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Biomedical subjects

T Grimm

Publications and source records attributed to T Grimm.

At least 55 records · Page 3Linked to original sources
PubMed1995

Discordance, in a malignant hyperthermia pedigree, between in vitro contracture-test phenotypes and haplotypes for the MHS1 region on chromosome 19q12-13.2, comprising the C1840T transition in the RYR1 gene.

A point mutation in the gene encoding the skeletal muscle calcium release channel (RYR1) has been proposed as the probable cause of malignant hyperthermia (MH) in swine, where it segregates with the disease in all MH-prone strains investigated. The same C-to-T exchange in nucleotide position 1840 of the human RYR1 cDNA sequence was found in a few human MH pedigrees. We report a German MH pedigree where in vitro contracture test (IVCT) results and haplotypes of markers for the MHS1/RYR1 region including this base transition have yielded several discrepancies. The MH-susceptible phenotype was defined by IVCT performed according to the European standard protocol. Haplotypes were constructed for markers for the MHS1/RYR1 region on chromosome 19 and include the C1840T base exchange. Discussing the probabilities for a number of hypotheses to explain these data, we suggest that our results may challenge the causative role of this mutation--and possibly the role of the RYR1 gene itself--in human MH susceptibility, at least in some cases.

Calcium Channels↗
PubMed1994

Characteristics of carcinoembryonic antigen (CEA) expressed in different cell types: evidence that CEA can function as an adhesion molecule and as a repulsion molecule.

The characteristics of carcinoembryonic antigen (CEA) molecules expressed by different cell types have been examined using cDNA transfection into cells of epithelial, neuroectodermal and hematopoietic origin. Variability in the CEA molecules was observed in terms of monoclonal antibody binding, apparent molecular weight and sialic acid content, although this was not cell type specific. CEA was found to mediate homotypic as well as heterotypic intercellular adhesion independently of the cell type and despite differences in the sialic acid content. Although CEA was shown to function as a homophilic cell adhesion molecule in most cells, expression of CEA in one cell line led to a reduction in both homotypic and heterotypic cell adhesion, suggesting that it can under certain circumstances also function as a repulsion molecule.

Animals↗
PubMed1994

Precise mapping of the brain alpha 2-adrenergic receptor gene within chromosome 4p16.

The gene encoding the brain alpha 2-adrenergic receptor (ADRA2C) is located on human chromosome 4. It has been circumstantially associated with a number of human disorders, including Parkinson disease, panic disorders, and Huntington disease (HD). Using somatic cell hybrids, we localized the gene to chromosome 4p16 distal to P8 (D4S62). To investigate this locus further, we isolated several cosmid clones covering the entire gene. The gene was found to be intronless. Two (GT)n repeats in close proximity to the ADRAC2 gene were analyzed and used to define its precise location. Linkage disequilibrium studies of one microsatellite in HD families showed strong nonrandom association to the HD mutation, indicating its tight linkage to the HD gene. The investigation of families carrying recombinant chromosomes, pulsed-field analysis, and genomic walking mapped the ADRA2C gene adjacent to D4S81, 500 kb proximal to the HD gene. The newly defined microsatellites at the ADRAC2 locus, its precise localization within 4p16, and the detailed PCR conditions facilitate the identification of any defect caused by this gene.

Base Sequence↗
PubMed1994

The human gene for alkaptonuria (AKU) maps to chromosome 3q.

Alkaptonuria (AKU; McKusick no. 203500) is a rare autosomal recessive disorder caused by the lack of homogentisic acid oxidase activity. Patients excrete large amounts of homogentisic acid in their urine and a black ochronotic pigment is deposited in their cartilage and collagenous tissues. Ochronosis is the predominant clinical complication of the disease leading to ochronotic arthropathy, dark urine, pigment changes of the skin, and other clinical features. A mutation causing alkaptonuria in the mouse has mapped to chromosome 16. Considering conserved synteny, we were able to map the human gene to chromosome 3q in six alkaptonuria pedigrees of Slovak origin.

Alkaptonuria↗
PubMed1994

Molecular genetic haplotype segregation studies in three families with X-linked lymphoproliferative disease.

