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Ursula G Froster

Publications and source records attributed to Ursula G Froster.

At least 19 recordsLinked to original sources
PubMed2006

Prenatal diagnosis and genetic counseling in a case of spina bifida in a family with Waardenburg syndrome type I.

OBJECTIVE: Waardenburg syndrome type I (WS I) is an autosomal dominant inherited disorder with an incidence of 1:45,000 in Europe. Mutations within the PAX3 gene are responsible for the clinical phenotype ranging from mild facial features to severe malformations detectable in prenatal diagnosis. METHODS: Here, we report a four-generation family with several affected members showing various symptoms of WS I. We diagnosed the syndrome first in a pregnant young woman; she was referred because of a spina bifida in prenatal diagnosis. We performed clinical genetic investigations and molecular genetic analysis in all available family members. RESULTS: The phenotype displays a wide intra-familial clinical variability of pigmentary disturbances, facial anomalies and developmental defects. Molecular studies identified a novel splice site mutation within the PAX3 gene in intron 5 in all affected family members, but in none of the unaffected relatives. CONCLUSIONS: This case demonstrates the prenatal diagnosis of spina bifida in a fetus which leads to the initial diagnosis of WS I. Further studies could identify a private splice site mutation within the PAX3 gene responsible for the phenotype in this family.

Abortion, Spontaneous↗
PubMed2006

The importance of arginine mutation for the evolutionary structure and function of phenylalanine hydroxylase gene.

Phenylalanine hydroxylase (PAH) gene mutations were investigated in 23 (46 alleles) unrelated phenylketonuria (PKU) patients in Cukurova region. First, all exons of PAH gene were screened by denaturing high performance liquid chromatography (DHPLC), and then, the suspicious samples were analyzed by direct sequencing technique. Consequently, the following results were obtained: IVS10-11g-->a splicing mutation in 27/46 (58.7%), R261Q mutation in 7/46 (15.2%) and E178G, R243X, R243Q, P281L, Y386C, R408W mutations, each found in the frequency of 2/46 (4.3%). In many countries, Arginine mutations have the highest frequency among PAH gene mutations in PKU patients. Although, CpG dinucleotids are effective in mutations resulting in arginine changes, this finding originated from the studies on the causes of mutations rather than the studies on the importance of arginine amino acid. In our analyses, we have detected that a majority of mutations causing a change in arginine and other amino acids concentrated in exon 7 comprising the catalytic domain (residues 143-410) of PAH gene. Several studies has emphasized the role of arginine amino acid; with the following outcomes; arginine repetition is significant for RNA binding proteins, and for histon proteins in eukaryotic gene expression, and also arginine repetition occurring in the structure of signal recognition particle's (SRPs) as a consequence of post-translational processes is very important in terms of gene expression. Therefore, the role of arginine amino acid in PAH gene is rather remarkable in that it shows the role of amino acids in the protein/RNA interaction that has started in the evolutionary process and is still preserved and maintained in the motif formation of active domain structure due to its strong binding properties. Thus, such properties imply that both arginine amino acid and exon 7 is of great significance with regards to the structure and function of the PheOH enzyme.

Alleles↗
PubMed2006

A missense mutation in the ZFHX1B gene associated with an atypical Mowat-Wilson syndrome phenotype.

Mowat-Wilson syndrome (MWS) is a rare mental retardation-multiple congenital anomalies syndrome associated with typical facial dysmorphism. Patients can show a variety of other anomalies like short stature, microcephaly, Hirschsprung disease, malformations of the brain, seizures, congenital heart defects and urogenital anomalies. Mutations leading to haploinsufficiency of the ZFHX1B gene have been described as the underlying cause of this condition. We report on the clinical findings in a 2(1/2)-year-old boy with some aspects out of the MWS-spectrum in addition to unusual anomalies and a novel missense mutation in the ZFHX1B gene.

Abnormalities, Multiple↗
PubMed2006

Expanding the spectrum of TBX5 mutations in Holt-Oram syndrome: detection of two intragenic deletions by quantitative real time PCR, and report of eight novel point mutations.

