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Biomedical subjects

L Tranebjaerg

Publications and source records attributed to L Tranebjaerg.

At least 19 recordsLinked to original sources
PubMed2001

A common ancestral origin of the frequent and widespread 2299delG USH2A mutation.

Usher syndrome type IIa is an autosomal recessive disorder characterized by mild-to-severe hearing loss and progressive visual loss due to retinitis pigmentosa. The mutation that most commonly causes Usher syndrome type IIa is a 1-bp deletion, described as "2299delG," in the USH2A gene. The mutation has been identified in several patients from northern and southern Europe and from North America, and it has been found in single patients from South America, South Africa, and China. Various studies have reported a range of frequencies (.16-.44) among patients with Usher syndrome, depending on the geographic origin of the patients. The 2299delG mutation may be the one that most frequently causes retinitis pigmentosa in humans. Given the high frequencies and the wide geographic distribution of the mutation, it was of interest to determine whether the mutation resulted from an ancestral mutational event or represented a mutational hotspot in the USH2A gene. Haplotype analysis was performed on DNA samples from 116 unrelated patients with Usher syndrome type IIa; the patients were from 14 countries and represented 148 2299delG alleles. On the basis of six single-nucleotide polymorphisms within the USH2A gene, 12 core haplotypes were observed in a panel of normal chromosomes. However, in our analysis, only one core haplotype was found to be associated with the 2299delG mutation. The data indicate that the widespread geographic distribution of the 2299delG mutation is the result of an ancestral mutation that has spread throughout Europe and into the New World as a result of migration.

Alleles↗
PubMed2001

The molecular basis of X-linked spondyloepiphyseal dysplasia tarda.

The X-linked form of spondyloepiphyseal dysplasia tarda (SEDL), a radiologically distinct skeletal dysplasia affecting the vertebrae and epiphyses, is caused by mutations in the SEDL gene. To characterize the molecular basis for SEDL, we have identified the spectrum of SEDL mutations in 30 of 36 unrelated cases of X-linked SEDL ascertained from different ethnic populations. Twenty-one different disease-associated mutations now have been identified throughout the SEDL gene. These include nonsense mutations in exons 4 and 5, missense mutations in exons 4 and 6, small (2-7 bp) and large (>1 kb) deletions, insertions, and putative splicing errors, with one splicing error due to a complex deletion/insertion mutation. Eight different frameshift mutations lead to a premature termination of translation and account for >43% (13/30) of SEDL cases, with half of these (7/13) being due to dinucleotide deletions. Altogether, deletions account for 57% (17/30) of all known SEDL mutations. Four recurrent mutations (IVS3+5G-->A, 157-158delAT, 191-192delTG, and 271-275delCAAGA) account for 43% (13/30) of confirmed SEDL cases. The results of haplotype analyses and the diverse ethnic origins of patients support recurrent mutations. Two patients with large deletions of SEDL exons were found, one with childhood onset of painful complications, the other relatively free of additional symptoms. However, we could not establish a clear genotype/phenotype correlation and therefore conclude that the complete unaltered SEDL-gene product is essential for normal bone growth. Molecular diagnosis can now be offered for presymptomatic testing of this disorder. Appropriate lifestyle decisions and, eventually, perhaps, specific SEDL therapies may ameliorate the prognosis of premature osteoarthritis and the need for hip arthroplasty.

Base Sequence↗
PubMed2001

A spectrum of functional effects for disease causing mutations in the Jervell and Lange-Nielsen syndrome.

OBJECTIVE: Jervell and Lange-Nielsen syndrome (JLNS) is a recessively inherited long QT syndrome (LQTS) characterised by profound sensorineural deafness and predisposition to syncope and sudden cardiac death. Mutation analysis has established the presence of mutations in affected individuals in the genes KCNQ1 and KCNE1: the potassium channel complex responsible for the cardiac I(Ks) current involved in repolarisation of the ventricular action potential. Our objective was to determine the functional effects of disease causing mutations in JLNS. METHODS: In this study we have investigated the electrophysiological effects of eight distinct JLNS mutations after expression of cRNA in Xenopus laevis oocytes. RESULTS: KCNE1 mutant T59P/L60P showed no dominant negative effect and was a pure loss of function mutation. KCNQ1 mutant E261D showed a strong dominant-negative effect. KCNQ1 mutant R243H produced a moderate dominant-negative effect, right shifted the steady-state activation curve and led to an increased deactivation rate. The behaviour of KCNQ1 mutants 572-576del, 1008delC, R518X, Q530X, R594Q depended on the relative quantities of mutant and wild-type proteins (with a weak dominant-negative effect present at 1:3 but not 1:1 injection ratios). These data indicate the presence of an additional assembly domain before S2-S3 and the importance of the S4-S5 region in channel function and gating. CONCLUSIONS: Our data suggest a spectrum of behaviour for disease causing mutations from simple loss of function through to prominent dominant negative behaviour.