Three families with X-linked lymphoproliferative disease were studied. Affected males clinically presented with severe or fatal infectious mononucleosis, acquired hypogammaglobulinaemia, hypergammaglobulinaemia M, and malignant lymphoma including Hodgkin disease. Haplotype analysis using various DNA markers from Xq25-q27 allowed the prediction of the carrier status in females and identification of the XLP status in asymptomatic males.

Base Sequence↗
PubMed1994

On the origin of deletions and point mutations in Duchenne muscular dystrophy: most deletions arise in oogenesis and most point mutations result from events in spermatogenesis.

We present the results of a study of the rate and origin of mutations in Duchenne muscular dystrophy (DMD). Depending on the type of mutation (deletion/duplication or point mutation) present in the patient, there are widely varying ratios of male to female mutation rates. In deletions, the male mutation rate is only 30% of the female one. In non-deletional/non-duplicational mutations (presumably containing a high proportion of point mutations) the male mutation rate is at least 2.2 as high as the female one and probably much higher. Allowing for the presence of autosomal recessive phenocopies we find that k in non-deletional/non-duplicational mutations is 40.3. These findings mean that the vast majority of deletions arise in oogenesis, while most point mutations stem from spermatogenesis. Previous investigations have shown that in other diseases and genes, most notably haemophilia B and A, but also the ZFY and ZFX genes, the male mutation rate for point mutations tends to be higher than the female one. Our results can be seen as a confirmation of this for the special case of DMD. The influence on risk figures is considerable. As an example, the risk of the mother of an isolated case of DMD without an apparent structural anomaly of the gene of being a carrier increases from 67% to at least 76%. Given the estimate of 40.3 for k, allowing for the presence of autosomal recessive phenocopies mentioned above, it increases even further to 98%. However, as confidence intervals are still large, more data are needed to improve the estimates. Germinal mosaicism in this context is discussed.

Fathers↗
PubMed1993

X-linked lymphoproliferative disease. Detection of a paternally inherited mutation in a German family using haplotype analysis.

OBJECTIVE: To study the inheritance of the X-linked lymphoproliferative disease (XLP) locus in a German family. DESIGN: Haplotype segregation analysis. SETTING: Departments of Pediatrics and Human Genetics, University of Würzburg and University of Ulm, Federal Republic of Germany. PARTICIPANTS: Fourteen members of a family with XLP. INTERVENTIONS: None. MEASUREMENTS/MAIN RESULTS: Using molecular genetic techniques, we diagnosed the XLP status of the members of a German family. Restriction fragment length polymorphism analysis with closely linked polymorphic X-chromosomal DNA markers (Xq25-q27) revealed XLP carrier status in a female infant. Moreover, the XLP mutation was suggested to have occurred in the germ cell of the grandfather. CONCLUSION: This is the first report of a paternally inherited XLP mutation. The recurrence risk for germ cell mosaicism in XLP may be similar to that of X-linked Duchenne muscular dystrophy.

Base Sequence↗
PubMed1993

Multipoint mapping of the central core disease locus.

A linkage analysis with 12 DNA markers from proximal 19q was performed in eight families with central core disease (CCO). Two-point analysis gave a peak lod score of Z = 4.95 at theta = 0.00 for the anonymous marker D19S190 and of Z = 2.53 at theta = 0.00 for the ryanodine receptor (RYR1) candidate gene. Multipoint linkage data place the CCO locus at 19q13.1, flanked proximally by D19S191/D19S28 and distally by D19S47. This map location includes the RYR1 gene. The results of the linkage study present no evidence for genetic heterogeneity of CCO.

Animals↗
PubMed1993

Patterns of deletions of the dystrophin gene in different European populations.

The distribution of deletion breakpoints in the dystrophin gene was studied in a series of subjects belonging to different European populations. The data, obtained from the literature or directly from the present study, refer to population samples from France, Finland, Germany, Italy, Netherlands, Switzerland, and U.K. (England, Scotland, Wales). In total, 1516 breakpoints were assigned to different introns, 359 in the region encompassing the first 40 exons and 1157 (76%) in the distal part of the gene. Intron 7 appears to be equally involved as the starting or ending breakpoint, whereas intron 44 is involved mostly as a starting breakpoint. Breakpoint distribution by intron seems to differ in different populations, reaching statistical significance in the case of introns 44, 49, and 53. This finding suggests that some intronic sequences might contain preferential breakpoints that might vary in different populations, possibly as a consequence of genetic drift.

