Chromosome (Chr) 12 and suggest that the SCAD gene is a single-copy gene. The evolutionary relationship between SCAD and five other members of the acyl-CoA dehydrogenase family was investigated by two independent approaches that gave similar phylogenetic trees.

Acyl-CoA Dehydrogenase↗
PubMed1997

Refinement of the dominant optic atrophy locus (OPA1) to a 1.4-cM interval on chromosome 3q28-3q29, within a 3-Mb YAC contig.

Dominant optic atrophy, type Kjer, is an autosomal dominant eye disease that is characterized by progressive optic atrophy with onset in early childhood, decrease of visual acuity, colour vision defects and centrocecal scotoma. By examination of 5 Danish families and the use of polymorphic markers, we have refined the localization of the OPA1 locus and assigned it to a 1.4-cM interval on chromosome 3q28-3q29, between markers D3S3669 and D3S3562. This localizes the gene on a 3-Mb YAC contig covering the disease locus. We have also located a possible candidate gene HRY to this contig.

Chromosome Mapping↗
PubMed1997

Assignment of human plasma methylumbelliferyl-tetra-N-acetylchitotetraoside hydrolase or chitinase to chromosome 1q by a linkage study.

Plasma methylumbelliferyl tetra-N-acetylchitotetraoside hydrolase or chitinase (CHIT) might play a role in degrading the chitin wall of some microorganisms. In about 6% of Caucasian people the enzyme shows pseudodeficiency (defined as very low activity without apparent symptoms). We have mapped this locus by linkage analysis to the marker D1S306 (z = 4.00 at theta M = F = 0.0) on chromosome 1q between the flanking markers D1S191 and D1S245 in the area of 1q31-1qter.

Blood Proteins↗
PubMed1997

CAG repeat expansion in autosomal dominant pure spastic paraplegia linked to chromosome 2p21-p24.

CAG repeat expansions have been identified as the disease-causing dynamic mutations in the coding regions of genes in several dominantly inherited neurodegenerative disorders, including spinobulbar muscular atrophy, Huntington's disease, dentatorubral-pallidoluysian atrophy, spinocerebellar ataxia type 1, 2 and 6 and Machado-Joseph disease. The CAG repeat expansions are translated to elongated polyglutamine tracts and an increased size of the polyglutamine tract correlates with anticipation, the cardinal feature, seen in all these diseases. Autosomal dominant pure spastic peraplegia (ADPSP) is a degenerative disorder of the central motor system clinically characterized by slowly progressive and unremitting spasticity of the legs, hyperreflexia and Babinski's sign. Like the established CAG repeat diseases ADPSP is characterized by both inter- and intrafamilial variation and anticipation. Using the Repeat Expansion Detection (RED) method, we have analyzed 21 affected individuals from six Danish families with the disease linked to chromosome 2p21-p24. We found that 20 of 21 affected individuals showed CAG repeat expansions versus two of 21 healthy spouses, demonstrating a strongly statistically significant association between the occurrence of the repeat expansion and the disease (Fisher's test, P < 10(-5)) suggesting that a CAG repeat expansion is involved presumably as a dynamic mutation in ADPSP linked to chromosome 2p21-p24. The size of the expansion is estimated to be > or = 60 CAG repeat copies in the affected individuals. The CAG repeat expansion is very likely translated and expressed as indicated by the detection of a polyglutamine-containing protein in an ADPSP patient.

Chromosomes, Human, Pair 2↗
PubMed1997

Susceptibility loci for bipolar affective disorder on chromosome 18? A review and a study of Danish families.

Chromosome 18 is one of the most promising chromosomes in the search for susceptibility genes for bipolar disorder based on results from cytogenetic, linkage, and association studies. Susceptibility loci on chromosome 18p and 18q have been suggested for bipolar affective disorder. We present a review of published studies which suggests that it is presently unclear whether one or more susceptibility loci on chromosome 18 exist, and that their more accurate localization is unknown. The present study investigated 27 DNA markers on chromosome 18 in two Danish families with bipolar affective disorder. We found positive lod scores in the larger family for markers on chromosome 18q12, especially for the affection status model which only includes bipolar patients. The highest lod score found was for marker D18S67, 1.83 at 0.05 recombination fraction.

Bipolar Disorder↗
PubMed1997

A survey of the newborn populations in Belgium, Germany, Poland, Czech Republic, Hungary, Bulgaria, Spain, Turkey, and Japan for the G985 variant allele with haplotype analysis at the medium chain Acyl-CoA dehydrogenase gene locus: clinical and evolutionary consideration.

