Biomedical subjects

Peter Nürnberg

Publications and source records attributed to Peter Nürnberg.

At least 73 records · Page 4Linked to original sources

PubMed2003

Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.

Brachydactyly (BD) type A2 is an autosomal dominant hand malformation characterized by shortening and lateral deviation of the index fingers and, to a variable degree, shortening and deviation of the first and second toes. We performed linkage analysis in two unrelated German families and mapped a locus for BD type A2 to 4q21-q25. This interval includes the gene bone morphogenetic protein receptor 1B (BMPR1B), a type I transmembrane serinethreonine kinase. In one family, we identified a T599 --> A mutation changing an isoleucine into a lysine residue (I200K) within the glycine/serine (GS) domain of BMPR1B, a region involved in phosphorylation of the receptor. In the other family we identified a C1456 --> T mutation leading to an arginine-to-tryptophan amino acid change (R486W) in a highly conserved region C-terminal of the BMPR1B kinase domain. An in vitro kinase assay showed that the I200K mutation is kinase-deficient, whereas the R486W mutation has normal kinase activity, indicating a different pathogenic mechanism. Functional analyses with a micromass culture system revealed a strong inhibition of chondrogenesis by both mutant receptors. Overexpression of mutant chBmpR1b in vivo in chick embryos by using a retroviral system resulted either in a BD phenotype with shortening and/or missing phalanges similar to the human phenotype or in severe hypoplasia of the entire limb. These findings imply that both mutations identified in human BMPR1B affect cartilage formation in a dominant-negative manner.

Amino Acid Sequence↗

PubMed2003

Distinct methylation profiles of glioma subtypes.

Gliomas are tumors of the central nervous system with a wide spectrum of different tumor types. They range from pilocytic astrocytoma, with a generally good prognosis, to the extremely aggressive malignant glioblastoma. In addition to these 2 types of contrasting neoplasms, several other subtypes can be distinguished, each characterized by specific phenotypic, as well as genotypic features. Recently, the epigenotype, as evident from differentially methylated DNA loci, has been proposed to be useful as a further criterion to distinguish between tumor types. In our study, we screened 139 tissue samples, including 33 pilocytic astrocytomas, 46 astrocytomas of different grades, 7 oligoastrocytomas, 10 oligodendrogliomas, 10 glioblastoma multiforme samples and 33 control tissues, for methylation at CpG islands of 15 different gene loci. We used the semiquantitative high throughput method MethyLight to analyze a gene panel comprising ARF, CDKN2B, RB1, APC, CDH1, ESR1, GSTP1, TGFBR2, THBS1, TIMP3, PTGS2, CTNNB1, CALCA, MYOD1 and HIC1. Seven of these loci showed tumor specific methylation changes. We found tissue as well as grade specific methylation profiles. Interestingly, pilocytic astrocytomas showed no evidence of CpG island hypermethylation, but were significantly hypomethylated, relative to control tissues, at MYOD1. Our results show that glioma subtypes have characteristic methylation profiles and, with the exception of pilocytic astrocytomas, show both locus specific hyper- as well as hypomethylation.

Adolescent↗

PubMed2003

A longitudinal study of age-specific reproductive output and body condition among male rhesus macaques, Macaca mulatta.

In many mammalian species, male reproductive success appears to climb sharply at young adulthood, form a brief plateau during prime ages, and decline among older animals, a pattern often attributed to reduced physical condition with ageing. However, solid evidence to either substantiate or refute this profile among nonhuman primates is lacking. Here, we combine a decade of genetic analysis of paternity among free-ranging rhesus macaques, Macaca mulatta, with information about body condition in order to evaluate how changes in morphology might govern age-specific reproduction among males. We show that age-specific reproductive success traverses the same life history profile as found in other mammals, but reductions in reproductive output with advanced age were associated with reduced chances of survivorship rather than accompanied by diminished body condition. We demonstrate that variance in male age at onset of reproduction is three times greater than variance in female age at onset of reproduction. We provide the first evidence from primates that age-specific reproductive output among males is not a consequence of age-related changes in body condition, but reflects social and demographic factors.

Aging↗

PubMed2003

Genome-wide linkage reveals a locus for human essential (primary) hypertension on chromosome 12p.