Chromosome Fragility↗
PubMed1993

Linkage of Van der Woude syndrome (VWS) to REN and exclusion of the candidate gene TGFB2 from the disease locus in a large pedigree.

Van der Woude syndrome (VWS) is an autosomal dominant disorder associated with one or more of the following features: clefting of the primary or secondary palate, hypodontia or lower lip pits. It has been estimated to account for 2% of all cases of cleft lip and palate. VWS is one of the rare disorders in which clefting of the primary and secondary palate may be seen to segregate as components associated with the same gene. Because of its autosomal dominant inheritance, VWS is readily accessable to linkage analysis as a preliminary step in the identification of the molecular abnormality underlying the clefting effect in the primary and secondary palate. A reported linkage between REN and VWS has promoted us to use pHRnX3.6 (REN) and several markers surrounding REN for a linkage analysis in a large Swiss family. In a second step, linkage analysis was performed to study restriction fragment length polymorphisms for the candidate gene TGFB2 and other loci recently mapped to the candidate region 1q32-1q41. Evidence for linkage (theta = 0.00, lod score = 3.01) between REN and VWS could be confirmed in this pedigree. TGFB2 demonstrated recombination with the disease locus and is unlikely to be causative in VWS. The results of a multipoint linkage analysis showed that VWS was flanked by D1S65 and TGFB2 at a maximum location score of 20.3.

Adolescent↗
PubMed1993

Direct and indirect estimation of the sex ratio of mutation frequencies in hemophilia A.

Carrier detection tests were carried out in 119 families with hemophilia A by using the data obtained with current DNA techniques (e.g., RFLP analysis and direct identification of mutations), conventional carrier detection tests (e.g., factor VIII:C and von Willebrand factor antigen), and pedigree information. On the basis of this data, we estimated the sex ratio of mutation frequencies with three completely different methods and compared the results. Since the classical indirect method derived from Haldane is substantially influenced by reproductive fitness (f), the sex ratio of mutation frequencies was estimated for both f = .3 and f = .5, resulting in a male:female mutation ratio of 5.37 (95% confidence interval 2.16-13.02) and 3.26 (95% confidence interval 0.97-8.73), respectively. According to the equilibrium-independent indirect method formulated by Rosendaal et al., the male:female ratio was estimated to be 3.4 (95% confidence interval 1.18-8.81). Since current DNA techniques provide information on the grandparental origin of the patient's X chromosome, we were twice able to estimate directly the male:female mutation ratio as 15:1, by using the quotients of mutation origin (maternal grandfather/maternal grandmother and maternal grandfather/patient's mother, respectively). Application of the Fisher test shows that the male mutation rate is higher than the female rate (P = 8.55 x 10(-7). Since all three completely different approaches unequivocally showed a higher male than female mutation frequency, this should be considered to be an established fact in calculating the risk in hemophilia A families.

Adolescent↗
PubMed1992

Solitary cerebellar metastasis from transitional cell carcinoma of bladder.

Brain metastasis from transitional cell carcinoma of the bladder is unusual, occurring most often in the presence of widespread systemic metastases. We report on a patient who presented with an isolated cerebellar metastasis and recurrent carcinoma of the bladder, after treatment with local excision and intravesical thiotepa. Further evaluation failed to demonstrate other distant metastases. Excision of the cerebellar lesion revealed transitional cell carcinoma identical to the original bladder tumor. In a review of the literature, we found reports of two similar patients in whom a solitary cerebellar lesion was the first sign of metastasis from carcinoma of the bladder; neither patient had evidence of other distant metastases, and neither previously had received systemic chemotherapy. These observations indicate that central nervous system metastasis from carcinoma of the bladder, while rare, should be considered in the differential diagnosis of solitary intracerebellar lesions in such patients.

