Biomedical subjects

H Eiberg

Publications and source records attributed to H Eiberg.

At least 19 recordsLinked to original sources

PubMed2006

Autosomal dominant optic atrophy associated with hearing impairment and impaired glucose regulation caused by a missense mutation in the WFS1 gene.

Autosomal dominant optic atrophy (ADOA) is genetically heterogeneous, with OPA1 on 3q28 being the most prevalently mutated gene. Additional loci are OPA3, OPA4, and OPA5, located at 19q13.2, 18q12.2, and 22q12.1-q13.1, respectively. Mutations in the WFS1 gene, at 4p16.3, are associated with either optic atrophy (OA) as part of the autosomal recessive Wolfram syndrome or with autosomal dominant progressive low frequency sensorineural hearing loss (LFSNHL) without any ophthalmological abnormalities. Linkage and sequence mutation analyses of the ADOA candidate genes OPA1, OPA3, OPA4, and OPA5, including the genes WFS1, GJB2, and GJB6 associated with recessive inherited OA or dominant LFSNHL, were performed. We identified one novel WFS1 missense mutation E864K, c.2590G-->A in exon 8 that co-segregates with ADOA combined with hearing impairment and impaired glucose regulation. This is the first example of autosomal dominant optic atrophy and hearing loss associated with a WFS1 mutation, supporting the notion that mutations in WFS1 as well as in OPA1 may lead to ADOA combined with impaired hearing.

Adult↗

PubMed2005

A mutation in the receptor binding site of GDF5 causes Mohr-Wriedt brachydactyly type A2.

BACKGROUND: Brachydactyly type A2 (OMIM 112600) is characterised by hypoplasia/aplasia of the second middle phalanx of the index finger and sometimes the little finger. BDA2 was first described by Mohr and Wriedt in a large Danish/Norwegian kindred and mutations in BMPR1B were recently demonstrated in two affected families. METHODS: We found and reviewed Mohr and Wriedt's original unpublished annotations, updated the family pedigree, and examined 37 family members clinically, and radiologically by constructing the metacarpo-phalangeal profile (MCPP) pattern in nine affected subjects. Molecular analyses included sequencing of BMPR1B, linkage analysis for STS markers flanking GDF5, sequencing of GDF5, confirmation of the mutation by a restriction enzyme assay, and localisation of the mutation inferred from the very recently reported GDF5 crystal structure, and by superimposing the GDF5 protein sequence onto the crystal structure of BMP2 bound to Bmpr1a. RESULTS: A short middle phalanx of the index finger was found in all affected individuals, but other fingers were occasionally involved. The fourth finger was characteristically spared. This distinguishes Mohr-Wriedt type BDA2 from BDA2 caused by mutations in BMPR1B. An MCPP analysis most efficiently detected mutation carrier status. We identified a missense mutation, c.1322T>C, causing substitution of a leucine with a proline at amino acid residue 441 within the active signalling domain of GDF5. The mutation was predicted to reside in the binding site for BMP type 1 receptors. CONCLUSION: GDF5 is a novel BDA2 causing gene. It is suggested that impaired activity of BMPR1B is the molecular mechanism responsible for the BDA2 phenotype.

Binding Sites↗

PubMed2005

Distinct CDH3 mutations cause ectodermal dysplasia, ectrodactyly, macular dystrophy (EEM syndrome).

BACKGROUND: EEM syndrome is the rare association of ectodermal dysplasia, ectrodactyly, and macular dystrophy. METHODS: We here demonstrate through molecular analysis that EEM is caused by distinct homozygous CDH3 mutations in two previously published families. RESULTS: In family 1, a missense mutation (c.965A-->T) causes a change of amino acid 322 from asparagine to isoleucine; this amino acid is located in a highly conserved motif likely to affect Ca2+ binding affecting specificity of the cell-cell binding function. In family 2, a homozygous frameshift deletion (c.829delG) introduces a truncated fusion protein with a premature stop codon at amino acid residue 295, expected to cause a non-functional protein lacking both its intracellular and membrane spanning domains and its extracellular cadherin repeats 3-5. Our mouse in situ expression data demonstrate that Cdh3 is expressed in the apical ectodermal ridge from E10.5 to E12.5, and later in the interdigital mesenchyme, a pattern compatible with the EEM phenotype. Furthermore, we discuss possible explanations for the phenotypic differences between EEM and congenital hypotrichosis with juvenile macular dystrophy (HJMD), which is also caused by CDH3 mutations. CONCLUSIONS: In summary, we have ascertained a third gene associated with ectrodactyly and have demonstrated a hitherto unrecognised role of CDH3 in shaping the human hand.

