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Biomedical subjects

S S Deeb

Publications and source records attributed to S S Deeb.

At least 91 records · Page 5Linked to original sources
PubMed1992

Defective colour vision associated with a missense mutation in the human green visual pigment gene.

All red/green colour vision defects described so far have been associated with gross rearrangements within the red/green opsin gene array (Xq28). We now describe a male with severe deuteranomaly without such a rearrangement. A substitution of a highly conserved cysteine by arginine at position 203 in the green opsins presumably accounted for his colour vision defect. Surprisingly, this mutation was fairly common (2%) in the population but apparently was not always expressed. In analogy with nonexpression of some 5'green-red hybrid genes in persons with normal colour vision, we suggest that failure of manifestation occurs when the mutant gene is located at a distal (3') position among several green opsin genes. This mutation might also predispose to certain X-linked retinal dystrophies.

Amino Acid Sequence↗
PubMed1992

Increased expression of beta-amyloid protein precursor and microtubule-associated protein tau during the differentiation of murine embryonal carcinoma cells.

Expression of the genes encoding the beta/A4 amyloid protein precursor (APP) and microtubule-associated protein tau was studied in an embryonal carcinoma cell line (P19) that differentiates in vitro into cholinergic neurons after treatment with retinoic acid. Expression of APP increased 34- (mRNA) and 50-fold (protein) during neuronal differentiation; APP-695 accounted for most of this increase. These remarkable increases in APP expression coincided with a proliferation of neuronal processes and with an increase in content of tau mRNA. Moreover, subsequent decreases in the levels of APP and tau mRNA coincided with the onset of the degeneration of the neuronal processes. Immunocytochemical staining suggested that greater than 85% of the P19-derived neurons are cholinergic and that APP is present in the neuronal processes and cell bodies. These results suggest that APP may play an important role in construction of neuronal networks and neuronal differentiation and also indicate that this embryonal carcinoma cell line provides an ideal model system to investigate biological functions of APP and the roles of APP and tau protein in development of Alzheimer's disease in cholinergic neurons.

Amyloid beta-Protein Precursor↗
PubMed1992

Genotype-phenotype relationships in human red/green color-vision defects: molecular and psychophysical studies.

The relationship between the molecular structure of the X-linked red and green visual pigment genes and color-vision phenotype as ascertained by anomaloscopy was studied in 64 color-defective males. The great majority of red-green defects were associated with either the deletion of the green-pigment gene or the formation of 5' red-green hybrid genes or 5' green-red hybrid genes. A rapid PCR-based method allowed detection of hybrid genes, including those undetectable by Southern blot analysis, as well as more precise localization of the fusion points in hybrid genes. Protan color-vision defects appeared always associated with 5' red-green hybrid genes. Carriers of single red-green hybrid genes with fusion in introns 1-4 were protanopes. However, carriers of hybrid genes with red-green fusions in introns 2, 3, or 4 in the presence of additional normal green genes manifested as either protanopes or protanomalous trichromats, with the majority being protanomalous. Deutan defects were associated with green-pigment gene deletions, with 5' green-red hybrid genes, or, rarely, with 5' green-red-green hybrid genes. Complete green-pigment gene deletions or green-red fusions in intron 1 were usually associated with deuteranopia, although we unexpectedly found three carriers of a single red-pigment gene without any green-pigment genes to be deuteranomalous trichromats. All but one of the other deuteranomalous subjects had green-red hybrid genes with intron 1, 2, 3, or 4 fusions, as well as several normal green-pigment genes. The one exception had a grossly normal gene array, presumably with a more subtle mutation. Amino acid differences in exon 5 largely determine whether a hybrid gene will be more redlike or more greenlike in phenotype. Various discrepancies as to severity (dichromacy or trichromacy) remain unexplained but may arise because of variability of expression, postreceptoral variation, or both. When phenotypic color-vision defects exist, the kind of defect (protan or deutan) can be predicted by molecular analysis. Red-green hybrid genes are probably always associated with protan color-vision defects, while the presence of green-red hybrid genes may not always manifest phenotypically with color-vision defects. Four subjects who were found to have 5' green-red hybrid genes in addition to normal red- and green-pigment genes had normal color vision as determined by anomaloscopy. These were discovered among a group of 129 Caucasian males who had been recruited as volunteers for a vision study.(ABSTRACT TRUNCATED AT 400 WORDS)

Base Sequence↗
PubMed1992

Molecular basis of familial chylomicronemia: mutations in the lipoprotein lipase and apolipoprotein C-II genes.

