Biomedical subjects
Publications and source records attributed to B D Hall.
A case is presented of a child born with a left forearm deficiency and a cavernous hemangioma covering the tip of the forearm and left elbow. Points relative to the potential associations of vascular abnormalities and limb deficiencies are discussed.
The mystique of skeletal dysplasias is gradually vanishing. Many more physicians are being taught about disorders of disproportionate shortness. The classification system is more practical, and the genetics of these individually uncommon disorders is better established. Metabolic studies will continue to identify the basic defect in these previously hard to get at disorders, allowing for prenatal diagnosis, carrier detection, and treatment. Advances such as bone marrow transplant, bone lengthening, and the encouraging positive effects of growth hormone therapy are exciting new interventions to aid the disproportionately short statured person. The scenario is set for clinicians to become effective participants in the realm of skeletal dysplasias, but it all starts with an accurate diagnosis.
We describe 2 Caucasian men with rheumatoid arthritis (RA) who developed non-Hodgkin's lymphoma of identical histological type during treatment with low dose oral weekly methotrexate (MTX). Both patients had longstanding RA and had been treated with MTX for over 2 years at time of tumor diagnosis; neither had secondary Sjögren's syndrome. The oncogenic potential of MTX and RA arthritis is reviewed.
We have previously reported on the isolation of the ret1-1 mutation in yeast, which reduces the efficiency of transcription termination by RNA polymerase III. We have cloned the RET1 gene by complementation of an ochre suppression phenotype in ret1-1 cells. The RET1 gene was mapped to near the HIS3 gene on the right arm of chromosome 15 by using hybridization to OFAGE gels. Sequencing of the RET1 gene has identified its product as the second-largest subunit of RNA polymerase III. We have carried out an extensive sequence alignment with other RNA polymerase second-largest subunits and discuss the conservation of several functional domains. The RET1 gene was used to recover the ret1-1 mutant allele from genomic DNA using an integration/excision technique. Plasmid-based fine mapping and fragment swapping were used to localize the ret1-1 mutation for sequencing. We discuss the ret1-1 sequence lesion with regard to possible roles in transcription. In particular, the recessive nature of the ret1-1 mutation may have major implications for our understanding of the transcription process.
Wheat germ nuclear extracts inhibited an active yeast polymerase III (pol III) transcription extract. We isolated two chromatin-associated fractions which harbored biochemically distinguishable inhibitory activities, each contributing about 40-50% to the total inhibitory activity. One fraction, which was released from the chromatin upon treatment with 350 to 900 mM NaCl, was purified to homogeneity and identified as histone H1. It inhibited the yeast extract by excluding the transcription machinery from the template DNA. It can be partially antagonized by additional nontemplate DNA together with templates that have strong pol III promoters. The other fraction, which was released from the chromatin between 0 and 350 mM NaCl, inhibited transcription by affecting transcription complex formation partially through transcription factor-inhibitor interactions. Furthermore, it affected the rate of transcription reinitiation but not the elongation rate. Ways to move towards an active DNA-dependent pol III plant extract are discussed.
The Marfan syndrome is a common autosomal dominant disorder of connective tissue. Despite many years of intensive investigation, the primary genetic defect has not yet been identified. Reverse genetic methods, targeted at mapping this disease gene, have resulted in an initial report of linkage of the genetic locus for the Marfan phenotype in Finnish families to two polymorphic markers on chromosome 15. We have investigated four large multiplex American families with classic Marfan syndrome using standard genetic linkage methods. Our data confirm the assignment of the Marfan syndrome gene to chromosome 15, but establish a more centromeric location (defined by markers D15S25 and D15S1) as the most probable site for the genetic defect (lod score = 12.1, theta = 0.00). These data should facilitate identification and characterization of the Marfan syndrome gene and, in selected families, have immediate application to diagnosis of equivocal cases or prenatal counseling.
In a genetic selection for Saccharomyces cerevisiae genes involved in transcription start site specification, two mutant genes which restore alcohol dehydrogenase activity to a functionally defective S. pombe ADH gene were recovered. Examination of S. pombe ADH initiation sites showed that mutations in the SHI gene shift the location of the transcription initiation window closer to TATA. The shi mutant also affected initiation site selection for two S. cerevisiae genes that were tested. For H2B mRNA, initiation occurred in the shi mutant at a series of initiation sites located 43 to 80 bp 3' of the histone H2B TATA sequence and at the usual initiation sites 102 and 103 bp downstream of the TATA sequence. Weakly used initiation sites ranging from 51 to 80 bp downstream of the TATA sequence were observed for the S. cerevisiae ADH1 gene in shi strains, in addition to the normal ADH1 initiation sites 89 and 99 bp from the TATA sequence. Restoration of function to the defective S. pombe ADH gene occurs only when this gene contains a TATA sequence; a single-base-pair TATA-to-TAGA change is sufficient to prevent this restoration of function. Genetic mapping placed the SHI locus on the left arm of chromosome VII, 22.3 centimorgans from cyh2; it does not correspond to any previously mapped gene.