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is an inborn error of fatty acid metabolism. It is one of the most frequent genetic metabolic disorders among Caucasian children. The G985 allele represented 90% of all the variant alleles of the MCAD gene in an extensive series of retrospective studies. To study the distribution of the G985 allele, newborn blood samples from the following countries were tested; 3000 from Germany (1/116). 1000 each from Belgium (1/77). Poland (1/98), Czech Republic (1/240). Hungary (1/168), Bulgaria (1/91), Spain (1/141). Turkey (1/216), and 500 from Japan (none). The frequency is shown in parentheses. The haplotype of G985 alleles in 1 homozygote and 57 heterozygote samples were then analyzed using two intragenic MCAD gene polymorphisms (Iaq1 and GT-repeat). The result indicated that only 1 of the 10 known haplotypes was associated with the G985 mutation, suggesting that G985 was derived originally from a single ancestral source. We made a compilation of the G985 frequencies in these countries and those in nine other European countries studied previously. The G985 distribution was high in the area stretching from Russia to Bulgaria in the east and in all northern countries in western and middle Europe, but low in the southern part of western and middle Europe. The incidence among ethnic Basques appeared to be low. This distribution pattern and the fact that all G985 alleles belong to a single haplotype suggest that G985 mutation occurred later than the delta F508 mutation of the CFTR, possibly in the neolithic or in a later period, and was brought into Europe by IndoEuropean-speaking people. The panEuropean distribution of the G985 allele, including Slavic countries from which patients with MCAD deficiency have rarely been detected, indicates the importance of raising the level of awareness of this disease.

Acyl-CoA Dehydrogenases↗
PubMed1997

Novel MODY3 mutations in the hepatocyte nuclear factor-1alpha gene: evidence for a hyperexcitability of pancreatic beta-cells to intravenous secretagogues in a glucose-tolerant carrier of a P447L mutation.

One form of maturity-onset diabetes of the young (MODY3) results from mutations in the hepatocyte nuclear factor (HNF)-1alpha gene, located on chromosome 12q24.2. The primary objective of the present study was to search for genetic variation in the HNF-1alpha gene in nine nonrelated Danish Caucasian subjects with MODY. Direct sequencing of the coding region and intron-exon boundaries of the HNF-1alpha gene revealed 2 novel and 1 previously reported missense mutations and 2 novel frameshift mutations in five of nine MODY subjects. These five mutations were found in neither 84 NIDDM patients nor 84 control subjects. One glucose-tolerant lean male with a P447L missense mutation, which in his relatives caused MODY, underwent an oral glucose tolerance test (OGTT), a tolbutamide modified frequently sampled intravenous glucose tolerance test, and a glucagon test to examine for a possible early beta-cell abnormality. He had a low insulin secretion rate during an OGTT, but a twofold increase in pancreatic beta-cell response after intravenous glucose and a 2.5- to 4-fold increase in beta-cell response after either intravenous tolbutamide or intravenous glucagon loads. In conclusion, 1) mutations in the HNF-1alpha gene are common in Danish Caucasian MODY patients, and 2) early stages in the pathogenesis of MODY3 caused by the P447L mutation may be characterized by a hyperexcitability of beta-cells to intravenous secretagogues.

Adolescent↗
PubMed1997

Clinical enuresis phenotypes in familial nocturnal enuresis.

The objective of the current study was to identify the associations between phenotype and genotype in children with nocturnal enuresis. Of the total of 167 wetting children, aged 5-10 years, without neurological or structural forms of incontinence, 110 were nocturnal enuretics. The examinations included a full psychiatric and psychological assessment, a paediatric and neurological examination, a family history with pedigree, ultrasonography, uroflowmetery, urinanalysis and bacteriology. Children with secondary nocturnal enuresis (n = 28) had a significantly higher rate of behavioural disorders, life events and continuous psychosocial stress than those with primary nocturnal enuresis (n = 82). Of the latter group, children with primary monosymptomatic nocturnal enuresis (n = 50) had an especially low rate of behavioural problems, when in comparison to primary non-monosymptomatic nocturnal enuretics (n = 32). Formal genetics point to a high genetic predisposition to nocturnal enuresis in all subgroups. Linkage studies to markers on chromosomes 8, 12 and 13 demonstrate both clinical, as well as genetic heterogeneity in nocturnal enuresis.

Chi-Square Distribution↗
PubMed1996

Linkage study between manic-depressive illness and chromosome 21.