Adult↗

PubMed2004

Loss of heterozygosity at 9q33 and hypermethylation of the DBCCR1 gene in oral squamous cell carcinoma.

The DBCCR1 gene at chromosome 9q33 has been identified as a candidate tumour suppressor, which is frequently targeted by promoter hypermethylation in bladder cancer. Here, we studied the possible involvement of DBCCR1 in the development of oral squamous cell carcinoma. DNA from 34 tumours was examined for loss of heterozygosity (LOH) at three markers surrounding DBCCR1 and for hypermethylation of the DBCCR1 promoter, using methylation-specific PCR and methylation-specific melting-curve analysis. LOH was found in 10 of 31 cases (32%), and DBCCR1 hypermethylation was present in 15 of 34 cases (44%). Hypermethylation of DBCCR1 was also present in three of seven epithelial tissues adjacent to the tumours, including two hyperplastic and one histologically normal epithelia. Furthermore, of four oral leukoplakias with dysplasia, one showed LOH at 9q33 and two showed DBCCR1 hypermethylation. These data suggest that LOH at 9q33 and hypermethylation of the DBCCR1 promoter are frequent and possibly early events in oral malignant development.

Adult↗

PubMed2004

Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation.

Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria, unipolar depression, epilepsy, migraine, and cognitive impairment was investigated. Genetic linkage analysis and sequencing of the SPG4 gene was performed and electrophysiologic investigations were carried out in six individuals and positron emission tomography (PET) in one patient. The disease was linked to the SPG4 locus on chromosome 2p as previously reported for pure HSP. Sequence analysis of the SPG4 (spastin) gene identified a novel 1593 C > T (GLN490Stop) mutation leading to premature termination of exon 12 with ensuing truncation of the encoded protein. However, the mutation was only identified in those individuals who were clinically affected by a complex phenotype consisting of HSP and cerebellar ataxia. Other features noted in this kindred including epilepsy, cognitive impairment, depression, and migraine did not segregate with the HSP phenotype or mutation, and therefore the significance of these features to SPG4 is unclear. Electrophysiologic investigation showed increased central conduction time at somatosensory evoked potentials measured from the lower limbs as the only abnormal finding in two affected individuals with the SPG4 mutation. Moreover, PET of one patient showed significantly relatively decreased regional cerebral blood flow in most of the cerebellum. We conclude that this kindred demonstrates a considerable overlap between cerebellar ataxia and spastic paraplegia, emphasizing the marked clinical heterogeneity of HSP associated with spastin mutations.

Adenosine Triphosphatases↗

PubMed2004

Cholestasis Familiaris Groenlandica/Byler-like disease in Greenland--a population study.

OBJECTIVES: Cholestasis Familiaris Groenlandica (CFG, or progressive familiar intrahepatic cholestasis type 1 (PFIC1)) is a very common lethal recessive inherited disease in Greenland. A missense mutation, 1660G>A (asp554asn) in the gene ATP8B1 causes the disease (Klomp et al. 2000). STUDY DESIGN: A family study examining medical files from the period 1951-2003 from East Greenland resulted in 46 cases of PFIC1 and more than 220 relatives showing carrier status. Further, random blood sample testing 953 anonymous persons from 11 major cities or districts all over Greenland have been analysed for carrier status of the mutation. METHODS: A sensitive PCR method is developed to distinguish between normal and mutant alleles for ATP8B1 in the Greenland population. RESULTS: The mutation 1660G>A is found in all areas of Greenland, and the frequency of the mutant allele vary all over the country. A shockingly high frequency for the mutant allele is found in East Greenland in Ittoqqortoormiit (0.16) and in Tasiilaq (0.077), whereas in Northwest Greenland lower frequencies are found in Uummannaq and Ilulissat (0.032), and Maniitsoq (0.005). CONCLUSIONS: The high frequency of the mutation in East and Northwest Greenland strongly indicates that routine screening of the population for carrier status should be done.

