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G Auburger

Publications and source records attributed to G Auburger.

At least 37 records · Page 2Linked to original sources
PubMed2000

OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.

Autosomal dominant optic atrophy (ADOA) is the most prevalent hereditary optic neuropathy resulting in progressive loss of visual acuity, centrocoecal scotoma and bilateral temporal atrophy of the optic nerve with an onset within the first two decades of life. The predominant locus for this disorder (OPA1; MIM 165500) has been mapped to a 1.4-cM interval on chromosome 3q28-q29 flanked by markers D3S3669 and D3S3562 (ref. 3). We established a PAC contig covering the entire OPA1 candidate region of approximately 1 Mb and a sequence skimming approach allowed us to identify a gene encoding a polypeptide of 960 amino acids with homology to dynamin-related GTPases. The gene comprises 28 coding exons and spans more than 40 kb of genomic sequence. Upon sequence analysis, we identified mutations in seven independent families with ADOA. The mutations include missense and nonsense alterations, deletions and insertions, which all segregate with the disease in these families. Because most mutations probably represent null alleles, dominant inheritance of the disease may result from haploinsufficiency of OPA1. OPA1 is widely expressed and is most abundant in the retina. The presence of consensus signal peptide sequences suggests that the product of the gene OPA1 is targeted to mitochondria and may exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity.

Amino Acid Sequence↗
PubMed1999

Identification of the physiological promoter for spinocerebellar ataxia 2 gene reveals a CpG island for promoter activity situated into the exon 1 of this gene and provides data about the origin of the nonmethylated state of these types of islands.

In order to further use the spinocerebellar ataxia 2 (SCA2) promoter for transgenic mice models of "CAG repeat" neurodegeneration, different fragments of this 5' end were ligated into pGL3-Luc plasmid to obtain the better promoter-activity of the physiological promoter for SCA2. Base-par composition of the SCA2-5' region, and promoter prediction algorithms such as TSSW and TSSG, together with the high firefly luciferase expression after 48 hours of transient transfection in mammalian cells lines, showed a typical CpG island for promoter-activity. The promoter activity was specifically localized into the exon 1 of the SCA2 gene. The higher expression of firefly luciferase in the embryonal F9 cells by the use of SCA2 promoter, rather than by the use of CMV promoter may be related with the origin of the nonmethylated CpG island during the early embryogenesis. Analysis of the 5' region from HD gene revealed to a CpG island, which could be containing the physiological promoter for this gene.

Algorithms↗
PubMed1999

Spinocerebellar ataxia 2 (SCA2): morphometric analyses in 11 autopsies.

Eleven autopsies of patients from the large founder-population with dominantly inherited spinocerebellar ataxia 2 (SCA2) in Holguín, Cuba, were analyzed by the same observers, including quantitative microscopic evaluation. As expected in this disease with highly unstable polyglutamine expansions, considerable variability was observed, which correlated to age at onset and to progression of clinical symptoms. The degeneration of the olivopontocerebellar regions as in classical olivopontocerebellar atrophy occurred early and severely in SCA2. The neuropathological progression soon included neuronal loss in the substantia nigra, striatum, pallidum and later even the neocortex, while the dentate nucleus was consistently spared. This widespread degeneration pattern goes clearly beyond purely cerebellar degenerations such as SCA5 and 6 and beyond spinocerebellar degenerations such as SCA1, 3, 7, also involves regions known to degenerate in Huntington's disease, and is quite similar to the degeneration pattern in sporadic patients with multi-system atrophy.

Adult↗
PubMed1999

Phenotypic variability of the DYT1 mutation in German dystonia patients.

Primary dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained involuntary muscle contractions causing repetitive movements and/or abnormal postures. Recently, the gene locus (DYT1) and mutation responsible for a substantial number of cases suffering from early-onset primary dystonia was described. Here we report 2 German families and 1 sporadic patient with early-onset dystonia due to the DYT1 mutation in order to illustrate the variability of clinical manifestation within this molecularly defined entity. We demonstrate that writer's cramp or focal cervical dystonia is a clinical presentation of DYT1 as well as generalized dystonia.

Adolescent↗
PubMed1999

Primary torsion dystonia: the search for genes is not over.

A GAG deletion in the DYT1 gene accounts for most early, limb onset primary torsion dystonia (PTD). The genetic bases for the more common adult onset and focal PTD are less well delineated. Genetic loci for an "intermediate dystonia" phenotype and for torticollis, named DYT6 and DYT7 respectively, have recently been mapped in single families. To evaluate the contribution of these genetic loci to other families with familial "non-DYT1" dystonia five large families with dystonia were studied using genetic markers spanning the DYT6 and DYT7 regions. There was no evidence of linkage to either locus in any family. These findings illustrate the genetic heterogeneity of the dystonias and indicate the existence of one or more as yet unmapped genes for dystonia. Large collaborative efforts will be required to identify these, and additional genes, causing PTD.

