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Biomedical subjects

B D Gelb

Publications and source records attributed to B D Gelb.

At least 55 records · Page 3Linked to original sources
PubMed1997

Molecular genetics of congenital heart disease.

This review of advances made toward understanding the molecular basis of congenital heart disease covers studies on subjects ranging from atrioventricular septal defects to zebrafish models. Genetically abnormal mice with atrioventricular septal defects have abnormal endocardial cushion development with the delayed appearance of mesenchymal cells and certain critical adhesion proteins. The prevalence of 22q11 deletions among patients with the conotruncal defects was estimated at 8% to 17%. Deletions were rare among patients lacking typical DiGeorge syndrome (DGS) or velocardiofacial (VCF) dysmorphic features, and more common in tetralogy of Fallot with pulmonary atresia than tetralogy of Fallot alone. Studies with patients with unusual 22q11 defects revealed that regional effects on several genes seem to underlie these complex phenotypes. A second DGS/VCF region on chromosome 10p13 was defined molecularly. Laterality defects (heterotaxy) have been associated with connexin43 mutations, and mice lacking connexin43 developed pulmonary atresia with intact ventricular septum. Three other groups failed to find connexin43 mutations in heterotaxy patients, suggesting genetic heterogeneity. Studies of cardiac looping with lower vertebrates revealed the critical role of the notochord. Ellis-van Creveld syndrome, an autosomal dominant skeletal dysplasia with atrial septal defects, and familial total anomalous pulmonary venous return, an autosomal dominant trait with reduced penetrance, were genetically linked to chromosomal bands 4p16 and 4p13-q12, respectively. The zebrafish has emerged as an important model for the study of the earliest stages of the cardiovascular system, and the miles apart and gridlock mutants, which have failure of heart tube fusion and aortic atresia, respectively, are discussed.

Animals↗
PubMed1997

Characterization of a de novo unbalanced chromosome rearrangement by comparative genomic hybridization and fluorescence in situ hybridization.

Fluorescence in situ hybridization (FISH) has proven useful for the identification of chromosomal material of unknown origin. More recently, comparative genomic hybridization (CGH) has been used to identify deletions and amplifications, particularly in neoplastic samples. Here, we describe the combined use of CGH and FISH to identify the origin of a de novo unbalanced translocation in a newborn with multiple congenital anomalies. GTG banding of metaphases from cultured lymphocytes showed an unbalanced karyotype, with extra material on a chromosome 5: 46,XX,add(5)(q35). Parental karyotypes were both normal. CGH revealed the additional material was from distal 11q (11q23-->'qter). This finding was confirmed by FISH with a whole chromosome paint for chromosome 11. Based on the CGH and FISH analyses, the proband's karyotype was therefore 46,XX,der(5)t(5;11)(q35.2; q23.2).ish der(5)(wcp11+). This case demonstrates the efficient use of CGH and confirmatory FISH for the identification of chromosomal material of unknown origin.

Abnormalities, Multiple↗
PubMed1997

Promoting physician referral services. Prospective users are not necessarily the best advertising target.

Providers of physician referral services (PRSs) often focus advertising toward consumers who are least aware that such services exist. However, focusing advertising toward a more aware audience might be more useful. A recent study found that consumers most familiar with health care services are most likely to remember the concept of a PRS. Since these consumers may discuss PRSs with others, there appears to be value in promoting PRSs to more aware consumers as intermediaries to diffuse information to less aware consumers.

Advertising↗
PubMed1996

Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency.

Pycnodysostosis, an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature, maps to chromosome 1q21. Cathepsin K, a cysteine protease gene that is highly expressed in osteoclasts, localized to the pycnodysostosis region. Nonsense, missense, and stop codon mutations in the gene encoding cathepsin K were identified in patients. Transient expression of complementary DNA containing the stop codon mutation resulted in messenger RNA but no immunologically detectable protein. Thus, pycnodysostosis results from gene defects in a lysosomal protease with highest expression in osteoclasts. These findings suggest that cathepsin K is a major protease in bone resorption, providing a possible rationale for the treatment of disorders such as osteoporosis and certain forms of arthritis.