Fragile X syndrome, an X-linked genetic disorder, is the third most common cause of mental retardation. The following is a case of a 6-year-old boy with fragile X syndrome and its characteristic cognitive and behavioral symptomatology, including attention deficit hyperactivity disorder. In addition, this child experienced initial insomnia and nocturnal enuresis, problems not previously reported with fragile X. Previous pharmacological treatment of the syndrome's behavioral difficulties and attention deficit has included stimulants, folic acid, and neuroleptics. This is the first report of the successful use of imipramine. Imipramine also improved the boy's insomnia and enuresis, whereas methylphenidate caused an overall worsening of his condition.
The roles of the TATA element and sequences near the mRNA initiation site in specifying the location of initiation sites in Saccharomyces cerevisiae were examined, using the Schizosaccharomyces pombe ADH gene. The importance of spacing was demonstrated by analysis of a series of deletions that removed from 8-50 bp between the TATA element and ATG translation initiation site of this gene. Primer extension mapping showed that increasing deletion length is associated with a progressive shift downstream in the location of the initiation sites. The distance of a given site from the promoter affected the relative ability of the site to be utilized for initiation. For this gene, a permissive region for transcription initiation exists between 55 and 125 bases downstream of the TATA element, and a zone of 75-115 bases allows maximal usage of an initiation site. The presence of a TATA sequence was shown to be necessary in S. cerevisiae for maintaining the location of this "window" of initiation. The TATA sequence is essential for function of the gene in S. pombe. This gene, as well as the majority of the 63 S. cerevisiae genes surveyed, uses initiation sites which fit a PyAA/T(Pu) consensus. Cis-acting mutations were recovered which restored ADH activity to a deletion allele that initiates its mRNAs downstream of the ATG. DNA sequence and transcript analysis with these mutants confirmed the requirement of proper spacing and conformity of initiation sites to the PyAA/T(Pu) consensus for efficient transcript initiation.
In eukaryotes, extended tracts of T residues are known to signal the termination of RNA polymerase III transcription. However, it is not understood how the transcription complex interacts with this signal. We have developed a selection system in yeast that uses ochre suppressors weakened by altered transcription termination signals to identify mutations in the proteins involved in termination of transcription by RNA polymerase III. Over 7600 suppression-plus yeast mutants were selected and screened, leading to the identification of one whose effect is mediated transcriptionally. The ret1-1 mutation arose in conjunction with multiple rare events, including uninduced sporulation, gene amplification, and mutation. In vitro transcription extracts from ret1-1 cells terminate less efficiently at weak transcription termination signals than those from RET1 cells, using a variety of tRNA templates. In vivo this reduced termination efficiency can lead to either an increase or a further decrease in suppressor strength, depending on the location of the altered termination signal present in the suppressor tRNA gene. Fractionation of in vitro transcription extracts and purification of RNA polymerase III has shown that the mutant effect is mediated by highly purified polymerase in a reconstituted system.
A mild to moderately affected mother with Nager acrofacial dysostosis produced a severely affected phocomelic son. This apparent autosomal dominant transmission and the extreme variability dictates a reassessment of the genetics of Nager acrofacial dysostosis.
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High fever occurred in a 30-year-old woman five weeks after transsphenoidal hypophysectomy for a pituitary adenoma. Extensive investigation failed to reveal any evidence of infection, and the clinical findings suggested the fever to be a manifestation of steroid withdrawal. Either suboptimal dosage of corticosteroid replacement therapy or omission of such therapy in adrenal insufficiency must be considered in the differential diagnosis of enigmatic postoperative fever.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
We report on a 12-yr-old female and a 14-yr-old male with Seckel syndrome. The 12-yr-old female had pancytopenia, which is seen occasionally in patients with Seckel syndrome and is also a feature of Fanconi anemia, a well-recognized autosomal recessive dwarfism syndrome with chromosome instability. Chromosome breakage analysis of both of our patients also indicated chromosome instability. We suggest that there may be a subgroup of Seckel syndrome patients with chromosome instability and/or hematological problems.
Yeast transcription factor tau (transcription factor IIIC) specifically interacts with tRNA genes, binding to both the A block and the B block elements of the internal promoter. To study the influence of A block-B block spacing, we analyzed the binding of purified tau protein to a series of internally deleted yeast tRNA(3Leu) genes with A and B blocks separated by 0 to 74 base pairs. Optimal binding occurred with genes having A block-B block distances of 30-60 base pairs; the relative helical orientation of the A and B blocks was unimportant. Results from DNase I "footprinting" and lambda exonuclease protection experiments were consistent with these findings and further revealed that changes in A block-B block distance primarily affect the ability of tau to interact with A block sequences; B block interactions are unaltered. When the A block-B block distance is 17 base pairs or less, tau interacts with a sequence located 15 base pairs upstream of the normal A block, and a new RNA initiation site is observed by in vitro transcription. We propose that the initial binding of tau to the B block activates transcription by enhancing its ability to bind at the A block, and that the A block interaction ultimately directs initiation by RNA polymerase III.