Adolescent↗
PubMed1998

Defects of mitochondrial respiratory chain in multiple symmetric lipomatosis.

Using lymphocytes from nine unrelated patients with multiple symmetric lipomatosis we investigated a possible defect in the mitochondrial respiratory chain as the biochemical cause for the disease. A significant decrease in oxygen consumption of intact lymphocytes as well as a decreased activity of the individual components of the respiratory chain were detected. These findings are consistent with the recently described deletions and point mutations of mitochondrial DNA in patients suffering from this disease.

Adult↗
PubMed1998

Quality assessment of whole genome mapping data in the refined familial spastic paraplegia interval on chromosome 14q.

Autosomal dominant familial spastic paraplegia (AD-FSP) is a genetically heterogeneous neurodegenerative disorder characterized by progressive spasticity of the lower limbs. Three loci on chromosome 14q (SPG3), 2p (SPG4), and 15q (SPG6) were shown to be responsible for AD-FSP. Analysis of recombination events in three SPG3-linked families allowed us to narrow the critical interval from 9 to 5 cM. An approximately 5-Mb YAC contig comprising 32 clones and 90 STSs was built from D14S301 to D14S991, encompassing this region of 14q21. Fifty-six ESTs assigned previously to this region with radiation hybrid (RH) panels Genebridge 4 and G3 were precisely localized on the YAC contig. The 90 STSs positioned on the contig were tested on the TNG RH panel to compare our YAC-based map with an RH map at a high level of resolution. Comparison between our map and the whole genome mapping data on this interval of chromosome 14q is discussed.

Chromosome Mapping↗
PubMed1998

An isoform of ataxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients.

Autosomal dominant spinocerebellar ataxias (SCA) form a group of clinically and genetically heterogeneous neurodegenerative disorders. The defect responsible for SCA3/Machado-Joseph disease (MJD) has been identified as an unstable and expanded (CAG)n trinucleotide repeat in the coding region of a novel gene of unknown function. The MJD1 gene product, ataxin-3, exists in several isoforms. We generated polyclonal antisera against an alternate carboxy terminus of ataxin-3. This isoform, ataxin-3c, is expressed as a protein of approximately 42 kDa in normal individuals but is significantly enlarged in affected patients confirming that the CAG repeat is part of the ataxin-3c isoform and is translated into a polyglutamine stretch, a feature common to all known CAG repeat disorders. Ataxin-3 like immunoreactivity was observed in all human brain regions and peripheral organs studied. In neuronal cells of control individuals, ataxin-3c was expressed cytoplasmatically and had a somatodendritic and axonal distribution. In SCA3 patients, however, C-terminal ataxin-3c antibodies as well as anti-ataxin-3 monoclonal antibodies (1 H9) and anti-ubiquitin antibodies detected intranuclear inclusions (NIs) in neuronal cells of affected brain regions. A monoclonal antibody, 2B6, directed against an internal part of the protein, barely detected these NIs implying proteolytic cleavage of ataxin-3 prior to its transport into the nucleus. These findings provide evidence that the alternate isoform of ataxin-3 is involved in the pathogenesis of SCA3/MJD. Intranuclear protein aggregates appear as a common feature of neurodegenerative polyglutamine disorders.

Amino Acid Sequence↗
PubMed1998

New genetic concepts and stroke prevention.

So far, stroke genetics has the reputation of daunting complexity and heterogeneity. However, progress through efforts at studying the human genome has provided novel technologies and focus, and 12 stroke genes or loci have already been identified in the last years, usually through the study of large pedigrees. However, particularly little is known about the ischemic form of stroke, and only recently could one chromosomal locus be shown to exert a major effect on stroke latency and outcome - through QTL studies in mouse strains. Whether the outstanding role of this one gene locus is also true in humans should be tested in linkage analyses of large pedigrees. The characterization of such families will probably be essential for progress in molecular genetics of ischemic stroke as well as being a challenge for clinical stroke centers.

Animals↗
PubMed1997

Evidence for DYT7 being a common cause of cervical dystonia (torticollis) in Central Europe.

Adult-onset focal idiopathic torsion dystonias (AFITD), such as torticollis, have a prevalence similar to that of multiple sclerosis and usually seem sporadic. Only recently has one large AFITD pedigree "K" with autosomal dominant inheritance and reduced penetrance from Northwest Germany provided the opportunity to identify a gene locus on chromosome 18p. We have now tested the relevance of this DYT7 gene locus in a collective of 18 nuclear AFITD families from Central Europe who were genotyped with chromosome 18p microsatellites. In three families, the affected relatives did not share a chromosome 18p haplotype, suggesting locus heterogeneity in AFITD. In the remaining 15 families, significant allelic association was observed for marker D18S1098. This result suggests that DYT7 is a common cause for AFITD at least in Central Europe, that many patients are descended from a common ancestor, and that the DYT7 gene is mapped in a 4.4 centimorgan subregion of chromosome 18p.