The molecular basis of familial chylomicronemia (type I hyperlipoproteinemia), a rare autosomal recessive trait, was investigated in six unrelated individuals (five of Spanish descent and one of Northern European extraction). DNA amplification by polymerase chain reaction (PCR) followed by single strand conformation polymorphism (SSCP) analysis allowed rapid identification of the underlying mutations. Six different mutant alleles (three of which are previously undescribed) of the gene encoding lipoprotein lipase (LPL) were discovered in the five LPL-deficient patients. These included an 11 bp deletion in exon 2, and five missense mutations: Trp 86 Arg (exon 3), His 136 Arg (exon 4), Gly 188 Glu (exon 5), Ile 194 Thr (exon 5), and Ile 205 Ser (exon 5). The Trp 86 Arg mutation is the only known missense mutation in exon 3. The other missense mutations lie in the highly conserved "central homology region" in close proximity with the catalytic site of LPL. These and other previously reported missense mutations provide insight into structure/function relationships in the lipase family. The missense mutations point to the important role of particular highly conserved helices and beta-strands in proper folding of the LPL molecule, and of certain connecting loops in the catalytic process. A nonsense mutation (Arg 19 Term) in the gene encoding apolipoprotein C-II (apoC-II), the cofactor of LPL, was found to underlie chylomicronemia in the sixth patient who had normal LPL but was apoC-II-deficient.

Adolescent↗
PubMed1991

A mutation in the human apolipoprotein A-I gene. Dominant effect on the level and characteristics of plasma high density lipoproteins.

Epidemiologic and genetic data suggest an inverse relationship between plasma high density lipoprotein (HDL) cholesterol and the incidence of premature coronary artery disease. Some of the defects leading to low levels of HDL may be a consequence of mutations in the genes coding for HDL apolipoproteins A-I and A-II or for enzymes that modify these particles. A proband with plasma apoA-I and HDL cholesterol that are below 15% of normal levels and with marked bilateral arcus senilis was shown to be heterozygous for a 45-base pair deletion in exon four of the apoA-I gene. This most likely represents a de novo mutation since neither parent carries the mutant allele. The protein product of this allele is predicted to be missing 15 (Glu146-Arg160) of the 22 amino acids comprising the third amphipathic helical domain. The HDL of the proband and his family were studied. Using anti-A-I and anti-A-II immunosorbents we found three populations of HDL particles in the proband. One contained both apoA-I and A-II, Lp(A-I w A-II); one contained apoA-I but no A-II, Lp(A-I w/o A-II); and the third (an unusual one) contained apoA-II but no A-I. Only Lp(A-I w A-II) and (A-I w/o A-II) were present in the plasma of the proband's parents and brother. Analysis of the HDL particles of the proband by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed two protein bands with a molecular mass differing by 6% in the vicinity of 28 kDa whereas the HDL particles of the family members exhibited only a single apoA-I band. The largely dominant effect of this mutant allele (designated apoA-ISeattle) on HDL levels suggests that HDL particles containing any number of mutant apoA-I polypeptides are catabolized rapidly.

Amino Acid Sequence↗
PubMed1991

Transcriptional activation of the lipoprotein lipase gene in macrophages by dexamethasone.

The effect of dexamethasone on lipoprotein lipase (LPL) gene expression during macrophage differentiation was investigated by using the human monocytic leukemia cell line THP-1 and human monocyte-derived macrophages. Addition of dexamethasone to THP-1 cells increased steady-state levels of LPL mRNA and LPL mass accumulation in the medium during PMA-induced differentiation by 4-fold. Studies with human monocyte-derived macrophages showed a similar effect of dexamethasone on LPL expression. Peak LPL mRNA levels were achieved 24-h post-dexamethasone addition to THP-1 cells. Optimal stimulation of LPL mRNA occurred when dexamethasone was added 24 h after induction with PMA. Thereafter, there was rapid decline in responsiveness to dexamethasone. Induction of LPL mRNA in THP-1 cells was completely blocked by actinomycin D, suggesting that induction was transcription dependent. The stability of LPL mRNA was not influenced by dexamethasone. Treatment of THP-1 cells with PMA led to a 2-fold increase in specific binding of dexamethasone and a 4-fold increase in glucocorticoid receptor mRNA within 12 h. Thus, dexamethasone stimulates LPL gene expression during differentiation of human macrophages, a process that involves induction of glucocorticoid receptor synthesis and activation.

