Biomedical subjects

H Kremer

Publications and source records attributed to H Kremer.

At least 55 records · Page 3Linked to original sources

PubMed1997

Two types of polyadenated mRNAs are synthesized from Drosophila replication-dependent histone genes.

The polyadenylation of replication-dependent histone H2B, H3 and H4 mRNAs in Drosophila melanogaster was analysed. Two types of mRNAs, containing a poly(A) tail, can be detected in addition to non-polyadenylated messengers, which represent the majority of replication-dependent histone mRNAs. Firstly, conventional polyadenylation signals, localized downstream from the stem-loop region, are used to produce polyadenylated mRNAs. The messengers of this type, generated from the D. melanogaster H2B gene, are preferentially synthesized in the testis of the fly. Secondly, a distinct type of polyadenylated histone mRNA has been identified. This mRNA, which is present in many different tissues and constitutes a minor part of the total histone mRNA pool, contains a short poly(A) tail, added to the end of the 3' terminal stem-loop structure, which is in most cases lacking several nucleotides from its 3' end. The sites of polyadenylation within the stem-loop are not preceded by a normal polyadenylation signal. The possible functions of the polyadenylated histone transcripts are discussed.

Animals↗

PubMed1997

Differential loss of heterozygosity in the region of the Cowden locus within 10q22-23 in follicular thyroid adenomas and carcinomas.

The susceptibility gene for Cowden disease (CD), an autosomal dominant inherited cancer syndrome, has recently been mapped to an approximately 6-cM interval on chromosome subband 10q22-23 between the markers D10S541 and D10S564. CD is characterized by hamartomas of many organ systems, including the thyroid, breast, skin, and gastrointestinal tract, as well as carcinoma of the thyroid and breast. Follicular thyroid adenomas and carcinomas are significant component tumors in CD; thus, we sought to examine their sporadic counterpart tumors for loss of heterozygosity (LOH) of microsatellite markers in the 20-cM region within and flanking the Cowden critical interval. In all, 38 sporadic thyroid tumors were analyzed. LOH within the CD interval was observed in 5 of 19 (26%) follicular thyroid adenomas and 1 of 9 (11%) Hürthle cell adenomas. Furthermore, of these adenomas with LOH, 3 of 4 (75%) were atypical follicular adenomas, whereas 2 of 15 (13%) were typical follicular adenomas. Surprisingly, no LOH was detected in this region in 10 follicular carcinomas. The shortest region of overlap includes the markers D10S1735 and D10S1739. If the LOH observed in these sporadic tumors is related to the CD gene, then the Cowden critical interval can be revised to lie within the interval defined by D10S579 and D10S564. LOH in this narrow interval implicates the CD gene, or another gene in that interval, in follicular thyroid tumorigenesis. However, this does not explain the lack of LOH in follicular carcinomas. Taken together, it may instead be evidence against a stepwise progression from atypical adenomas to carcinomas. Alternatively, sporadic thyroid adenoma formation may be independent of that locus, but loss of this region could prevent carcinoma formation, thus implying that the CD gene may be an oncogene or growth promoter.

Adenoma↗

PubMed1997

Naturally occurring testis-specific histone H3 antisense transcripts in Drosophila.

While analysing the transcription of the cluster of cell-cycle regulated histone genes in Drosophila hydei, we have found transcripts spanned both histone H3 and H4 genes and were antisense for histone H3. As the two histone genes are in opposite orientation, these transcripts contained the sense strand of the histone H4 gene. Such transcripts were present in both poly(A)+ and poly(A)- RNA fractions. The polyadenylated molecules contained a poly(A) tail at the 3' end of the stem-loop structure, which is characteristic for cell-cycle regulated histone mRNAs. The antisense RNA of histone H3 is synthesized exclusively in testes. By developing an improved protocol of in situ hybridization to Drosophila testis squashes, we could demonstrate that the antisense transcripts are localized in the nuclei of primary spermatocytes. Possible functions of this RNA are discussed.