Chromosome 21, of interest as potentially containing a disease gene for manic-depressive illness as possible evidence for a gene pre-disposing to affective disorder, has recently been reported in a single large family as well as samples of families. The present study investigates for linkage between manic-depressive illness and markers covering the long arm of chromosome 21 in two manic-depressive families, using ten microsatellite polymorphisms as markers. No conclusive evidence for a disease gene on the long arm of chromosome 21 was found. Assuming either a dominant or recessive mode of inheritance, close linkage to the marker PFKL, which has been reported as possibly linked to affective disorder, seems unlikely in the families studied here. PFKL and more telomeric markers yielded small positive lod scores at higher recombination fractions in the largest family, and small positive lod scores at lower recombination fractions in the affected-only analyses in the smallest family.

Bipolar Disorder↗
PubMed1996

Allele-specific measurement of low-density lipoprotein receptor transcript levels.

We have developed an assay for allele-specific determination of low-density lipoprotein receptor (LDLR) mRNAs. Transcript levels are measured by reverse transcription (RT), PCR, and electrophoresis on an automatic DNA sequencer using fluorescence-labeled primers and direct quantitation of the allele-specific RT-PCR products. The discrimination between the allelic products is based on the use of DNA polymorphisms located in the coding regions of the gene as markers for the individual alleles. Using this method on LDLR mRNA from heterozygous patients with familial hypercholesterolemia (FH) due to a defective LDLR protein, it is possible to relate the expression of the mutant allele directly to the expressed amounts of the normal allele, thus overcoming the problems of using artificial internal standards in the PCR. To validate the method we have measured (1) the range of normal LDLR allele transcript levels, and (2) the transcript levels in patients heterozygous for different types of mutant LDLR alleles associated with FH. The method is general in principle and can be applied in the allele-specific analysis of transcripts from all genes harbouring DNA polymorphisms in their coding regions.

Alleles↗
PubMed1996

Dombrock blood group (DO): assignment to chromosome 12p.

The Dombrock blood group system (DO) is a common polymorphism in Caucasians, represented by two red cell antigen alleles. In a linkage study in our family material of 832 families from the Copenhagen area, we found a strong indication of tight linkage with the two flanking DNA polymorphisms D12S358 (z = 7.66; at theta M = 0.001, theta F = 0.031) and D12S364 (z = 8.53; at theta M = 0.068, theta F = 0.031). DO is assigned to the region 12p13.2-12p12.1 by physically localised markers.

Blood Group Antigens↗
PubMed1996

Dominant optic atrophy mapped to chromosome 3q region. II. Clinical and epidemiological aspects.

Sixty-two patients from three large Danish families with autosomal dominant optic atrophy were clinically examined, and retrospective follow-up was made on 30 patients. We found great inter-and intrafamiliar variation in visual acuity and visual decline. One hundred and seventy-five chromosomal markers were analyzed in 118 family members. Linkage was demonstrated between the disease gene (OPA1) and the microsatellite markers D3S1314, D3S1262, D3S1265 and D3S1601, with the highest Lod score to D3S1601 Z=11.75. All markers are located on chromosome 3q in the telomeric area, the most probable location for the OPA1 gene being D3S1601-OPA1-D3S1265. Using data from the Danish Family Register of Hereditary Eye Diseases, the minimum prevalence rate was estimated to 1:12.301, making DOA the most common hereditary optic atrophy.

Adolescent↗
PubMed1996

Assignment of genes coding for brown eye colour (BEY2) and brown hair colour (HCL3) on chromosome 15q.

Brown eye colour (BEY), or total brown iris pigmentation is one of the most common phenotypes of iris colour. Data of eye colour as well as hair colour were obtained for linkage analysis through an enquiry in our family material of 832 families from Copenhagen area. By exclusion mapping with 80 markers in 120 segregating families and 290 markers in 5 segregating families, we obtained some indication of a locus BEY2 for brown eye colour on chromosome 15. For possible confirmation, we selected a total of 45 families from our DNA bank segregating for BEY. All these were tested for chromosome 15 markers in the area between D15S11 and CYP19. We found a strong indication of tight linkage with the DNA polymorphism D15S165 (Z = 24.25; theta M = F = 0.010) and with the flanking markers D15S156 (Z = 14.04; theta M = F = 0.0.029) and D15S144 (Z = 12.99; theta M = F = 0.060). BEY2 is assigned to the region 15q11-15q21 by physically localized markers. A new locus for brown hair colour (HCL3) was localized by indication of linkage to BEY2 in our 45 families segregating for BEY (Z = 9.93; theta M = F = 0.10). The gene (DN10 or P) homologous to the pink-eye-dilution gene (p) in mice could be a candidate gene for BEY2 or for HCL3.