Amino Acid Sequence↗
PubMed1996

Cathepsin K: isolation and characterization of the murine cDNA and genomic sequence, the homologue of the human pycnodysostosis gene.

Cathepsin K(EC 3.4.22.38) is a lysosomal cysteine protease that is strongly implicated in bone resorption. The human cathepsin K gene is highly expressed in osteoclasts and gene mutations cause pycnodysostosis, an autosomal recessive skeletal dysplasia. To investigate the evolutionary relatedness of cathepsin K across species, the mouse cathepsin K gene was isolated. A mouse heart cDNA clone, pMCatKl, contained the 3' untranslated region, mature enzyme coding sequence, and most of the propeptide. The remainder of the gene was amplified from mouse melanocyte RNA using 5' rapid amplification of cDNA ends. The gene contained a 990-bp open reading frame, predicting a 329-amino-acid prepropolypeptide. The structure of the protein included a 15-amino-acid presignal, a 99-amino-acid proregion, and a 215-amino-acid mature enzyme. Two potential N-glycosylation sites were identified, one in the proregion and one in the mature enzyme. The 5' untranslated region was 135 bp. The 3' untranslated region was 470 bp including a 9-bp poly(A) tract and contained two polyadenylation signals. The mouse cathepsin K nucleotide and amino acid sequences were highly conserved with the human, rabbit, and chicken homologues across the proregion and mature enzyme. The mouse cathepsin K gene was isolated from an V129 genomic library, and characterization of its genomic structure and intron sizes revealed exons with the initiation ATG in exon 2 and termination TGA in exon 8, a genomic organization that was highly conserved with its human homologue. The availability of the mouse cathepsin K cDNA and genomic sequences will facilitate generation of a mouse model of cathepsin K deficiency by gene targeting.

Amino Acid Sequence↗
PubMed1996

Pycnodysostosis: refined linkage and radiation hybrid analyses reduce the critical region to 2 cM at 1q21 and map two candidate genes.

Pycnodysostosis (PKND) is a rare, autosomal recessive skeletal dysplasia, which has been mapped previously to a 4-cM interval between D1S442 to D1S305 at chromosome 1q21. Only D1S498 did not recombine with the disease locus in a large, consanguineous Arab family with PKND. In the present studies, five new Généthon markers (D1S2343, D1S2344, D1S2345, D1S2346, and D1S2347) were tested against DNA from this family and against the Stanford G3 diploid radiation hybrid panel. The results permitted ordering of some loci previously mapped at no recombinant distance: D1S442-D1S2344-(D1S498/D1S2347)-(D1S2343/+ ++D1S2345)-D1S2346-D1S305.The PKND critical region was refined to the 2-cM interval from D1S2344 to D1S343/D1S2347. In addition, sequence-tagged sites were developed for the two PKND candidate genes, IL6R and MCL1. Use of radiation hybrids revealed that IL6R was tightly linked to D1S305, excluding it from the PKND critical region. MCL1 was most tightly linked to D1S498 and D1S2347, placing it within the critical region.

Base Sequence↗
PubMed1995

Genetic mapping of the cleidocranial dysplasia (CCD) locus on chromosome band 6p21 to include a microdeletion.

Cleidocranial dysplasia (CCD) is a generalized skeletal dysplasia with autosomal dominant inheritance. Recently, the CCD disease locus was localized to 23 [Mundlos et al., 1995] and 17 cM regions [Feldman et al., 1995], of chromosome band 6p21 by linkage studies of seven affected families. Of note, the 23 cM region contained a microdeletion detected in one family at D6S459, an interval that was excluded in the 17 cM overlapping region. Here, linkage of CCD to 6p21 was independently confirmed with a maximal two-point LOD score of Z = 5.12 with marker D6S452 at theta = 0.00. Recombinant events in two affected individuals defined a CCD region of 7 cM from D6S465 to D6S282, which overlapped with the CCD region containing the microdeletion but did not overlap with the 17 cM critical region from D6S282 to D6S291. These results suggest the refined localization of the CCD region to 6 cM spanning markers D6S438 to D6S282, thereby reviving the possibility that the CCD gene lies within the microdeletion at D6S459.