Animals↗
PubMed2001

Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world.

SBMA (spinal and bulbar muscular atrophy), also called Kennedy disease, is an X-chromosomal recessive adult-onset neurodegenerative disorder caused by death of the spinal and bulbar motor neurones and dorsal root ganglia. Patients may also show signs of partial androgen insensitivity. SBMA is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene on the X-chromosome. Our previous study suggested that all the Nordic patients with SBMA originated from an ancient Nordic founder mutation, but the new intragenic SNP marker ARd12 revealed that the Danish patients derive their disease chromosome from another ancestor. In search of relationships between patients from different countries, we haplotyped altogether 123 SBMA families from different parts of the world for two intragenic markers and 16 microsatellites spanning 25 cM around the AR gene. The fact that different SBMA founder haplotypes were found in patients from around the world implies that the CAG repeat expansion mutation has not been a unique event. No expansion-prone haplotype could be detected. Trinucleotide diseases often show correlation between the repeat length and the severity and earlier onset of the disease. The longer the repeat, the more severe the symptoms are and the onset of the disease is earlier. A negative correlation between the CAG repeat length and the age of onset was found in the 95 SBMA patients with defined ages at onset.

Exons↗
PubMed2001

Analysis of FMR1 (CGG)(n) alleles and DXS548-FRAXAC1 haplotypes in three European circumpolar populations: traces of genetic relationship with Asia.

Fragile X syndrome, the most common form of inherited mental retardation, is caused by expansion of a (CGG)(n) repeat located in the FMR1 gene. The molecular factors involved in the mutation process from stable (CGG)(n) alleles towards unstable alleles are largely unknown, although family transmission studies and population studies have suggested that loss of AGG interruptions in the (CGG)(n) repeat is essential. We have analysed the AGG interspersion pattern of the FMR1 (CGG)(n) repeat and the haplotype distribution of closely located microsatellite markers DXS548 and FRAXAC1, in three circumarctic populations: Norwegians, Nenets and Saami. The data confirm the conservation, reported in all human populations studied so far, of an AGG interruption for each 9-10 CGG and support the stabilising effect of AGG interruptions. The data also indicate the existence of chromosomes of Asian origin in the Saami and Nenets population, thereby confirming a genetic relationship between Northern Europe and Asia. DXS548-FRAXAC1 haplotype frequencies were compared between 24 Norwegian fragile X males and 119 normal males. Significant linkage disequilibrium were found between the fragile X mutation and haplotype 6-4 and between normal (CGG)(n) alleles and haplotype 7-3.

Alleles↗
PubMed2001

Screening for mutations and polymorphisms in the genes KCNH2 and KCNE2 encoding the cardiac HERG/MiRP1 ion channel: implications for acquired and congenital long Q-T syndrome.

BACKGROUND: The voltage-gated, rapid-delayed rectifier current (I(Kr)) is important for repolarization of the heart, and mutations in the genes coding for the K+-ion channel conducting this current, i.e., KCNH2 for the alpha-subunit HERG and KCNE2 for the beta-subunit MiRP1, cause acquired and congenital long Q-T syndrome (LQTS) and other cardiac arrhythmias. METHODS: We developed a robust single-strand conformation polymorphism-heteroduplex screening analysis, with identical thermocycling conditions for all PCR reactions, covering all of the coding exons in KCNH2 and KCNE2. The method was used to screen 40 unrelated LQTS patients. RESULTS: Eleven mutations, of which six were novel, were found in KCNH2. Interestingly, six mutations were found in the region of the gene coding for the Per-Arnt-Sim (PAS) and PAS-S1 regions of the HERG protein, stressing the need to examine the entire gene when screening for mutations. No mutations were found in KCNE2, suggesting that direct involvement of MiRP1 in LQTS is rare. Furthermore, four novel single-nucleotide polymorphisms (SNPs) and one amino acid polymorphism (R1047L) were identified in KCNH2, and one novel SNP and one previously known amino acid polymorphism (T8A) were found in KCNE2. CONCLUSIONS: The potential role of rare polymorphisms in the HERG/MiRP1 K+-channel should be clarified with respect to drug interactions and susceptibility to arrhythmia and sudden death.