Chromosome Mapping↗
PubMed1995

Linkage analysis between manic-depressive illness and markers on the long arm of chromosome 11.

The long arm of chromosome 11 is one of the most interesting regions in the search for major genes involved in the etiology of manic-depressive illness. Several candidate genes have been identified, including the gene encoding the dopamine D2 receptor, the M1 muscarinic receptor, and porfobillinogen deaminase. Furthermore, different families with co-segregation of psychiatric illness and structural chromosome abnormalities involving regions 11q21, 11q22.3, and 11q25 have been reported. Using narrow as well as broad phenotypic models, conservative genetic parameters, models with dominant or recessive modes of inheritance, and various methods to reduce misclassification, the present study did not find evidence for a major gene causing manic-depressive illness on the long arm of chromosome 11. In the broader phenotypic models multi-point analyses excluded at least 11q14 to 11q23.3, approximately 60 cM, even in one large family. Assuming homogeneity close linkage to DRD2 was excluded for all dominant models, and also in the affecteds-only analyses in the large family alone.

Biomarkers↗
PubMed1995

Assignment of congenital cataract Volkmann type (CCV) to chromosome 1p36.

Congenital cataract, type Volkmann (McKusick no 115665, gene symbol CCV) is an autosomal dominant eye disease. The disease is characterized by a progressive, central and zonular cataract, with opacities both in the embryonic, fetal and juvenile nucleus and around the anterior and posterior Y-suture. We examined blood samples from 91 members of a Danish pedigree comprising 426 members, by using highly informative short tandem repeat polymorphisms and found the closest linkage of the disease gene (CCV) to a (CA)n dinucleotide repeat polymorphism at locus D1S243 (Zmax = 14.04 at theta M = 0.025 theta F = 0.000), at a penetrance of 0.90. Using two additional chromosome 1 markers, we were able to map the CCV gene in the sequence 1pter-(CCV, D1S243)-D1S468-D1S214. The (enolase 1) gene has been mapped to this area; however, a mutation described in this gene did not give eye disease.

Cataract↗
PubMed1995

Assignment of dominant inherited nocturnal enuresis (ENUR1) to chromosome 13q.

Nocturnal enuresis, or nightly bedwetting in children more than seven years of age affects about 10% of seven-year-old children, with a wide range of frequencies between populations. The affliction is often linked to major social maladjustments and occupies considerable time in general practice. From the age of seven there is a spontaneous cure rate of 15% per year, such that few remain affected after the age of 16 years. There are two types of nocturnal enuresis: type I (PEN1, primary) with at least three nightly episodes in children above seven years, where the child has always had the disorder and type II (secondary) where the child has been dry for at least six months, but enuresis has recurred. Among some 400 Danish, mostly three-generation families, we have found 17 families with nocturnal enuresis. Eleven of these family had type I nocturnal enuresis (PEN1) that appeared to follow an autosomal dominant mode of inheritance with penetrance above 90%. We now describe strong evidence of linkage with the DNA polymorphisms D13S291 (Z = 3.55; theta M = F = 0.07) and D13S263 (Z = 2.67; theta M = F = 0.08). Multipoint analysis indicates that these markers flank the disease locus at chromosome 13q13-q14.3.

Adolescent↗
PubMed1995

A search for genes predisposing to manic depressive illness on chromosome 20.

Very few studies have investigated linkage between manic depressive illness and markers from chromosome 20. Apparently no cytogenetic abnormalities involving chromosome 20 have been described in patients with affective disorders. Several interesting candidate genes of possible psychiatric relevance have been mapped to chromosome 20, including genes encoding a G-protein subunit and two enzymes involved in the phosphatidylinositol cycle, which have been implicated in the pathophysiology of affective disorder as well as the action of lithium, and two alpha-adrenergic receptors. The present study investigated linkage between manic depressive illness and 11 markers from chromosome 20 in two manic depressive families, and did not find evidence for a major disease allele. A single microsatellite marker, D20S39, yielded positive lod scores or all models in each family in the two-point affecteds-only analyses. However, this was not supported by two-point analyses with flanking markers or multi-point affecteds-only analyses. No evidence of linkage between manic depressive illness and markers covering chromosome 20 was found assuming dominant or recessive mode of inheritance.

Bipolar Disorder↗