Adenosine Triphosphatases↗

PubMed2004

Cholestasis Familiaris Groenlandica: an epidemiological, clinical and genetic study.

OBJECTIVES: Accumulation of Cholestasis Familiaris Groenlandica (CFG) or progressive familial intrahepatic cholestasis type 1 (PFIC1) occurs in indigenous Inuit families in Greenland. It is an autosomal recessive inherited liver disease. From early childhood the children suffer from failure to thrive, jaundice, pruritus and enlarged liver. Affected persons generally die very young. STUDY DESIGN: Patients' information has been collected from the Greenlandic death register and hospital records. METHODS: Detailed genealogy including clinical description and examination if possible. Interviews of parents and relatives, linkage and DNA analysis of the probands and the closest relatives have been studied. RESULTS: 46 affected cases from a highly inbred population have been diagnosed since 1943. The disease is caused by a missense mutation in the FIC1 gene ATP8B1, chromosome 18q21. Six affected children are alive aged 1-21 years. Among the tested relatives 220 are heterozygote. One prenatal diagnosis has been performed. CONCLUSION: The mutation causing Cholestasis Familiaris Groenlandica is widespread in Greenland, but accumulation is seen in certain areas. The disease is burdensome for the child, the parents and the Greenlandic society. Genetic counselling and carrier screening are strongly recommended.

Adenosine Triphosphatases↗

PubMed2003

A novel mutation in the epsilon-sarcoglycan gene causing myoclonus-dystonia syndrome.

Two families were referred with different clinical diagnoses of dystonia. Twenty-four family members were examined clinically, and mutation analyses were performed. Most of the affected individuals had laryngeal myoclonus and more severe dystonia of the legs than usually reported in myoclonus-dystonia syndrome. Sequence analyses revealed a previously unreported deletion (974delC or R325X) in exon 7 in the epsilon-sarcoglycan gene in members of both families. The two families were found to be related.

Age of Onset↗

PubMed2003

Heterogeneity of FeNO response to inhaled steroid in asthmatic children.

BACKGROUND: Nitric oxide in exhaled air is regarded as an inflammation marker, and may be used to monitor the anti-inflammatory control from inhaled corticosteroids (ICSs). However, this response to ICSs exhibits a heterogeneous pattern. OBJECTIVE: The study aimed to describe the independent variables associated with the heterogeneity in the response of exhaled nitric oxide to ICSs. METHODS: Exhaled nitric oxide (FeNO), lung function, bronchial hyper-responsiveness (BHR), specific IgE to common inhalant allergens, blood eosinophils, other atopic manifestations and variants in nitric oxide synthethase 1 (NOS1) gene were studied in a double-blind, placebo-controlled crossover comparison of budesonide (BUD) Turbohaler 1600 mcg daily vs. placebo in asthmatic schoolchildren. RESULTS: Forty children were included in the study from a screening of 184 asthmatic children with moderately persistent asthma, well controlled on regular BUD 400 mcg daily: 20 children with normal FeNO and 20 with raised FeNO. FeNO, BHR and forced expiratory volume in 1 s improved significantly after BUD 1600 mcg (BUD1600). However, FeNO after ICS treatment exhibited a Gaussian distribution and FeNO was significantly raised in 15 children. Allergy and BHR, but none of the other independent variables under study were significantly related to FeNO after BUD1600. CONCLUSION: Exhaled nitric oxide exhibited a heterogeneous response to ICS in asthmatic schoolchildren. Allergy and BHR were driving FeNO level independently of high-dose steroid treatment. This should be considered when using FeNO for steroid dose titration and monitoring of ICS anti-inflammatory control in asthmatic children.

Administration, Inhalation↗

PubMed2001

A frameshift mutation in exon 28 of the OPA1 gene explains the high prevalence of dominant optic atrophy in the Danish population: evidence for a founder effect.