Cation Transport Proteins↗
PubMed2000

Ancestral origins of the Machado-Joseph disease mutation: a worldwide haplotype study.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder originally described in families of Portuguese-Azorean ancestry. The cloning of the MJD1 gene allowed identification of the disease in many other populations, and MJD is now known to be the most common cause of dominant spinocerebellar ataxia. The hypothesis that its present world distribution could result from the spread of an original founder mutation has been raised, both at historical and molecular levels. In the present study, we tested this hypothesis by linkage-disequilibrium analysis of tightly linked polymorphisms and by haplotype comparison, in 249 families from different countries. We typed five microsatellite markers surrounding the MJD1 locus (D14S1015, D14S995, D14S973, D14S1016, and D14S977), and three intragenic single-base-pair polymorphisms (A(669)TG/G(669)TG, C(987)GG/G(987)GG, and TAA(1118)/TAC(1118)). The results show two different haplotypes, specific to the island of origin, in families of Azorean extraction. In families from mainland Portugal, both Azorean haplotypes can be found. The majority of the non-Portuguese families also share the same intragenic haplotype seen in the families coming from the island of Flores, but at least three other haplotypes were seen. These findings suggest two introductions of the mutation into the Portuguese population. Worldwide, the sharing of one intragenic haplotype by the majority of the families studied implies a founder mutation in MJD.

Alleles↗
PubMed2000

BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is a potentially lethal disorder, because the elevation of the pulmonary arterial pressure may result in right-heart failure. Histologically, the disorder is characterized by proliferation of pulmonary-artery smooth muscle and endothelial cells, by intimal hyperplasia, and by in situ thrombus formation. Heterozygous mutations within the bone morphogenetic protein type II receptor (BMPR-II) gene (BMPR2), of the transforming growth factor beta (TGF-beta) cell-signaling superfamily, have been identified in familial and sporadic cases of PPH. We report the molecular spectrum of BMPR2 mutations in 47 additional families with PPH and in three patients with sporadic PPH. Among the cohort of patients, we have identified 22 novel mutations, including 4 partial deletions, distributed throughout the BMPR2 gene. The majority (58%) of mutations are predicted to lead to a premature termination codon. We have also investigated the functional impact and genotype-phenotype relationships, to elucidate the mechanisms contributing to pathogenesis of this important vascular disease. In vitro expression analysis demonstrated loss of BMPR-II function for a number of the identified mutations. These data support the suggestion that haploinsufficiency represents the common molecular mechanism in PPH. Marked variability of the age at onset of disease was observed both within and between families. Taken together, these studies illustrate the considerable heterogeneity of BMPR2 mutations that cause PPH, and they strongly suggest that additional factors, genetic and/or environmental, may be required for the development of the clinical phenotype.

Adolescent↗
PubMed2000

Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III.

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Three subtypes have been described: TRPS I, caused by mutations in the TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses. To investigate whether TRPS III is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, we performed extensive mutation analysis and evaluated the height and degree of brachydactyly in patients with TRPS I or TRPS III. We found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicates that TRPS1 is the major locus for TRPS I and TRPS III. We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the five missense mutations alter the GATA DNA-binding zinc finger, and six of the seven unrelated patients with these mutations may be classified as having TRPS III. Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene.

Adolescent↗
PubMed2000

[Genetic causes of hearing loss--status and perspectives].

Hearing impairment, defined as > or = 40 dB hearing loss, is the most prevalent sensory handicap, present in 1:750 children and in 4-36% of adults, depending on age. Genetic factors are of major importance in more than 50% of all hearing loss. An important distinction is made between syndromic deafness and isolated deafness depending on the presence or not of associated manifestations from other organs. The knowledge about genetic deafness has increased dramatically in the last few years. As of March 1999, at least 53 loci for isolated deafness of different types of monogenic inheritance have been identified. Suspected genetic heterogeneity has thus been confirmed. At least 15 genes for syndromic deafness have been cloned, leading to increased biological insight in shared developmental pathways in different species and leading to better diagnostic tools applicable to patients. The identification of a particularly frequent mutation in a gap junction gene, GJB2 (connexin 26), may turn out to be of particular diagnostic importance in the aetiological evaluation of childhood deafness even in isolated cases. Application of early screening tests, like otoacoustic emission (OAE), in combination with genetic tests will facilitate early and specific diagnosis of hearing impairment and thereby improve audiological rehabilitation. Syndromic deafness involves all organs, and care for and evaluation of affected individuals should be a multiprofessional task.