Adolescent↗
PubMed1997

Spinocerebellar ataxia type 2. Genotype and phenotype in German kindreds.

BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia (ADCA) for which the disease-causing mutation has recently been characterized as an expanded CAG trinucleotide repeat. We investigated 64 families of German ancestry with ADCA and 55 patients with sporadic ataxia for the SCA2 mutation. RESULTS: Expanded alleles were found in 6 of the 64 families and in 1 patient with sporadic ataxia. This patient had a de novo mutation from an intermediate paternal allele. Length of repeats in 21 patients with SCA2 ranged from 36 to 52 CAG motifs and was inversely correlated with age at onset and progression of the disease. Expanded alleles were unstable during meiosis; paternal transmission especially caused significant anticipation of onset up to 26 years earlier. The SCA2 phenotype differed from those of SCA1 and SCA3 with higher frequencies of slowed ocular movements, postural and action tremor, myoclonus, and hyporeflexia. However, no single feature was sufficient to permit a specific clinical diagnosis. CONCLUSIONS: Spinocerebellar ataxia type 2 accounts for about 10% of German families with ADCA but may also be present in sporadic ataxia due to de novo mutations. Clinical features are highly variable among and even within families. However, the size of the expanded repeat influences the phenotype and is relevant for course and prognosis of the disease.

Adolescent↗
PubMed1997

Sporadic focal dystonia in northwest Germany: molecular basis on chromosome 18p.

Idiopathic focal dystonia (IFD) is the most common form of idiopathic torsion dystonia in the Euroamerican population, with a prevalence of about 30 per 100,000. Although most patients claim a negative family history, we recently mapped this syndrome to chromosome 18p as an autosomal dominant trait in Family K from Northwest Germany. We now have investigated sporadic patients with IFD from the same geographic area both clinically and molecularly with chromosome 18p markers. The data indicate that most of these apparently sporadic patients have inherited the same mutation as Family K from a common ancestor and, in fact, owe their disease to autosomal dominant inheritance at low penetrance. The data also indicate that this dystonia mutation (DYT7) is the predominant cause of IFD, at least in this area of Northwest Germany, and that its location can be narrowed from a 30- to a 6-centimorgan region close to marker D18S1098.

Chromosomes, Human, Pair 18↗
PubMed1997

Frequency of familial inheritance among 488 index patients with idiopathic focal dystonia and clinical variability in a large family.

Idiopathic torsion dystonia is characterized by involuntary twisting movements and postures. One molecularly defined form with generalized dystonia has been shown to be autosomal dominantly inherited with reduced penetrance in chromosome 9q34.1, especially in Ashkenazi Jewish families, while other generalized families from Europe and families with other subtypes of dystonia have been excluded from linkage to this locus. Genealogical studies suggest that the much more frequent focal dystonia follows an autosomal dominant inheritance with reduced penetrance as well. For our study, 488 patients with focal dystonia, without a tendency for generalization, were interviewed for their family history. Evidence for hereditary disposition was found in 88 individuals. In a second step, all available family members of 17 of the 488 index patients (chosen for cooperation) were clinically examined. Objective diagnosis of affected relative was established in 13 families, whereas only 4 of the 17 index patients had previously admitted a positive family history. Furthermore, a large three-generation family with focal dystonia linked to chromosome 18p (linkage data described elsewhere) was identified. The familial pattern of all reported families is compatible with autosomal dominant inheritance with reduced penetrance. Assessment only on patients' report leads to underestimation of the frequency of familial idiopathic focal dystonia.

Adult↗
PubMed1997

SCA2 trinucleotide expansion in German SCA patients.

Autosomal dominant spinocerebellar ataxias (SCA) are a group of clinically and genetically heterogeneous neurodegenerative disorders which lead to progressive cerebellar ataxia. A gene responsible for SCA type 2 has been mapped to human chromosome 12 and the disease causing mutation has been identified as an unstable and expanded (CAG)n trinucleotide repeat. We investigated the (CAG)n repeat length of the SCA2 gene in 842 patients with sporadic ataxia and in 96 German families with dominantly inherited SCA which do not harbor the SCA1 or MJD1/SCA3 mutation, respectively. The SCA2 (CAG)n expansion was identified in 71 patients from 54 families. The (CAG)n stretch of the affected allele varied between 36 and 64 trinucleotide units. Significant repeat expansions occurred most commonly during paternal transmission. Analysis of the (CAG)n repeat lengths with the age of onset in 41 patients revealed an inverse correlation. Two hundred and forty-one apparently healthy octogenerians carried alleles between 16 and 31 repeats. One 50-year old, healthy individual had 34 repeats; she had transmitted an expanded allele to her child. The small difference between 'normal' and disease alleles makes it necessary to define the extreme values of their ranges. With one exception, the trinucleotide expansion was not observed in 842 ataxia patients without a family history of the disease. The SCA2 mutation causes the disease in nearly 14% of autosomal dominant SCA in Germany.

Adolescent↗