Dominant optic atrophy (DOA) is a hereditary optic neuropathy characterised by decreased visual acuity, colour vision deficits, centro-coecal scotoma and optic nerve pallor. The gene OPA1, encoding a dynamin-related GTPase, has recently been identified within the genetic linkage interval for the major locus for DOA on chromosome 3q28 and shown to harbour genetic aberrations segregating with disease in DOA families. The prevalence of the disorder in Denmark is reported to be the highest of any geographical location, suggestive of a founder effect. In order to establish the genetic basis of disease in a sample of 33 apparently unrelated Danish families, we screened DNA from affected members for OPA1 gene mutations by heteroduplex analysis and direct sequencing. A novel identical mutation in exon 28 (2826delT) was associated with DOA in 14 pedigrees and led to a frameshift and abnormal OPA1 protein -COOH terminus. Haplotype analysis of a region of approximately 1 Mb flanking the OPA1 gene using eight polymorphic markers revealed a common haplotype shared by all 14 patients; this haplotype was markedly over-represented compared with ethnically matched controls. Statistical analysis confirmed significant linkage disequilibrium with DOA over approximately 600 kb encompassing the disease mutation. We have therefore demonstrated that the relatively high frequency of DOA in Denmark is attributable to a founder mutation responsible for approximately 42% of the examined families and suggest that presymptomatic screening for the (2826delT) mutation may facilitate diagnosis and genetic counselling in a significant proportion of DOA patients of Danish ancestry.

Alleles↗

PubMed2001

Genetic linkage of autosomal dominant primary open angle glaucoma to chromosome 3q in a Greek pedigree.

A locus for juvenile onset open angle glaucoma (OAG) has been assigned to chromosome 1q in families with autosomal dominant inheritance (GLC1A), due to mutations in the TIGR/MYOC gene. For adult onset OAG, called primary open angle glaucoma or POAG, five loci have so far been mapped to different chromosomes (GLC1B-GLC1F). Except for the GLC1B locus, the other POAG loci have so far been reported only in single large pedigrees. We studied a large family identified in Epirus, Greece, segregating POAG in an autosomal dominant fashion. Clinical findings included increased cup to disc ratio (mean 0.7), characteristic glaucomatous changes in the visual field, and intraocular pressure before treatment more than 21 mmHg (mean 31 mmHg), with age at diagnosis 33 years and older. Linkage analysis was performed between the disease phenotype and microsatellite DNA polymorphisms. Linkage was established with a group of DNA markers located on chromosome 3q, where the GLC1C locus has previously been described in one large Oregon pedigree. A maximal multipoint lod score of 3.88 was obtained at marker D3S1763 (penetrance 80%). This represents the second POAG family linked to the GLC1C locus on chromosome 3q, and haplotype analysis in the two families suggests an independent origin of the genetic defect.

Adult↗

PubMed2001

The genetics of enuresis: a review.

PURPOSE: Formal studies of the genetics of enuresis have been performed since the 1930s and molecular genetics since 1995, both highlighting the importance of hereditary factors in the etiology of nocturnal enuresis. We summarize the current state of knowledge with respect to the genetics of nocturnal enuresis and its genotype-phenotype interactions. MATERIALS AND METHODS: A comprehensive review of the published data available on the genetic basis of enuresis was performed. RESULTS: Genetic factors are the most important in the etiology of nocturnal enuresis but somatic and psychosocial environmental factors have a major modulatory effect. Most commonly, nocturnal enuresis is inherited via an autosomal dominant mode of transmission with high penetrance (90%). However, a third of all cases are sporadic, and the difference between sporadic and familial forms is not known. Four gene loci associated with nocturnal enuresis have been identified but the existence of others is presumed (locus heterogeneity). All likely candidate genes have been excluded so far. There is no specific association among the different loci, type of wetting and other aspects of the phenotype. All subtypes of nocturnal enuresis (primary, secondary, combined day/night wetting) are susceptible to comparable genetic influences. Certain syndromes of day wetting follow their own genetic mechanisms but this association with the genetics of nocturnal enuresis is not known. CONCLUSIONS: Nocturnal enuresis is a common, genetic and heterogeneous disorder. The associations between genotype and phenotype are complex and are susceptible to environmental influences. Therefore, exact assessment of the clinical phenotype and identification of intermediary phenotypes or traits are needed. Future research will focus on the identification of genes, gene products and their interaction with environmental factors.