Essential (primary) hypertension is an important risk factor for cardiovascular morbidity and mortality. Blood pressure is largely heritable; however, the genetic factors contributing to essential hypertension are mostly unknown. We examined a large Chinese kindred (n=387) and selected a subset of 94 individuals for genotyping. An additional 32 Chinese nuclear families with essential hypertension were also recruited. Genome-wide parametric linkage analysis identified a new locus for primary hypertension on chromosome 12p (parametric LOD score 3.44). This locus overlaps with the assigned locus that causes severe autosomal-dominant hypertension and brachydactyly, the only form of monogenic hypertension known to date that resembles primary hypertension. We suggest that this genomic region, spanning 18 annotated genes, will be of great relevance in elucidating new mechanisms for primary hypertension.

Adult↗

PubMed2003

Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy.

BACKGROUND: Muscle LIM protein (MLP) is an essential nuclear regulator of myogenic differentiation. Additionally, it may act as an integrator of protein assembly of the actin-based cytoskeleton. MLP-knockout mice develop a marked cardiac hypertrophy reaction and dilated cardiomyopathy (DCM). MLP is therefore a candidate gene for heritable forms of hypertrophic cardiomyopathy (HCM) and DCM in humans. METHODS AND RESULTS: We analyzed 1100 unrelated individuals (400 patients with DCM, 200 patients with HCM, and 500 controls) for mutations in the human CRP3 gene that encodes MLP. We found 3 different missense mutations in 3 unrelated patients with familial HCM but detected no mutation in the DCM group or the controls. All mutations predicted an amino acid exchange at highly conserved residues in the functionally important LIM1 domain, which is responsible for interaction with alpha-actinin and with certain muscle-specific transcription factors. Protein-binding studies indicate that mutations in the CRP3 gene lead to a decreased binding activity of MLP to alpha-actinin. All 3 index patients were characterized by typical asymmetrical septal hypertrophy. Family studies revealed cosegregation of clinically affected individuals with the respective mutations in MLP. CONCLUSION: Here, we present evidence that mutations in the CRP3/MLP gene can cause HCM.

Actinin↗

PubMed2003

Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification.

Idiopathic infantile arterial calcification (IIAC; OMIM 208000) is characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. We analyzed affected individuals from 11 unrelated kindreds and found that IIAC was associated with mutations that inactivated ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). This cell surface enzyme generates inorganic pyrophosphate (PP(i)), a solute that regulates cell differentiation and serves as an essential physiologic inhibitor of calcification.

Arteries↗

PubMed2003

Exploration of a putative susceptibility locus for idiopathic generalized epilepsy on chromosome 8p12.

PURPOSE: A recent genome-wide scan revealed a major susceptibility locus for idiopathic generalized epilepsies (IGEs) in the chromosomal region 8p12 in 32 IGE families without members with juvenile myoclonic epilepsy (JME). This study explored the presence of an IGE locus in the chromosomal region 8p12. METHODS: Our study included 176 multiplex families of probands with common IGE syndromes. Parametric and nonparametric multipoint linkage analyses were carried out between the IGE trait and six microsatellite polymorphisms encompassing the putative susceptibility locus. To explore the associated phenotype-genotype relation, two distinct subgroups of families were selected by the presence (n = 64) or absence (n = 112) of a family member with JME. To adjust the phenotypic spectrum toward adolescent-onset IGEs, a third subgroup of 28 families without JME was chosen through an IGE proband with seizure onset at age 10-20 years. RESULTS: Parametric and nonparametric multipoint linkage analyses provided no evidence for linkage between IGE and markers encompassing the putative IGE locus in the chromosomal region 8p12. Furthermore, we found no hint of linkage along the candidate region in any of the three family subgroups. CONCLUSIONS: We failed to provide evidence for a major IGE locus in the chromosomal region 8p12. On the contrary, these parametric linkage results provide strong evidence against linkage across the candidate region under a broad range of genetic models. If there is a susceptibility locus for IGE in the chromosomal region 8p12, then the size of the effect or the proportion of linked families is too small to detect linkage in the investigated family sample.

Adult↗

PubMed2003

Genome scan for childhood and adolescent obesity in German families.

OBJECTIVE: Several genome scans have been performed for adult obesity. Because single formal genetic studies suggest a higher heritability of body weight in adolescence and because genes that influence body weight in adulthood might not be the same as those that are relevant in childhood and adolescence, we performed a whole genome scan. METHODS: The genome scan was based on 89 families with 2 or more obese children (sample 1). The mean age of the index patients was 13.63 +/- 2.75 years. A total of 369 individuals were initially genotyped for 437 microsatellite markers. A second sample of 76 families was genotyped using microsatellite markers that localize to regions for which maximum likelihood binomial logarithm of the odd (MLB LOD) scores on use of the concordant sibling pair approach exceeded 0.7 in sample 1. RESULTS: The regions with MLB LOD scores >0.7 were on chromosomes 1p32.3-p33, 2q37.1-q37.3, 4q21, 8p22, 9p21.3, 10p11.23, 11q11-q13.1, 14q24-ter, and 19p13-q12 in sample 1; MLB LOD scores on chromosomes 8p and 19q exceeded 1.5. In sample 2, MLB LOD scores of 0.68 and 0.71 were observed for chromosomes 10p11.23 and 11q13, respectively. CONCLUSION: We consider that several of the peaks identified in other scans also gave a signal in this scan as promising for ongoing pursuits to identify relevant genes. The genetic basis of childhood and adolescent obesity might not differ that much from adult obesity.