Abnormalities, Multiple↗
PubMed2000

Immunodeficiency in alpha-mannosidosis: a matched case-control study on immunoglobulins, complement factors, receptor density, phagocytosis and intracellular killing in leucocytes.

UNLABELLED: Patients with the autosomal recessive lysosomal storage disease alpha-mannosidosis suffer from recurrent infections. To study the mechanisms of this immunodeficiency, six patients were matched against six healthy controls and their humoral and cellular immunocompetence investigated. No differences in the number of circulating leucocytes including B-cells, levels of immunoglobulin main classes, nor IgG subclasses were observed. However, post-immunisation serum levels of specific antibodies against poliovirus, diphtheria toxin and tetanus toxin were significantly reduced. In patients, the density of the complement-binding receptor CD11b and the Fc-receptor CD16 was significantly enhanced on monocytes and polymorphonuclear neutrophils (PMN) and the number of phagocytosing PMN was significantly increased in the presence of pooled human serum. This was not observed in the presence of autologous serum, indicating altered opsonic properties. Also in normal PMN, phagocytosis was inhibited by a factor in the serum from the patients. Despite maintained oxidative burst, patient PMN demonstrated insufficient intracellular bacterial killing. CONCLUSION: Our data indicate that patients with alpha-mannosidosis have an immunodeficiency at both the humoral and cellular level.

Adolescent↗
PubMed2000

Mutational spectrum in the cardioauditory syndrome of Jervell and Lange-Nielsen.

Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive syndrome characterised by profound congenital sensorineural deafness and prolongation of the QT interval on the electrocardiogram, representing abnormal ventricular repolarisation. In a study of ten British and Norwegian families with JLNS, we have identified all of the mutations in the KCNQ1 gene, including two that are novel. Of the nine mutations identified in this group of 10 families, five are nonsense or frameshift mutations. Truncation of the protein proximal to the recently identified C-terminal assembly domain is expected to preclude assembly of KCNQ1 monomers into tetramers and explains the recessive inheritance of JLNS. However, study of a frameshift mutation, with a dominant effect phenotypically, suggests the presence of another assembly domain nearer to the N-terminus.

Amino Acid Substitution↗
PubMed2000

A de novo missense mutation in a critical domain of the X-linked DDP gene causes the typical deafness-dystonia-optic atrophy syndrome.

We report the first de novo mutation in the DDP gene in a Dutch 11-year-old boy with deafness and dystonia. Previously reported mutations in the DDP gene have all been frameshifts/nonsense mutations or deletion of the entire gene as part of a larger deletion encompassing the BTK gene. The clinical presentation was uniformly characterised by sensorineural hearing loss, dystonia, mental deterioration, paranoid psychotic features, and optic atrophy, indicating progressive neurodegeneration. Our report illustrates that de novo mutations occur and that a missense mutation, C66W, may cause an equally severe clinical picture. The diagnosis of sensorineural hearing impairment associated with neurologic and visual disability in a male, therefore, should encourage the search for mutations in the DDP gene, even in sporadic cases. The association of deafness-dystonia syndrome with a missense mutation provides valuable information for in vitro investigations of the functional properties of the deafness-dystonia peptide which was recently shown to be the human homolog of a yeast protein, Tim8p, belonging to a family of small Tim proteins involved in intermembrane protein transport in mitochondria.

Adult↗
PubMed2000

Identification of novel USH2A mutations: implications for the structure of USH2A protein.

Usher syndrome type II is an autosomal recessive disorder, characterised by stable hearing impairment from childhood and progressive retinitis pigmentosa from the late teens. Mutations in the USH2A gene, located on 1q41, were recently shown to be responsible for Usher syndrome type IIa. We have investigated the molecular pathology of Usher type II by screening the USH2A gene for mutations in 31 unrelated patients from Denmark and Norway. Besides the frequent 2299delG mutation, which accounted for 44% of the disease alleles, a heterogeneous spectrum of mutations was identified. Sixteen new, putative disease-causing mutations were detected, of which 12 were private and four were shared by unrelated patients. The disease-causing mutations were scattered throughout the gene and included six nonsense and seven missense mutations, two deletions and one small insertion. In addition, six non-pathogenic polymorphisms were identified. All missense mutations resulted in major amino acid side-chain alterations. Four missense mutations affected the N-terminal part of USH2A, whereas three missense mutations affected the laminin-type epidermal growth factor-like (LE) domain. The structural consequences of the mutations affecting the LE domain are discussed in relation to the three-dimensional structure of a LE-module of the mouse laminin gamma1 chain.

Adolescent↗