Mutations in the gene TBX5 cause Holt-Oram syndrome (HOS), an autosomal dominant disorder characterized by anterior (i.e., radial ray) upper limb malformations and congenital heart defects and/or cardiac conduction anomalies. The detection rate for TBX5 mutations in HOS patients has been given as 30-35% in most reports. However, a detection rate of 74% was reported when strict clinical inclusion criteria for HOS were applied prior to TBX5 analysis. Still, in a significant proportion of typical HOS cases no mutation can be found within the TBX5 coding region and flanking intronic sequences. One explanation could be that large but submicroscopic deletions of TBX5 could cause HOS, yet only one such TBX5 deletion has been reported to date. We developed a quantitative Real Time PCR strategy to detect large, submicroscopic deletions in TBX5. Using this assay, we screened a total of 102 TBX5 mutation negative patients and discovered two novel intragenic deletions. One deletion of 7756 bp removes exon 6 and a considerable part of the neighboring intronic sequences, and the other of 3695 bp removes exon 9 with the stop codon and the 3'UTR completely as well as a part of the preceding intron 8. We conclude that quantitative Real Time PCR is a reliable method to detect submicroscopic deletions within TBX5. However, such deletions explain only approximately 2% of the TBX5 mutational spectrum in HOS cases. In addition, we also present eight novel TBX5 mutations (three nonsense, one splice mutation, four short deletions) as detected by direct sequencing in 21 families not previously analyzed for mutations.

Arrhythmias, Cardiac↗
PubMed2005

Molecular and cytogenetic characterization of a non-mosaic isodicentric Y chromosome in a patient with Klinefelter syndrome.

We report on an adult male with Klinefelter phenotype and an isodicentric Y chromosome (47,XX,+idic(Y)(q12)), a combination which has to the best of our knowledge not been reported before. The patient was hospitalized in forensic psychiatry because of repeated delinquency, aggressive, aberrant and inappropriate behavior, and borderline intelligence. Molecular cytogenetic studies (FISH) showed that the SRY gene was present on both ends of the idicY, while there was only one signal for the Yq subtelomere probe. Molecular investigations by multiplex PCR, using STS markers covering the short and long arm of the Y chromosome did not indicate a deletion of Y chromosomal material. Molecular investigations of STR markers located on Xp22.3 and Xq28 indicated paternal origin of the additional X chromosome and an error in paternal meiosis I. Results of FISH analysis and molecular investigations are compatible with a phenotype as described for individuals with a 48,XXYY karyotype and support the findings that isodicentric Y chromosomes are frequently accompanied by other sex chromosomal abnormalities.

Adult↗
PubMed2005

SALL4 mutations in Okihiro syndrome (Duane-radial ray syndrome), acro-renal-ocular syndrome, and related disorders.

Okihiro/Duane-radial ray syndrome (DRRS) is an autosomal dominant condition characterized by radial ray defects and Duane anomaly (a form of strabismus). Other abnormalities reported in this condition are anal, renal, cardiac, ear, and foot malformations, and hearing loss. The disease is the result of a mutation in the SALL4 gene, a human gene related to the developmental regulator spalt (sal) of Drosophila melanogaster. SALL4 mutations may also cause acro-renal-ocular syndrome (AROS), which differs from DRRS by the presence of structural eye anomalies, and phenotypes similar to thalidomide embryopathy and Holt-Oram syndrome (HOS). The SALL4 gene product is a zinc finger protein that is thought to act as a transcription factor. It contains three highly conserved C2H2 double zinc finger domains, which are evenly distributed. A single C2H2 motif is attached to the second domain, and at the amino terminus SALL4 contains a C2HC motif. Seventeen of the 22 SALL4 mutations known to date (five of which are presented here for the first time) are located in exon 2, and five are located in exon 3. These are nonsense mutations, short duplications, and short deletions. All of the mutations lead to preterminal stop codons and are thought to cause the phenotype via haploinsufficiency. This assumption is supported by the detection of six larger deletions involving the whole gene or single exons. This article summarizes the current knowledge about SALL4 defects and associated syndromes, and describes the clinical distinctions with similar phenotypes caused by other gene defects.