Blotting, Northern↗
PubMed1990

Molecular genetics of X chromosome-linked color vision among populations of African and Japanese ancestry: high frequency of a shortened red pigment gene among Afro-Americans.

Red-green color vision in humans is mediated by the X chromosome-linked highly homologous red and green pigment genes. Color vision defects are caused by deletions and fusions involving these genes. However, we found the frequency of molecular abnormalities among Caucasians to be twice as high as that of phenotypic color vision defects. Among Japanese the frequency of phenotypic and molecular color vision defects was similar (approximately 5%). Among Afro-Americans, molecular defects (largely green-red fusion genes) were at least five times more frequent (21%) than phenotypic color vision defects (approximately 4%). In addition, 35% of Afro-Americans, 2% of Japanese, and less than 1% of Caucasians had a shortened red pigment gene not associated with phenotypic color vision defects. This gene lacked 1.9 kilobases in its first intron and had the identical size as the green pigment gene from which it presumably originated by gene conversion in an ancestral African population. This gene and the closely linked glucose-6-phosphate dehydrogenase A+ variant were in linkage equilibrium. A model for the evolutionary origin of the color vision pigment genes in higher primates is portrayed.

Black People↗
PubMed1990

Coexistence of abnormalities of hepatic lipase and lipoprotein lipase in a large family.

A large family is reported with familial hepatic triglyceride lipase (HTGL) deficiency and with the coexistence of reduced lipoprotein lipase (LPL) similar to the heterozygote state of LPL deficiency. The proband was initially detected because of hypertriglyceridemia and chylomicronemia. He was later demonstrated to have beta-VLDL despite an apo E3/E3 phenotype and the lack of stigmata of type III hyperlipoproteinemia. The proband had no HTGL activity in postheparin plasma. Two of his half-sisters had very low HTGL activity (39 and 31 nmol free fatty acids/min/ml; normal adult female greater than 44). His son and daughters had decreased HTGL activity (normal male and preadolescent female greater than 102), which would be expected in obligate heterozygotes for HTGL deficiency. Low HTGL activity was associated with LDL particles which were larger and more buoyant. Several family members, including the proband, had reduced LPL activity and mass less than that circumscribed by the 95% confidence-interval ellipse for normal subjects and had hyperlipidemia similar to that described in heterozygote relatives of patients with LPL deficiency. All the sibs with hyperlipidemia had a reduced LPL activity and mass, while subjects with isolated reduced HTGL (with normal LPL activity) had normal lipid phenotypes. Analysis of genomic DNA from these subjects by restriction-enzyme digestion revealed no major abnormalities in the structure of either the HTGL or the LPL gene. Compound heterozygotes for HTGL and LPL deficiency show lipoprotein physiological characteristics typical for HTGL deficiency, while their variable lipid phenotype is typical for LPL deficiency.

Adolescent↗
PubMed1990

A splice-junction mutation responsible for familial apolipoprotein A-II deficiency.

The first case of familial apolipoprotein A-II (apo A-II) deficiency was recently reported from Hiroshima, Japan, and designated apo A-IIHiroshima. The proband had no immunologically detectable apo A-II in her plasma. DNA sequence analysis showed that the proband was homozygous for a G----A transition at position 1 of intron 3 of the apo A-II gene. A sister of the proband, who had an intermediate level of plasma apo AII, was shown to be heterozygous for this base substitution. This splice-junction alteration is most likely responsible for apo A-II deficiency, since it would be expected to completely block splicing of intron 3 from the primary transcript and therefore prevent formation of functional mRNA. This deficiency seems to have little influence either on lipid and lipoprotein profiles or on the occurrence of coronary artery disease.

Apolipoprotein A-II↗
PubMed1989

Structure of the human lipoprotein lipase gene.

Human genomic clones that span the entire lipoprotein lipase (LPL) gene have been isolated and used to determine its structure. The gene is approximately 30 kilobase (kb) pairs in length in which the mRNA specifying sequence is divided into 10 exons. Exons 1-9 are of average size (105-276 bp) whereas exon 10, which specifies the entire 3' uncoding sequence, is 1948 bp in length. Exon 1 codes for the signal peptide, exon 2 includes the protein domain that was shown to bind to the lipoprotein substrate, and exons 6 and 9 code for sequences that are relatively rich in basic amino acids and therefore likely to be involved in anchoring of the enzyme to the capillary endothelium by interaction with the acidic domain of heparan sulfate. Four closely spaced mRNA 5' termini were observed, indicating multiple transcription initiation sites, one of which seems to be favored. Two potential enhancer sequence motifs in the 5' upstream region were observed. One may specify expression in response to intracellular Ca2+ mobilization, and the other may be responsible for expression in adipocytes.