Animals↗

PubMed1997

Familial spastic paraplegia: evidence for a fourth locus.

Autosomal dominant familial spastic paraparesis (AD-FSP) is a genetically heterogeneous disorder of the central nervous system characterized by a progressive spasticity of the legs. One gene causing AD-FSP (FSP1) has recently been mapped to chromosome 14q, another gene (FSP2) to chromosome 2p, and a third gene (FSP3) to chromosome 15q. We now report a large Dutch family with AD-FSP without linkage to any of these chromosomes, providing evidence for a fourth locus (FSP4).

Adult↗

PubMed1997

Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease.

Cowden disease, also known as multiple hamartoma syndrome, is an autosomal dominant cancer syndrome with a high risk of breast and thyroid cancer. The gene involved has been localized to chromosome 10q22-23. Recently, the tumour suppressor gene PTEN/MMAC1, encoding a putative protein tyrosine or dual-specificity phosphatase, was cloned from that region and three mutations were detected in patients with Cowden disease. We confirmed that the PTEN/MMAC1 gene is indeed the gene for Cowden disease by a refined localization of the gene to the interval between D10S1761 and D10S541, which contains the PTEN/MMAC1 gene and, by mutation analysis in eight unrelated familial and 11 sporadic patients with Cowden disease. Eight different mutations were detected in various regions of the PTEN/MMAC1 gene. One mutation was detected twice. All detected changes in the gene can be predicted to have a very deleterious effect on the putative protein. Five of the nine patients have a mutation in exon 5 coding for the putative active site and flanking amino acids. Evaluation of the clinical data of the patients in which a mutation could be detected gives no clear indications for a correlation between the genotype and phenotype. In 10 patients no mutation could be detected so far. In support of the linkage data, no evidence has emerged from the phenotype of these patients suggestive for genetic heterogeneity.

Adult↗

PubMed1996

A gene for nonspecific X-linked mental retardation (MRX41) is located in the distal segment of Xq28.

We report on a family in which nonsyndromal mild to moderate mental retardation segregates as an X-linked trait (MRX41). Two point linkage analysis demonstrated linkage between the disorder and marker DXS3 in Xq21.33 with a lod score of 2.56 at theta = 0.0 and marker DXS1108 in Xq28 with a lod score of 3.82 at theta = 0.0. Multipoint linkage analysis showed that the odds for a location of the gene in Xq28 vs Xq21.33 are 100:1. This is the fourth family with non-specific X-linked mental retardation with Xq28-qter as the most likely gene localization.

Chromosome Mapping↗

PubMed1996

No difference in catheter sepsis between standard and antiseptic central venous catheters. A prospective randomized trial.

OBJECTIVE: To determine the efficacy of antiseptic compared with standard triple lumen central venous catheters (CVCs) in reducing the incidence of catheter sepsis and catheter site infection in patients with CVCs for total parenteral nutrition. DESIGN: A prospective, randomized, controlled trial. SETTING: Truman Medical Center, the public teaching hospital for University of Missouri, Kansas City, School of Medicine. PATIENTS: Seventy-two inpatients on the Metabolic Support Service received a CVC for the infusion of total parenteral nutrition. Diagnoses included pancreatic disease, cancer, bowel obstruction, and intestinal surgery, among others. Patients who had a higher risk for contamination during insertion, such as those with a catheter placed through an introducer, inserted in the emergency department, or changed over a guidewire were excluded from the study. INTERVENTION: The control group received a standard CVC without antiseptics. The treatment group received a CVC with a coating of silver sulfadiazine and chlorhexidine gluconate. Each CVC was inspected for infection or malfunction by the Metabolic Support Service 5 times per week. A transparent occlusive dressing was changed every 7 days or more often if there were signs of infection or nonocclusion. When the CVC was removed, the catheter tip, the blood, and the insertion site were cultured. MAIN OUTCOME MEASURES: Although 88 catheters were inserted, only 72 catheters were evaluable. There were 40 patients in the standard group and 32 in the antiseptic group. There were no statistically significant differences between the 2 groups for diagnosis, sex, age, length of stay, days with a CVC, or catheter location. The catheter sepsis rate in the standard group was 8% and in the antiseptic group it was 6%. There were no statistically significant differences between the 2 groups in frequency of site infections or catheter sepsis. CONCLUSIONS: In this study, there were no statistically significant differences in the incidence of catheter-related sepsis or catheter site infections between the standard and antiseptic groups. Future prospective, randomized controlled trials with a larger number of antiseptic catheters are encouraged to confirm or refute these results.