Chromosomes, Human, Pair 6↗
PubMed1995

Linkage of pycnodysostosis to chromosome 1q21 by homozygosity mapping.

Pycnodysostosis is an autosomal recessive sclerosing skeletal dysplasia of unknown aetiology which is inherited with complete penetrance. The clinical features, fully delineated in 1962 by Maroteaux & Lamy and by Andrén et al., include osteosclerosis, acro-osteolysis of the distal phalanges, bone fragility, clavicular dysplasia, reduced stature and skull deformities with delayed suture closure. Although rare, pycnodysostosis has attained prominence because the French artist Henri de Toulouse-Lautrec was retrospectively diagnosed as having been affected with this disorder. For rare autosomal recessive traits, homozygosity mapping provides a powerful approach to disease gene mapping. We have now used this approach to map the locus for pycnodysostosis. Following a genome-wide search in a large Arab family with 16 affected relatives, we established linkage to a narrow region on chromosome 1q21, with a maximal lod score of 11.72. A single marker, D1S498, was homozygous-by-descent in all affecteds and defined the gene locus to a region of 4 cM. Two candidate genes in the region--the interleukin-6 receptor gene (IL6R) and the myeloid cell leukaemia-1 gene (MCL1)--are involved in the differentiation of monocyte/macrophages into osteoclasts, the most likely site of the primary defect in pycnodysostosis.

Abnormalities, Multiple↗
PubMed1994

Leigh syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation (T8993G).

Mutation of mitochondrial (mt) DNA at nucleotide (nt) 8993 has been reported to cause neurogenic weakness, ataxia, retinitis pigmentosa (NARP), or Leigh syndrome (LS). We report a family in whom the mutation was expressed clinically as LS and hypertrophic cardiomyopathy (CMP) in a boy who presented with a history of developmental delay and hypotonia, and who had recurrent lactic acidosis. The mother's first pregnancy resulted in the birth of a stillborn female; an apparently healthy older brother had died suddenly (SIDS) at age 2 months. MtDNA analysis identified the presence of the T8993G point mutation, which was found to be heteroplasmic in the patient's skeletal muscle (90%) and fibroblasts (90%). The identical mutation was present in leukocytes (38%) isolated from the mother, but not from the father or maternal grandmother. Our findings expand the clinical phenotype of the nt 8993 mtDNA mutation to include hypertrophic cardiomyopathy and confirm its cause of LS.

Acidosis, Lactic↗
PubMed1994

Using mass media communication for health promotion: results from a cancer center effort.

Administrators at a cancer center initiated a program they hoped would reduce exposure to the sun, and therefore the incidence of skin cancer. They also hoped for association of the value of the program with their institution. Research measuring the impact of the program showed that it reached more than one million individuals in three cities, and that awareness of the program was associated with behaviors expected to reduce the risk of skin cancer. In its home city, the program was associated with the sponsoring hospital by 22 percent of those who said they were familiar with it; association in other cities was significantly lower.

Cancer Care Facilities↗
PubMed1994

Consequences of bad publicity: one example.

When Houston's leading newspaper investigated local for-profit psychiatric hospitals and ran a series of stories that ranged from unflattering to shocking, any hospital administrator might reasonably have expected dramatic effects on public perceptions of the specific hospitals named, and also perhaps on other psychiatric hospitals in the metropolitan area. In fact, a survey that tracks consumer awareness and impressions of all Houston-area hospitals found no such outcome. These results may be counterintuitive, but they are easily reconcilable with communications theory.

Awareness↗
PubMed1993

Transcatheter closure of residual atrial septal defect following cardiac transplantation.

An almost 3-year-old boy had a residual atrial septal defect after cardiac transplantation. The patient was symptomatic and had arrhythmia and cardiac enlargement. An atrial septal defect occlusion device was employed to close the communication with excellent results. Transcatheter occlusion enabled the patient to avoid further surgery and did not interfere with follow-up endomyocardial biopsies.