Base Sequence↗
PubMed1989

Molecular patterns of X chromosome-linked color vision genes among 134 men of European ancestry.

We used Southern blot hybridization to study X chromosome-linked color vision genes encoding the apoproteins of red and green visual pigments in 134 unselected Caucasian men. One hundred and thirteen individuals (84.3%) had a normal arrangement of their color vision pigment genes. All had one red pigment gene; the number of green pigment genes ranged from one to five with a mode of two. The frequency of molecular genotypes indicative of normal color vision (84.3%) was significantly lower than had been observed in previous studies of color vision phenotypes. Color vision defects can be due to deletions of red or green pigment genes or due to formation of hybrid genes comprising portions of both red and green pigment genes [Nathans, J., Piantanida, T.P., Eddy, R.L., Shows, T.B., Jr., & Hogness, D.S. (1986) Science 232, 203-210]. Characteristic anomalous patterns were seen in 15 (11.2%) individuals: 7 (5.2%) had patterns characteristic of deuteranomaly (mild defect in green color perception), 2 (1.5%) had patterns characteristic of deuteranopia (severe defect in green color perception), and 6 (4.5%) had protan patterns (the red perception defects protanomaly and protanopia cannot be differentiated by current molecular methods). Previously undescribed hybrid gene patterns consisting of both green and red pigment gene fragments in addition to normal red and green genes were observed in another 6 individuals (4.5%). Only 2 of these patterns were considered as deuteranomalous. Thus, DNA testing detected anomalous color vision pigment genes at a higher frequency than expected from phenotypic color vision tests. Some color vision gene arrays associated with hybrid genes are likely to mediate normal color vision.

Color Perception↗
PubMed1989

Regulation of the low density lipoprotein receptor and hydroxymethylglutaryl coenzyme A reductase genes by protein kinase C and a putative negative regulatory protein.

Transcription of the low density lipoprotein receptor (LDL-R) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase genes was rapidly and transiently induced (8.5- and 2.3-fold, respectively) early during phorbol 12-myristate 13-acetate (PMA)-induced macrophage differentiation of the human monocytic leukemia cell line THP-1. The levels of mRNA coding for LDL-R and HMG-CoA reductase increased soon after induction, reached a maximum (12- and 7-fold increase, respectively) in 2-3 hr, and then rapidly returned to the low constitutive levels observed before induction. The stability of LDL-R mRNA did not change significantly during differentiation, whereas that of HMG-CoA reductase mRNA decreased by about 5-fold 6 hr after the addition of PMA. Transcriptional induction of both LDL-R and HMG-CoA reductase genes (5.6- and 2-fold, respectively) was also observed when undifferentiated cells were treated with cycloheximide (CHX), resulting in a transient increase in steady-state mRNA (7- and 3-fold, respectively). These results suggest that expression of the two genes is maintained at low constitutive levels in uninduced THP-1 cells by a protein with a short half-life. Superinduction of both genes occurred when PMA and CHX were added simultaneously. The induction of LDL-R and HMG-CoA reductase mRNAs during early macrophage differentiation is mediated by protein kinase C. It is hypothesized that protein kinase C acts directly or indirectly to inactivate the labile negative regulatory protein. Induction of LDL-R mRNA was also observed when the human hepatocarcinoma cell line Hep G2 was treated with PMA and CHX, suggesting that this mechanism of regulation may exist in several cell types.

Cell Line↗
PubMed1989

Involvement of second messengers in regulation of the low-density lipoprotein receptor gene.

Transcription of the low-density lipoprotein receptor (LDL-R) gene in the human monocytic leukemic cell line THP-1 and in the human hepatocarcinoma cell line Hep-G2 is regulated by second messengers of the diacylglycerol-protein kinase C (DAG-PKC), inositol 1,4,5-triphosphate-Ca2+, and cyclic AMP pathways. Exogenous phospholipase C (which releases DAG and inositol 1,4,5-triphosphate), PKC activators (phorbol esters and DAG), Ca2+ ionophores, and a cyclic AMP analog all transiently induced accumulation of LDL-R mRNA. The effects of these three signal-transducing pathways were to a large extent additive. Furthermore, PKC stimulation effected an increase in LDL binding, which suggested that the increase in LDL-R mRNA resulted in an increase in functional cell surface receptor activity. These results suggest that uptake of cholesterol by these cells is under control of both intracellular cholesterol levels and external signals.