Adolescent↗

PubMed2002

Mal de Meleda (MDM) caused by mutations in the gene for SLURP-1 in patients from Germany, Turkey, Palestine, and the United Arab Emirates.

Mal de Meleda (MDM) or keratosis palmoplantaris transgrediens of Siemens is an autosomal recessive skin disorder characterized by diffuse palmoplantar keratoderma (PPK) and transgressive keratosis with an onset in early infancy. There is no associated involvement of other organs; however, a spectrum of clinical presentations with optional and variable features has been described. Mutations in the ARS (component B)-81/s gene ( LY6LS) on chromosome 8q24-qter, which encodes SLURP-1, have recently been identified in patients with MDM. Here, we have analyzed four MDM families for mutations in SLURP-1. In a large Palestinian pedigree with multiple consanguinity, patients are homozygous for a new mutation that substitutes an arginine for a conserved glycine residue at position 86. A different mutation in Turkish patients results in the same amino acid exchange. Some remarkable similarities are seen in the clinical picture of patients from both families. Patients of an Emirati Bedouin family have a homozygous alteration of the translation initiation codon. In a German family with no known consanguinity, we have shown pseudodominant inheritance. Three affected children and their affected mother are homozygous for the missense mutation W15R. Our findings indicate that the MDM type of transgressive PPK is caused by SLURP-1 mutations in patients from various origins and demonstrate allelic heterogeneity for mutations in SLURP-1.

Adult↗

PubMed2002

A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution.

Nephronophthisis (NPHP) comprises a group of autosomal recessive cystic kidney diseases, which constitute the most frequent genetic cause for end-stage renal failure in children and young adults. The most prominent histologic feature of NPHP consists of development of renal fibrosis, which, in chronic renal failure of any origin, represents the pathogenic event correlated most strongly to loss of renal function. Four gene loci for NPHP have been mapped to chromosomes 2q13 (NPHP1), 9q22 (NPHP2), 3q22 (NPHP3), and 1p36 (NPHP4). At all four loci, linkage has also been demonstrated in families with the association of NPHP and retinitis pigmentosa, known as "Senior-Løken syndrome" (SLS). Identification of the gene for NPHP type 1 had revealed nephrocystin as a novel docking protein, providing new insights into mechanisms of cell-cell and cell-matrix signaling. We here report identification of the gene (NPHP4) causing NPHP type 4, by use of high-resolution haplotype analysis and by demonstration of nine likely loss-of-function mutations in six affected families. NPHP4 encodes a novel protein, nephroretinin, that is conserved in evolution--for example, in the nematode Caenorhabditis elegans. In addition, we demonstrate two loss-of-function mutations of NPHP4 in patients from two families with SLS. Thus, we have identified a novel gene with critical roles in renal tissue architecture and ophthalmic function.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Mutations in the WFS1 gene that cause low-frequency sensorineural hearing loss are small non-inactivating mutations.

Hereditary hearing impairment is an extremely heterogeneous trait, with more than 70 identified loci. Only two of these loci are associated with an auditory phenotype that predominantly affects the low frequencies (DFNA1 and DFNA6/14). In this study, we have completed mutation screening of the WFS1 gene in eight autosomal dominant families and twelve sporadic cases in which affected persons have low-frequency sensorineural hearing impairment (LFSNHI). Mutations in this gene are known to be responsible for Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), which is an autosomal recessive trait. We have identified seven missense mutations and a single amino acid deletion affecting conserved amino acids in six families and one sporadic case, indicating that mutations in WFS1 are a major cause of inherited but not sporadic low-frequency hearing impairment. Among the ten WFS1 mutations reported in LFSNHI, none is expected to lead to premature protein truncation, and nine cluster in the C-terminal protein domain. In contrast, 64% of the Wolfram syndrome mutations are inactivating. Our results indicate that only non-inactivating mutations in WFS1 are responsible for non-syndromic low-frequency hearing impairment.

Audiometry↗

PubMed2002

Mapping of gene loci for nephronophthisis type 4 and Senior-Løken syndrome, to chromosome 1p36.