Abnormalities, Multiple↗
PubMed2005

The human TBX5 gene mutation database.

Germline mutations of the TBX5 gene were identified as the primary cause in up to 70% of patients with Holt-Oram syndrome (HOS), an autosomal dominant disorder characterized by malformations of the upper limbs and cardiac defects. Furthermore, somatic mutations of the TBX5 gene have been described in diseased heart tissues of patients with congenital heart defects of different cause. The relationship between genotype and phenotype remains unclear and the underlying mechanism of the pathogenic effect is not solved. In this report, we introduce the 'TBX5 Gene Mutation Database,' an online locus specific database containing germline and somatic mutations of the TBX5 gene. The permanently updated data collection includes all reported mutations beginning with the first description of the gene in 1997. With our database we complement the existing resources by: 1) giving a complete review of the so far reported mutation spectrum in TBX5 considering the clinical relevance; 2) linkage of the mutational data to the corresponding gene location and PubMed-Abstracts; and 3) additional links to other related resources like SNP database, sequences and literature references. The usage of our database will help to quickly find informations about genetic variations within the TBX5 gene. Here we describe the database structure, content, and potential applications (http://www.uni-leipzig.de/~genetik/TBX5).

Databases, Genetic↗
PubMed2005

Molecular genetic and ocular findings in patients with holt-oram syndrome.

PURPOSE: The autosomal dominant Holt-Oram syndrome (HOS) is characterized by upper limb and cardiac septal defects. Mutations of the TBX5 gene have been identified as the underlying gene defect in HOS. Embryonic expression of TBX5 has been found in the human retina. This is the first report of ocular findings in two unrelated families with mutations in the TBX5 gene. METHODS: Six living persons affected with HOS and 10 unaffected family members were subjected to mutation analysis and complete ophthalmological examination, including electrophysiological examinations (EOG and flash ERG). RESULTS: A heterozygous single base-pain substitution in exon 5 (408C --> A) was detected in all affected patients. All examined affected patents were ophthalmological asymptomatic with normal EOG. A scotopic elongated b-wave latency was found in affected family members who were older than 35 years. The ERG was normal in the young patients. CONCLUSIONS: Haploinsufficiency of TBX5 alters the dorsal-ventral polarity in developing eye vesicles without amy detected functional loss in human. Slight ERG abnormalities later in life may be a result of changes induced by the inner ganglion cell layer in the inner nuclear layer.

Adolescent↗
PubMed2004

A new mutation in the skeletal ryanodine receptor gene (RYR1) is potentially causative of malignant hyperthermia, central core disease, and severe skeletal malformation.

Malignant hyperthermia susceptibility (MHS) and central core disease (CCD) have been shown to result from missense mutations in the ryanodine receptor gene of the skeletal muscle (RYR1). A 15-year-old patient who had spondylocostal dysostosis (SCD) developed an MH crisis during general anesthesia. The patient was characterized phenotypically by block vertebrae, vertebral fusion, short neck and thorax, fused ribs, craniofacial abnormalities, spina bifida occulta, and a diaphragmatic defect closed surgically in early infancy. The diagnosis MH susceptible (MHS) was confirmed by the in vitro contracture test (IVCT) on a muscle biopsy. Surprisingly, the histopathological investigation revealed the presence of CCD too. Molecular genetic investigation of the RYR1 gene was performed to search for known MH-related mutations. Cluster regions of the RYR1 gene, in which mutations have already been found, were examined by direct automated sequencing. In addition to the diagnosis MHS and CCD we were able to identify a novel RYR1 mutation in exon 46: 7358ATC > ACC, resulting in an Ile2453Thr substitution. This mutation was also present in the mother, in whom MH disposition and CCD were determined by muscle investigations. We suggest that the newly identified RYR1 mutation is closely associated with MH and CCD. A probable causative role of the RYR1 gene in SCD patients should be assessed by further genetic investigations.

Adolescent↗
PubMed2004

Cytogenetic and molecular cytogenetic analyses in diffuse astrocytomas.