Adult↗

PubMed1996

Genetic fine mapping of the gene for recessive Stargardt disease.

Stargardt disease (STGD) is one of the most frequent causes of macular degeneration in childhood. Linkage analysis in families with recessive STGD has recently shown genetic homogeneity and a location of the underlying gene at 1p22-p21 in a 4-cM interval. Haplotype analysis in seven Dutch STGD families with 11 highly polymorphic markers spanning the critical region has enabled us to refine the location of the underlying gene to a 2-cM region flanked by the loci D1S406 and D1S236. We have identified one 45-year-old nonpenetrant individual who carries two disease alleles. In another family, an affected individual inherited the paternal but not the maternal disease chromosome, suggesting genetic heterogeneity or a different mechanism leading to the disease in this family.

Alleles↗

PubMed1996

Localization of the gene (or genes) for a syndrome with X-linked mental retardation, ataxia, weakness, hearing impairment, loss of vision and a fatal course in early childhood.

Linkage analysis is described in a family with X-linked mental retardation, ataxia, weakness, floppiness, delayed motor development, absence of deep tendon reflexes, hearing impairment and loss of vision (MIM no. 301835). The disease has a fatal course due to the susceptibility of the patients to infections, especially of the respiratory tract. Clinical signs indicate impairment of the posterior columns, peripheral motor and sensory neurons and the second and eighth cranial nerves and/or their nuclei. The involvement of the posterior columns of the spinal cord is further suggested by the almost complete absence of myelinated fibers therein. We localized the responsible gene(s) to Xq21.33-q24 between DXS1231 and DXS1001 with a maximum lod score of 6.97. The proteolipid protein gene, which codes for two myelin proteins of the central nervous system and is located in this region, was considered as a candidate gene for this disorder. However, no mutations were found in the protein-coding part of this gene.

Ataxia↗

PubMed1996

Localization of the gene for Cowden disease to chromosome 10q22-23.

Cowden disease (CD) (MIM 158350), or multiple hamartoma syndrome, is a rare autosomal dominant familial cancer syndrome with a high risk of breast cancer. Its clinical features include a wide array of abnormalities but the main characteristics are hamartomas of the skin, breast, thyroid, oral mucosa and intestinal epithelium. The pathognomonic hamartomatous features of CD include multiple smooth facial papules, acral keratosis and multiple oral papillomas. The pathological hallmark of the facial papules are multiple trichilemmomas. Expression of the disease is variable and penetrance of the dermatological lesions is assumed to be virtually complete by the age of twenty. Central nervous system manifestations of CD were emphasized only recently and include megalencephaly, epilepsy and dysplastic gangliocytomas of the cerebellum (Lhermitte-Duclos disease, LDD). Early diagnosis is important since female patients with CD are at risk of developing breast cancer. Other lesions include benign and malignant disease of the thyroid, intestinal polyps and genitourinary abnormalities. To localize the gene for CD, an autosomal genome scan was performed. A total of 12 families were examined, resulting in a maximum lod score of 8.92 at theta = 0.02 with the marker D10S573 located on chromosome 10q22-23.