For nephronophthisis (NPHP), the primary genetic cause of chronic renal failure in young adults, three loci have been mapped. To identify a new locus for NPHP, we here report on total-genome linkage analysis in seven families with NPHP, in whom we had excluded linkage to all three known NPHP loci. LOD scores >1 were obtained at nine loci, which were then fine mapped at 1-cM intervals. Extensive total-genome haplotype analysis revealed homozygosity in one family, in the region of the PCLN1 gene. Subsequent mutational analysis in this gene revealed PCLN1 mutations, thereby allowing exclusion of this family as a phenocopy. Multipoint linkage analysis for the remaining six families with NPHP together yielded a maximum LOD score (Z(max)) of 8.9 (at D1S253). We thus identified a new locus, NPHP4, for nephronophthisis. Markers D1S2660 and D1S2642 are flanking NPHP4 at a 2.9-cM critical interval. In one family with NPHP4, extensive genealogical studies were conducted, revealing consanguinity during the 17th century. On the basis of haplotype sharing by descent, we obtained a multipoint Z(max) of 5.8 for D1S253 in this kindred alone. In addition, we were able to localize to the NPHP4 locus a new locus for Senior-Løken syndrome, an NPHP variant associated with retinitis pigmentosa.

Chromosome Mapping↗

PubMed2002

A comprehensive linkage analysis for myocardial infarction and its related risk factors.

Coronary artery disease and myocardial infarction (MI) are leading causes of death in the western world. Numerous studies have shown that risk factors such as diabetes mellitus, arterial hypertension and hypercholesterolemia contribute to the development of the disease. Although each risk factor by itself is partly under genetic control, a positive family history is an independent predictor, which suggests that there are additional susceptibility genes. We have scanned the whole genome in 513 families to identify chromosomal regions linked to myocardial infarction and related risk factors that are known to be under genetic control. Here we show, by using variance component analysis and incorporating risk factors, that risk of myocardial infarction maps to a single region on chromosome 14 with a significant lod score of 3.9 (pointwise P=0.00015, genome-wide P<0.05), providing evidence of a principal MI locus. To characterize this locus we analyzed each risk factor by itself. Serum concentrations of lipoprotein (a) show linkage to both the apolipoprotein (a) locus (lod score 26.99) and a new locus on chromosome 1 (lod score 3.8). There is suggestive linkage for diabetes mellitus on chromosome 6 (lod score 2.96), for hypertension on chromosomes 1 and 6, for high-density and low-density lipoprotein cholesterol on chromosomes 1 and 17, and for triglyceride concentrations on chromosome 9. Although some of these risk factors overlap with previously identified loci, none overlaps with the newly identified susceptibility locus for myocardial infarction and coronary artery disease.

Aged↗

PubMed2002

Multiple sirehood in free-ranging twin rhesus macaques (Macaca mulatta).

Rhesus macaque females regularly copulate with a number of partners, and produce a single offspring per reproductive cycle in over 99% of cases. We used genotyping of 10 STR markers to determine paternity in the Cayo Santiago population of rhesus macaques. About 1,500 monkeys have been analyzed to date, with their marker genotypes entered into a computerized database. These data enable us to report the first documented case in any cercopithecine nonhuman primate species of the production of twin offspring sired by different males.

Animals↗

PubMed2002

Evaluation of a potential epigenetic biomarker by quantitative methyl-single nucleotide polymorphism analysis.

Tumorigenesis is characterized by alterations of methylation profiles including loss and gain of 5-methylcytosine. Recently, we identified a single CpG, which seemed to be consistently hypomethylated in pilocytic astrocytomas but not in other gliomas. To evaluate its applicability as a biomarker, we examined its methylation status in a large panel of gliomas (n = 97). Methylation-dependent DNA sequence variation may be considered a kind of single nucleotide polymorphism (methylSNP). MethylSNPs can be easily converted into common SNPs of the C/T type by sodium bisulfite treatment of the DNA and afterwards subjected to conventional SNP typing. We adapted SnaPshot trade mark and Pyrosequencing trade mark to determine the methylation of our test CpG in a quantitative manner. The adapted methods, called SNaPmeth and PyroMeth, respectively, gave nearly identical results, however data obtained with PyroMeth showed less scattering. Furthermore, the integrated software for allele frequency determination from Pyrosequencing could be used directly for data analysis while SnaPmeth data had to be exported and processed manually. Although data did not confirm our previous result of a preferential hypomethylation of the tested CpG in pilocytic astrocytomas, we consider quantitative methylSNP analysis by SNaPmeth or PyroMeth a favorable alternative to existing high-throughput methylation assays. It combines single CpG analysis with accurate quantitation and is amenable to high throughput.