Aged↗
PubMed1992

Parental origin of factor IX gene mutations, and their distribution in the gene.

Genomic amplification followed by direct sequencing enabled us to establish the causative mutation in 67 unrelated hemophilia B patients of predominantly German origin. With the detection of the mutation, extensive pedigree analysis has become feasible. We therefore anticipated that determination of the origin of mutation could be achieved in a comparatively great number of families. Although these investigations often were restricted by the availability of blood samples from the maternal grandparents or great-grandparents, we were able to prove a de novo mutation in 9 of 20 families with sporadic hemophilia B and in 3 of 20 families with a history of the disease. This could be achieved with the aid of RFLP analysis and, in one case, where the mutation is still unknown, with the aid of biochemical and immunological factor IX assays. Since the maternal grandfather was decreased in two of these families, the germ line of origin could not be determined precisely. In the remaining families, the female and male germ lines turned out to be the origin of mutation in six and four cases, respectively, and an effect of paternal age on the mutations observed could not be excluded. Furthermore, our data indicate that the hemophilia B gene pool is mainly renewed by variable mutations.

Factor IX↗
PubMed1991

Linkage data suggesting allelic heterogeneity for paramyotonia congenita and hyperkalemic periodic paralysis on chromosome 17.

Paramyotonia congenita (PC), an autosomal dominant non-progressive muscle disorder, is characterised by cold-induced stiffness followed by muscle weakness. The weakness is caused by a dysfunction of the sodium channel in muscle fibre. Parts of the gene coding for the alpha-subunit of the sodium channel of the adult human skeletal muscle (SCN4A) have been localised on chromosome 17. To investigate the role of this gene in the etiology of PC, a linkage analysis in 17 well-defined families was carried out. The results (zeta = 20.61, theta = 0.001) show that the mutant gene responsible for the disorder is indeed tightly linked to the SCN4A gene. The mutation causing hyperkalemic periodic paralysis (HyperPP) with myotonia has previously been mapped to this gene locus by the same candidate gene approach. Thus, our data suggest that PC and HyperPP are caused by allelic mutations at a single locus on chromosome 17.

Alleles↗
PubMed1991

Evidence for linkage of the central core disease locus to the proximal long arm of human chromosome 19.

Central core disease of muscle (CCD; MIM 117000) is a rare inheritable myopathy that is frequently found in association with susceptibility to malignant hyperthermia (MHS). This observation has prompted us to perform a linkage study in CCD families using various chromosome 19q probes that are linked to the MHS locus and map close to the ryanodine receptor gene (RYR1), a strong MHS candidate gene. Our genetic linkage data support a location of the CCD gene on proximal 19q13.1 and thus suggest that CCD and MHS may be allelic.

Alleles↗
PubMed1991

X-linked centronuclear myopathy: mapping the gene to Xq28.

The X-linked recessive centronuclear/myotubular myopathy (XLR-CNM/MTM1), a severe neonatal disorder characterized by generalized hypotonia, muscle weakness and primary asphyxia, has recently been mapped to Xq28. This report presents linkage analysis data of eight families with X-linked centronuclear myopathy. Four probes from the region Xq26-27 and five Xq28 probes were used to get more precise gene localization and marker order. St14 (DXS52), fully informative in all families, shows significant linkage to the CNM gene (z = 3.60; theta = 0.05), followed by DX13 (DXS15) (z = 2.03; theta = 0.06) and F8 (z = 1.86; theta = 0.00). Combination of the physical map derived by Kenwrick and Gitschier (1989) and our linkage data lead to the most probable order R/GCP-G6PD-(XLR-CNM-F8)-p767-St14-cpX67-++ +DX13 placing the CNM gene close to F8. The results of this study confirm strong linkage of the CNM gene to the region Xq28 and will permit carrier testing and prenatal diagnosis in CNM families. We conclude that the precise localization of this devastating disorder may be of great importance for genetic counselling in families at risk. The lack of information about gene frequency and mutation rate as well as the severity and burden of the disease point to the inevitable need for accurate clinical diagnosis.

Chromosome Mapping↗