Breast Neoplasms↗

PubMed1996

Localization of a gene for Möbius syndrome to chromosome 3q by linkage analysis in a Dutch family.

Möbius syndrome (MIM no. 157900) consists of a congenital paresis or paralysis of the VIIth cranial nerve, frequently accompanied by paralysis of other cranial nerves, orofacial and limb malformations, defects of the musculoskeletal system and mental retardation. Although most patients are sporadic cases, familial recurrence is not rare. Different pedigrees suggest different modes of inheritance. We performed linkage analysis in a large family with autosomal dominantly inherited Möbius syndrome, consisting essentially of asymmetric bilateral facial pareses. After exclusion of the candidate region for Möbius syndrome on 13q12.2-q13, we localized the gene to chromosome 3q21-22, indicating genetic heterogeneity of Möbius syndrome. This heterogeneity is further proven by the exclusion of both loci in a second family with Möbius syndrome.

Chromosome Mapping↗

PubMed1995

Male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor gene.

Leydig cell hypoplasia is a rare autosomal recessive condition that interferes with normal development of male external genitalia in 46,XY individuals. We have studied two Leydig cell hypoplasia patients (siblings born to consanguineous parents), and found them to be homozygous for a missense mutation (Ala593Pro) in the sixth transmembrane domain of the luteinizing hormone (LH) receptor gene. In vitro expression studies showed that this mutated receptor binds human choriogonadotropin with a normal KD, but the ligand binding does not result in increased production of cAMP. We conclude that a homozygous LH receptor gene mutation underlies the syndrome of autosomal recessive congenital Leydig cell hypoplasia in this family. These results have implications for the understanding of the development of the male genitalia.

Amino Acid Sequence↗

PubMed1995

Tumoral fibrosis and lack of circumscription in granular cell tumor of the breast.

Granular cell tumors are benign neoplasms of putative Schwann cell origin that most commonly occur in the tongue. While granular cell tumors in the breast are uncommon, the occurrence of this tumor at this site warrants special consideration, since the mammographic, gross, and microscopic appearance can mimic carcinoma. We describe the case of a 61-year-old white woman with a granular cell tumor of the left breast. Our case and a review of the international literature show that desmoplasia and lack of circumscription are common features of granular cell tumor of the breast.

Breast↗

PubMed1995

Structure and expression of histone H3.3 genes in Drosophila melanogaster and Drosophila hydei.

We demonstrate that in Drosophila melanogaster the histone H3.3 replacement variant is encoded by two genes, H3.3A and H3.3B. We have isolated cDNA clones for H3.3A and cDNA and genomic clones for H3.3B. The genes encode exactly the same protein but are widely divergent in their untranslated regions (UTR). Both genes are expressed in embryos and adults; they are expressed in the gonads as well as in somatic tissues of the flies. However, only one of them, H3.3A, shows strong testes expression. The 3' UTR of the H3.3A gene is relatively short (approximately 250 nucleotides (nt)). H3.3B transcripts can be processed at several polyadenylation sites, the longest with a 3' UTR of more than 1500 nt. The 3' processing sites, preferentially used in the gonads and somatic tissues, are different. We have also isolated the Drosophila hydei homologues of the two H3.3 genes. They are quite similar to the D. melanogaster genes in their expression patterns. However, in contrast to their vertebrate counterparts, which are highly conserved in their noncoding regions, the Drosophila genes display only limited sequence similarity in these regions.

Animals↗

PubMed1995

A missense mutation in the second transmembrane segment of the luteinizing hormone receptor causes familial male-limited precocious puberty.