Adolescent↗

PubMed2002

Failure to replicate an allelic association between an exon 8 polymorphism of the human alpha(1A) calcium channel gene and common syndromes of idiopathic generalized epilepsy.

The present replication study tested the validity of a previously reported allelic association between a single nucleotide polymorphism in exon 8 (SNP8) of the gene encoding the alpha(1A)-calcium channel subunit (CACNA1A) and common subtypes of idiopathic generalized epilepsy (IGE). Pyrosequencing was applied to assess the SNP8 genotypes in 354 unrelated German IGE probands, both parents of 118 IGE probands, and 186 healthy control subjects of German descent. Our population-based association analysis did not provide evidence for an allelic association of SNP8 with either IGE or two phenotypically more homogeneous IGE subtypes, consisting of either 139 probands with juvenile myoclonic epilepsy or 207 probands whose IGE started with typical absence seizures (P>0.72). In addition, the transmission disequilibrium test did not indicate a preferential transmission of SNP8 alleles in 97 informative parent-child transmissions (McNemar chi(2)=0.093, df=1, P=0.76). Accordingly, we failed to confirm previous evidence that genetic variation of the CACNA1A gene confers susceptibility to common IGE syndromes.

Alleles↗

PubMed2002

Association of the 867Asp variant of the human anion exchanger 3 gene with common subtypes of idiopathic generalized epilepsy.

Genetic factors play a major role in the etiology of idiopathic generalized epilepsies (IGE). Our recent genome-wide search revealed suggestive evidence for a susceptibility locus for common IGE syndromes in the chromosomal region 2q36. The gene encoding the anion exchanger isoform 3 (AE3; gene symbol: SLC4A3) has been mapped to this candidate region. AE3 is prominently expressed in the brain and performs an electroneutral exchange of chloride and bicarbonate. To study the potential role of AE3 in the epileptogenesis of IGE, we performed a mutation analysis of the AE3 coding region, including the adjacent exon/intron boundaries, and the 5'-untranslated region in 16 IGE probands of families linked to chromosome 2q36 (cumulative two-point lod score: Z=5.32 at D2S371). Three exonic sequence variants were found: exon 17: 2600C/A, Ala867Asp; exon 21: 3391C/T, Leu1131Leu; exon 23: 3771G/A, 3'-UTR. Our subsequent population-based association study of the Ala867Asp substitution polymorphism revealed a significant increase of the 867Asp variant in 366 unrelated German IGE patients compared with 183 German control subjects (chi(2)=5.37, df=1, P=0.021). Consistently, the transmission disequilibrium test (TDT) of 121 parent-child trios showed a significant preferential transmission of the 867Asp allele (McNemar chi(2)=5.81, df=1, P=0.016). Our results support the hypothesis that variation of the AE3 gene confers a common but small susceptibility effect to the etiology of a broad spectrum of IGE syndromes.

Alleles↗

PubMed2002

A 4-bp insertion in the eya-homologous region (eyaHR) of EYA4 causes hearing impairment in a Hungarian family linked to DFNA10.

BACKGROUND: Hereditary hearing impairment (HHI) is a heterogeneous class of disorders that shows various patterns of inheritance and involves a multitude of different genes. Mutations in the EYA4 gene are responsible for postlingual, progressive, autosomal dominant hearing loss at the DFNA10 locus. EYA4 is orthologous to the Drosophila gene eya ("eyes absent"), a key regulator of eye formation. EYA4 plays an important role in several developmental processes. MATERIAL AND METHODS: Here we report a Hungarian family displaying sensorineural, progressive hearing impairment. The family comprising four generations with 11 affected and 8 unaffected members was subjected to genome-wide linkage analysis and candidate gene sequencing. RESULTS: By linkage analysis, the chromosomal region 6q22.3 was shown to segregate with the disease. Mutation analysis of the EYA4 gene, which maps to 6q22.3, revealed an insertion of 4 bp (1558insTTTG) in all affected family members. This insertion creates a frameshift and results in a stop codon at position 379. Hence, nearly the complete "eya homologous region" (eyaHR), which is essential for the protein function, would be deleted in the mutant EYA4 protein if the transcription were found to be stable. CONCLUSIONS: This family is the third one linked to DFNA10 and revealing a mutation in the EYA4 gene. In all three families, the mutations are localized in different regions of the eyaHR, suggesting that this protein contains several functional subregions with different tissue-specific importance.

Base Sequence↗