Diffuse astrocytomas are highly variable tumors and show complex biologic behavior that is based on multi-step oncogenesis. We report cytogenetic and molecular cytogenetic investigations in 23 cases of diffuse astrocytomas. The results of conventional karyotyping, interphase fluorescence in situ hybridization (FISH), comparative genomic hybridization, multicolor FISH, and spectral karyotyping are reported. Various numerical and structural chromosomal aberrations were identified. Clustering of structural alterations in the short arm of chromosome 2 (2p) and the long arm of chromosome 7 (7q) were detected. Using spectral karyotyping, additional chromosome rearrangements not detectable by conventional methods were found. Some of these anomalies have not been previously described in diffuse astrocytomas. An independent validation of these discrepant findings is required.

Aneuploidy↗
PubMed2003

DHPLC mutation analysis of phenylketonuria.

Denaturing high-performance liquid chromatography (DHPLC) is a sensitive and fast method for the detection of mutations which has been successfully used for mutation screening in several disease-related genes. Phenylketonuria (PKU, OMIM* 261600; McKusick 1986) is one of the most common autosomal recessive disorders in Europe. Mutations in the PAH gene mainly involve point mutations. In this study we report the successful use of DHPLC to analyse rapidly the complete coding sequence of the PAH gene in a total of 125 unrelated patients with PKU.

Base Sequence↗
PubMed2002

Molecular breakpoint analysis and relevance of variable mosaicism in a woman with short stature, primary amenorrhea, unilateral gonadoblastoma, and a 46,X,del(Y)(q11)/45,X karyotype.

We report on a 30-year-old woman with short stature, completely female external genitalia, primary amenorrhea, bilateral streak gonads, unilateral gonadoblastoma, and a 46,X,del(Y)(q11)/45,X karyotype. Variable levels of mosaicism were found in blood and cultivated fibroblasts from both the skin and ovaries, with the percentage of the 45,X lineage never exceeding 33%. Fluorescence in situ hybridization (FISH) was performed with alpha satellite centromere region probes of the X and Y chromosomes (DXZ1 and DXZ3) as well as with the unique-sequence, locus-specific, sex-determining region of the Y chromosome gene (SRY) and the DXZ1 probes. Each signal was noted for DXZ1 on the X chromosome and for the Y probes on the marker chromosome. Molecular investigations with a panel of PCR markers spread over the whole Y chromosome indicated a deletion breakpoint between sY 78 (interval 4) and sY 151 (interval 5F). No mutation of the high mobility group-box (HMG-box) of the SRY gene could be found following sequence analysis. The phenotype/genotype correlation demonstrates the broad phenotypic range of low-level 45,X mosaicism with the resultant short stature and external female phenotype, despite the presence of SRY in a high proportion of cells in various tissues.

Adult↗
PubMed2002

Comparative genomic hybridization in glioma: a meta-analysis of 509 cases.

Much data about genetic imbalances in tumors have been accumulated by comparative genomic hybridization (CGH). In order to distinguish between significantly and coincidentally involved regions in glioma by means of a meta-analysis, we summarized and analyzed the CGH results of 509 cases published in 26 reports between 1992 and 2001. The expansion of all aberrations to the 850-band level impressively visualized distinct patterns in astrocytoma, oligodendroglioma, and ependymoma as well as loci of frequent aberrations. For example, in astrocytoma the frequency of gains culminated at 7p12, 8q24.1, and 12q13-q15 (the loci of EGF-R, C-MYC and CDK4, respectively) and losses at 9p21 (the locus of p15 and p16) and 10q23.3 where PTEN resides. Most chromosomes were variably prone to copy number changes at different scales of aberrations. At the whole chromosome level the analysis showed +7, -10 in astrocytoma and +9, +18 in ependymoma, but +20q, -9p in astrocytoma and +1q, -22q in ependymoma at the p-q arm level. Furthermore, we could confirm the correlation between the average number of copy alterations per patient (average number of copy alterations [ANCA] index) and malignancy for astrocytoma in a refined graduation as well as for oligodendroglioma. As a new parameter, the average number of affected GTG-bands per patient (average number of affected GTG bands [ANAG] index) showed an even more striking correlation with the World Health Organization grade for gains and losses.

Astrocytoma↗