Patients with familial male-limited precocious puberty present with early onset of puberty. Several missense mutations in the LH receptor gene that cause amino acid substitutions in the sixth transmembrane segment of the receptor protein have been shown to be a cause of the disorder. We have identified a novel LH receptor gene mutation in a patient with familial male-limited precocious puberty that results in a threonine for methionine substitution at position 398 in the second transmembrane segment of the receptor protein. In vitro expression in human embryonic kidney 293 cells of this LH receptor mutant and two previously described LH receptor mutants showed that cAMP production in the absence of hormone was elevated up to 25-fold compared to the basal level of the wild-type receptor. The ED50 values of hormone-induced cAMP production were within the same range for wild-type and mutant receptors, but maximal hormone-induced cAMP production was relatively low for mutant receptors. We also produced receptors containing amino acid substitutions in both the second and sixth transmembrane segments. For these double mutants, basal receptor activities were similar to the basal activities observed in single mutants, whereas hormone-induced receptor activation was almost completely abolished.

Base Sequence↗

PubMed1994

Localization of the gene for dominant cystoid macular dystrophy on chromosome 7p.

In a family with autosomal dominant cystoid macular dystrophy (DCMD) linkage was detected with the dinucleotide marker D7S435 on the short arm of chromosome 7. With markers flanking D7S435, the DCMD locus could be assigned to the interval D7S493-D7S526 at 7p15-p21, which spans approximately 20 cM. Three-point linkage yielded a maximal lod score of 9.46 and location score of 43.5 and suggested that DCMD is 5,5 cM proximal to D7S493. Recently, a retinitis pigmentosa (RP7) locus has been mapped in roughly the same area of chromosome 7. Genetic data of both studies described below, allow a region of overlap between the location of the DCMD and the RP7 gene between D7S435 and D7S526. Both genes being one and the same will further substantiate the close relationship between macular degeneration and retinitis pigmentosa.

Age of Onset↗

PubMed1994

Genetic linkage of the keratin type II gene cluster with ichthyosis bullosa of Siemens and with autosomal dominant ichthyosis exfoliativa.

Ichthyosis bullosa of Siemens is an autosomal dominant disease characterized by mild hyperkeratosis and blistering. Autosomal dominant ichthyosis exfoliativa is a recently described disease with clinical features similar to ichthyosis bullosa of Siemens, but in contrast to ichthyosis bullosa of Siemens no histologic signs typical for epidermolytic hyperkeratosis are observed. We used linkage analysis to test whether keratin gene mutations might underlie both diseases. This analysis showed linkage of both disorders with the region of chromosome 12 in which the keratin type II gene cluster is located. The keratin type I gene cluster on chromosome 17 is excluded. These data, combined with clinical observations, strongly suggest that the genes coding for keratin 1 or keratin 2e, both expressed in the suprabasal compartment of the epidermis and located in the type II gene cluster, are candidate genes for ichthyosis bullosa of Siemens and ichthyosis exfoliativa.

Base Sequence↗

PubMed1994

Ichthyosis bullosa of Siemens is caused by mutations in the keratin 2e gene.

Ichthyosis bullosa of Siemens is a blistering disorder with autosomal dominant inheritance. The disease resembles bullous congenital ichthyosiform erythroderma but is less severe. Keratins K1 and K10 have been implicated in bullous congenital ichthyosiform erythroderma. Linkage analysis pointed to the involvement of a keratin type II gene (12q11-13) in ichthyosis bullosa of Siemens. Mutations in the highly conserved regions of K1, a member of the type II gene cluster, were excluded. The gene coding for keratin 2e is also located in the type II gene cluster and the expression of the gene coincides with the occurrence of epidermolytic hyperkeratosis. Sequence analysis revealed the presence of mutations in the K2e gene in patients with ichthyosis bullosa of Siemens. Three different mutations were detected, one in the 1A domain and two in the 2B domain of the rod. Furthermore, histologic and ultrastructural examination of skin biopsies indicated that ichthyosis exfoliativa is identical to ichthyosis bullosa of Siemens. This was confirmed by the results of the molecular analysis. In the family diagnosed as ichthyosis exfoliativa, a mutation was detected that was identical to the mutation found in one of the families with ichthyosis bullosa of Siemens.

Adult↗