Child, Preschool↗
PubMed1993

Genomic structure of and a cardiac promoter for the mouse carnitine palmitoyltransferase II gene.

The mouse carnitine palmitoyltransferase II gene has been isolated and its genomic structure determined. The gene contained five exons, including an unusually long 1305-nt exon 4. The exon/intron boundaries were sequenced and conformed to the consensus splice junction sequences. The transcription start site was determined from adult mouse heart mRNA by primer extension analysis and confirmed by 5' rapid amplification of cDNA ends. A promoter that differs from the previously published promoter for the carnitine palmitoyltransferase II gene was isolated and sequenced. When placed in a mammalian expression vector, this promoter was shown to drive the chloramphenicol acetyltransferase gene in mouse hepatoma cells. This new promoter is the major driver of carnitine palmitoyltransferase II gene expression in heart and may also be active in liver.

Animals↗
PubMed1992

Developmental expression of hexokinase 1 in the rat.

Hexokinase 1 (HK1) activity varies in a developmental stage- and tissue-specific manner and is a key step in glucose homeostasis and energy metabolism. We conducted studies to determine if HK1 expression is regulated at the transcriptional level. Expression of HK1 was examined in selected pre- and postnatal rat tissues using Northern blot analyses and RNAase protection assays. We found that brain and kidney exhibited significantly higher expression than heart, lung, spleen and skeletal muscle. Brain HK1 expression was constant prenatally, peaked at 7 days of age and reached a constant level after weaning. In kidney, HK1 expression was essentially constant or perhaps gradually decreased after weaning. HK1 transcription in heart, skeletal muscle and liver was higher during fetal stages than postnatally. Lung expression was essentially constant except in the adult. HK1 mRNA levels were compared to phosphoglycerate kinase (PGK) mRNA. PGK steady state mRNA levels were relatively constant in all tissues and developmental stages, except in skeletal muscle where there was a postnatal rise. The developmental profiles of HK1 and PGK mRNA expression are not consistent with enzyme activity measurements in all the tissues examined. We conclude that regulation of HK1 expression involves both transcriptional and posttranscriptional mechanisms that are tissue and stage specific.

Animals↗
PubMed1992

Targeting of hexokinase 1 to liver and hepatoma mitochondria.

The proportion of hexokinase (HK; EC 2.7.1.1) isozyme 1 (HK1) that is bound to the outer mitochondrial membrane is tissue specific and developmentally regulated. HK activity is known to be markedly elevated in many cancer cells and a significant fraction is mitochondrial bound. This study examined the role of the 15-amino acid N-terminal domain of HK1 in binding to liver and hepatoma mitochondria. A chimeric reporter construct, pCMVHKCAT, encoding this HK1 domain coupled to the chloramphenicol acetyltransferase (CAT) gene was electroporated into mouse Hepa 1-6 hepatoma cells. After digitonin treatment, cell fractions were assayed for HK, lactate dehydrogenase, and CAT activities. Digitonin (75 micrograms/mg of protein) caused cytosolic leak but 70% of HK remained with the pellet. HKCAT, like HK, remained predominantly with the pellet; CAT form the control, pCMVCAT, remained mostly unbound. Binding of membrane-free cell extracts to rat liver mitochondria in vitro showed 91% of the HKCAT bound, whereas only 12% of CAT bound. Specificity of HKCAT binding to mitochondria was demonstrated by competition of HK1 for HKCAT binding sites on rat liver mitochondria as well as by blockage of HKCAT binding by N,N'-dicyclohexylcarbodiimide, which covalently binds to porin and blocks HK1 binding. Deletional mutant constructs of HKCAT showed reduced binding with increasing deletion size. In summary, these studies demonstrate that the 15-amino acid N-terminal domain of HK1 is necessary and sufficient to confer mitochondrial binding properties to CAT and that there is specificity for this binding to the mitochondria.

Animals↗