Child↗

PubMed2001

Linkage study of a large Danish 4-generation family with urge incontinence and nocturnal enuresis.

PURPOSE: We studied a large 4-generation family in which night and day voiding problems segregated in an autosomal dominant pattern with a high penetrance. We mapped the gene(s) causing these forms of incontinence using a total genome scan approach. MATERIALS AND METHODS: The family comprises 74 subjects in 4 generations. The clinical phenotypes were evaluated by detailed questionnaires and frequency volume charts. Genetically, a genome scan approach with 500 polymorphic marker systems was used to localize a chromosome area for the trait(s) and to narrow down a candidate region. The 3 different genetic models studied were 1) a single gene causing either day, night or day and night incontinence; 2) a gene primarily causing night incontinence; and 3) 2 different genes each causing only day or night incontinence. RESULTS: For model 2 we found 2 areas that gave a high lod score on 2-point analysis (D4S2960, 4p16.1, Z = 3.66 and D12S86, 12q24.2, Z = 3.22) on chromosome 4p and 12q. With an estimated penetrance of 75% only 4p linkage was significant. Models 1 and 3 were excluded as causes due to lack of the affected haplotype in affected subjects. Based on manual haplotype and 2-point analyses, all other areas were excluded for linkage. CONCLUSIONS: The most likely genetic model in this kindred seems to be a gene located on chromosome 4p16.1 causing primarily nocturnal enuresis. However, involvement of chromosome 12q24.3 cannot be excluded for linkage. The dopamine receptors DRD5 and D1B are mapped to chromosome 4p16. These genes are candidate genes for nocturnal enuresis and urge incontinence.

Child↗

PubMed2000

[Epidermolysis bullosa simplex: genotype-phenotype correlation in Danish patients].

Epidermolysis bullosa simplex (EBS) is a group of autosomal dominant inherited skin disorders caused by mutations in the keratin genes K5 or K14. We examined five Danish families with EBS-Weber-Cockayne (WC) or EBS-Koebner (K) and two sporadic cases of EBS-Dowling-Meara (DM) in order to investigate the mutational spectrum and evaluate the genotype-phenotype correlation in Danish patients. Three new K14 mutations, one new and one previously described K5 mutation were identified by DNA sequence analysis. The positions of the EBS-DM mutations were consistent with previous studies, whereas the EBS-WC and EBS-K mutations were found in regions of the keratin genes not typically associated with this type of EBS mutations. In conclusion, we found a strict genotype-phenotype correlation. Furthermore, we found that the position of the mutation in the keratin gene is not the only determinant for severity of the disease; the nature of the amino acid substitution should also be considered when predicting the severity of the EBS disorder.

DNA Mutational Analysis↗

PubMed2000

A missense mutation in FIC1 is associated with greenland familial cholestasis.

Greenland familial cholestasis is a severe form of intrahepatic cholestasis described among indigenous Inuit families in Greenland. Patients present with jaundice, pruritus, bleeding episodes, and steatorrhea, and die in childhood due to end-stage liver disease. We investigated the possibility that Greenland familial cholestasis is caused by a mutation in FIC1, the gene defective in patients with progressive familial intrahepatic cholestasis type 1 and many cases of benign recurrent intrahepatic cholestasis. Using single-strand conformation polymorphism analysis and sequencing of the FIC1 exons, a missense mutation, 1660 G-->A (D554N), was detected and was shown to segregate with the disease in Inuit patients from Greenland and Canada. Examination of liver specimens from 3 Inuit patients homozygous for this mutation revealed bland canalicular cholestasis and, on transmission electron microscopy, coarsely granular Byler bile, as previously described in patients with progressive familial intrahepatic cholestasis type 1. These data establish Greenland familial cholestasis as a form of progressive familial intrahepatic cholestasis type 1 and further underscore the importance of unimpeded FIC1 activity for normal bile formation.

Adenosine Triphosphatases↗

PubMed2000

Missense mutations in the human insulin promoter factor-1 gene and their relation to maturity-onset diabetes of the young and late-onset type 2 diabetes mellitus in caucasians.