Calcimycin↗
PubMed1989

Loss of copper-zinc superoxide dismutase gene expression in differentiated cells of myelo-monocytic origin.

Changes in the production of reactive oxygen species and total superoxide dismutase activity have been observed during differentiation of some hematopoietic cells. We therefore investigated whether the steady-state level and rate of transcription of superoxide dismutase-1 (SOD-1) mRNA change during terminal differentiation of the human leukemia cell lines THP-1, HEL, and HL-60 into macrophages and/or granulocytes, respectively. Macrophage differentiation is accompanied by a gradual decrease in both the transcription rate (10x) and the steady-state level (6x) of SOD-1 mRNA. No decrease was observed after treatment with the diacylglycerol analog 1,2 dioctanol-rac-glycerol (di-C8), which like phorbol 12-myristate 13-acetate also activates protein kinase C but does not induce differentiation at the concentration used. The same decrease in SOD-1 mRNA level was observed when HL-60 cells were induced to differentiate into granulocytes by treatment with dimethylsulfoxide. These data suggest that a decrease in SOD-1 mRNA to almost undetectable levels accompanies differentiation of macrophages and granulocytes.

Cell Differentiation↗
PubMed1988

Absence of linkage of chromosome 21q21 markers to familial Alzheimer's disease.

Alzheimer's disease is the most common form of dementia among the elderly population. Although the etiology is unknown, inheritance plays a role in the pathogenesis of the disease. Recent work indicates that an autosomal dominant gene for Alzheimer's disease is located on chromosome 21 at band q21. In the present study of a group of autopsy-documented kindreds, no evidence for linkage was found between familial Alzheimer's disease (FAD) and chromosome 21q21 markers (D21S1/D21S72 and the amyloid beta gene). Linkage to the D21S1/D21S72 locus was excluded at recombination fractions (theta) up to 0.17. Linkage to the amyloid gene was excluded at theta = 0.10. Apparent recombinants were noted in two families for the amyloid gene and in five families for the D21S1/D21S72 locus. These data indicate that FAD is genetically heterogeneous.

Alzheimer Disease↗
PubMed1987

The use of apolipoprotein CII as a genetic marker for myotonic dystrophy.

In five families we have confirmed the close linkage between the genes for myotonic dystrophy and apolipoprotein CII. The total maximum lod (log of the odds) score was 3.32 at 0 recombination. We demonstrate that the use of a Ban I restriction site polymorphism for apolipoprotein CII adds additional useful information when combined with the more commonly used Taq I polymorphism. The potential practical clinical use of these markers for the prenatal diagnosis of myotonic dystrophy is demonstrated.

Apolipoprotein C-II↗
PubMed1987

Association of an apolipoprotein CII allele with familial dementia of the Alzheimer type.

In order to identify the genetic locus responsible for familial dementia of the Alzheimer type (DAT), we are studying 10 families in which DAT appears to be inherited as an autosomal dominant trait. Genotypes for a TaqI restriction fragment length polymorphism (RFLP) at the apolipoprotein CII locus were determined for the following groups: affected and unaffected DAT family members, DAT subjects with no family history of the disease, and normal control subjects. The control group included 103 individuals from our study and 123 from the study of Wallis et al. (Hum. Genet., 68 (1984) 286). The frequency of the TaqI fast (F) allele in the affected familial DAT subjects (0.64 +/- 0.08) differed significantly from that for the control group (0.39 +/- 0.02) (Z = 2.87, P less than 0.005). In contrast, the F-allele frequency for the unaffected family members was 0.31 +/- 0.09, which was similar to that of the combined control group (Z = 0.78, P greater than 0.40). Subsequently, genotypes were determined for two other polymorphisms at the Apo CII locus: a BanI RFLP and a BglI RFLP. For these two polymorphisms, the allele frequencies for the familial DAT subjects differed from the unaffected control groups but the differences were smaller and not statistically significant. These data suggest a previously unrecognized association between the Apo CII TaqI F-allele and familial DAT.

Aged↗