Increasing evidence suggests that defects in genes encoding transcription factors that are expressed in the pancreatic beta-cells may be important contributors to the genetic basis of type 2 diabetes mellitus. Maturity-onset diabetes of the young (MODY) now exists in five subtypes (MODY1-5), four of which are caused by mutations in transcription factors hepatocyte nuclear factor-4alpha (HNF-4alpha), HNF-1alpha, insulin promoter factor-1 (IPF-1), and HNF-1beta (MODY1, -3, -4, and -5). Recent evidence from the British population even suggested that IPF-1 may be a predisposing gene for type 2 diabetes. Thus, highlighting the potential role of this transcription factor in the genetic basis of Danish and Italian MODY as well as in Danish patients with late-onset type 2 diabetes mellitus, we have examined the human IPF-1 gene for mutations by single strand conformation polymorphism and heteroduplex analysis in 200 Danish patients with late-onset type 2 diabetes and in 44 Danish and Italian MODY patients. In the patients with late-onset type 2 diabetes we identified a noncoding G insertion/deletion polymorphism at nucleotide -108, a silent G54G, and a rare missense D76N variant. Moreover, a Danish MODY patient was carrier of an A140T variant. Neither the D76N nor the A140T segregated with diabetes, and their transcriptional activation of the human insulin promoter expressed in vitro was indistinguishable from that of the wild type (115 +/- 21% and 84 +/- 12% vs. 100%). We conclude that variants in IPF-1 are not a common cause of MODY or late-onset type 2 diabetes in the Caucasian population, and that in terms of insulin transcription both the N76 and the T140 mutations are likely to represent functionally normal IPF-1 variants with no direct role in the pathogenesis of MODY or late-onset type 2 diabetes mellitus.

3T3 Cells↗

PubMed2000

NeuroD/BETA2 gene variability and diabetes: no associations to late-onset type 2 diabetes but an A45 allele may represent a susceptibility marker for type 1 diabetes among Danes. Danish Study Group of Diabetes in Childhood, and the Danish IDDM Epidemiology and Genetics Group.

Mutations in the NeuroD/BETA2 gene have been shown to associate with type 2 diabetes. In the present study, we examined mutations in the NeuroD/BETA2 gene for association with either type 1 or 2 diabetes. Three variants were identified in patients with type 2 diabetes: Ala45Thr (allelic frequency 0.36, 95% CI 0.31-0.41), Pro197His (0.01), and Ser259Ser (0.01). Ala45Thr and Pro197His were not associated with type 2 diabetes, but the transmission disequilibrium test showed unequal transmission of the A45 allele to offspring with type 1 diabetes (chi2 = 5.90, P < 0.02, odds ratio 1.55, 95% CI 0.91-2.63). This association could not be explained by linkage disequilibrium between the Ala45 allele and IDDM7 (D2S152), which is also located on chromosome 2q32. When tested in vitro, the biological activity of Thr45 (117+/-36% vs. Ala45) and His197 (90+/-28% vs. Pro197) on the regulation of the human insulin gene promoter appeared normal. In conclusion, mutations in the NeuroD/BETA2 gene are not a common cause of late-onset type 2 diabetes among Danes. However, in the type 1 diabetic Danish population, the Ala45Thr variant of NeuroD/BETA2 may represent a susceptibility marker independent of IDDM7 on chromosome 2q32.

Age of Onset↗

PubMed2000

Linkage of Cholestasis Familiaris Groenlandica/Byler-like disease to chromosome 18.

In East Greenland (Tasiilaq) a common recessive disease, Cholestasis Familiaris Groenlandica (CFG)/Byler-like disease, occurs in Eskimo children. Samples from 123 persons, from a large consanguineous pedigree in East Greenland including 7 affected and 3 small families from West Greenland with a total of 4 affected children, have been collected for linkage and homozygosity studies. An earlier hint of linkage to chromosome 18q (lod score of 1.5 to blood group JK) is now raised to a multipoint lod score of Z = 3.25 in the area of the DNA markers D18S851 and D18S858. Different haplotypes follow the disease gene among Inuits in West Greenland and a possibility of locus heterogeneity of CFG between East and West Greenland exist.

Child↗