Biomedical subjects
Publications and source records attributed to C R Scott.
The gene frequencies of ADH2(2) and ALDH2(2) were lower in Tibetan and Mongolian populations than in Vietnamese, Han Chinese, and three Chinese minority populations.
Mutations in the AVPR2 gene encoding the receptor for arginine vasopressin in the kidney (V2 ADHR) have been reported in patients with congenital nephrogenic diabetes insipidus, a predominantly X-linked disorder of water homeostasis. We have used restriction-enzyme analysis and direct DNA sequencing of genomic PCR product to evaluate the AVPR2 gene in 11 unrelated affected males. Each patient has a different DNA sequence variation, and only one matches a previously reported mutation. Cosegregation of the variations with nephrogenic diabetes insipidus was demonstrated for two families, and a de novo mutation was documented in two additional cases. Carrier detection was accomplished in one family. All the variations predict frameshifts, truncations, or nonconservative amino acid substitutions in evolutionarily conserved positions in the V2 ADHR and related receptors. Of interest, a 28-bp deletion is found in one patient, while another, unrelated patient has a tandem duplication of the same 28-bp segment, suggesting that both resulted from the same unusual unequal crossing-over mechanism facilitated by 9-mer direct sequence repeats. Since the V2 ADHR is a member of the seven-transmembrane-domain, G-protein-coupled receptor superfamily, the loss-of-function mutations from this study and others provide important clues to the structure-function relationship of this and related receptors.
mtDNA sequence variation was examined in 60 Native Americans (Mixtecs from the Alta, Mixtecs from the Baja, Valley Zapotecs, and Highland Mixe) from southern Mexico by PCR amplification and high-resolution restriction endonuclease analysis. Four groups of mtDNA haplotypes (haplogroups A, B, C, and D) characterize Amerind populations, but only three (haplogroups A, B, and C) were observed in these Mexican populations. The comparison of their mtDNA variation with that observed in other populations from Mexico and Central America permits a clear distinction among the different Middle American tribes and raises questions about some of their linguistic affiliations. The males of these population samples were also analyzed for Y-chromosome RFLPs with the probes 49a, 49f, and 12f2. This analysis suggests that certain Y-chromosome haplotypes were brought from Asia during the colonization of the Americas, and a differential gene flow was introduced into Native American populations from European males and females.
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Hawkinsinuria, a disorder of tyrosine metabolism has been documented in two families in the United States, in one of which there was clear evidence of autosomal dominant inheritance. Metabolic acidosis and failure to thrive appear to be confined to infancy. Tyrosyl metabolites and 5-oxoproline are also found only in infancy, while 4-hydroxycyclohexylacetic acid was present only with time. The disease may be detected by organic acid analysis or by staining an electropherogram for sulfur containing compounds.
The frequencies of the alleles encoding isozymes of alcohol dehydrogenase and aldehyde dehydrogenase were low in Northwest Coast Amerindians compared to Chinese subjects.
We encountered an infant with clinical and histopathologic features of Gaucher's disease (infantile, type 2) with normal glucocerebrosidase (D-glucosyl-N-acylsphingosine glucohydrolase, E.C.3.2.1.45) activity. Biochemical analysis was performed on leukocytes, cultured skin fibroblasts, and liver. Normal activity of glucocerebrosidase previously has been reported in an older child with juvenile onset (type 3) Gaucher's disease and attributed to a deficiency of a sphingolipid activator protein. These rare cases illustrate and expand our concept of Gaucher's disease and may have both diagnostic and therapeutic implications.
The fragile-X syndrome of mental retardation is associated with an expansion in the number of CGG repeats present in the FMR1 gene. The repeat region is within sequences characteristic of a CpG island. Methylation of CpG dinucleotides that are 5' to the CGG repeat has been shown to occur on the inactive X chromosome of normal females and on the X chromosome of affected fragile-X males, and is correlated with silencing of the FMR1 gene. The methylation status of CpG sites 3' to the repeat and within the repeat itself has not previously been reported. We have used two methylation-sensitive restriction enzymes, AciI and Fnu4HI, to further characterize the methylation pattern of the FMR1 CpG island in normal individuals and in those carrying fragile-X mutations. Our results indicate that: (i) CpG dinucleotides on the 3' side of the CGG repeat are part of the CpG island that is methylated during inactivation of a normal X chromosome in females; (ii) the CGG repeats are also part of the CpG island and are extensively methylated as a result of normal X-chromosome inactivation; (iii) similar to normal males, unaffected fragile-X males with small CGG expansions are unmethylated in the CpG island; for affected males, the patterns of methylation are similar to those of a normal, inactive X chromosome; (iv) in contrast to the partial methylation observed for certain sites in lymphocyte DNA, complete methylation was observed in DNA from cell lines containing either a normal inactive X chromosome or a fragile-X chromosome from an affected male.(ABSTRACT TRUNCATED AT 250 WORDS)
Gene frequencies and haplotypes for two factor IX markers, F9-192 and F9-Hha1, were determined in a Chinese population. The frequencies for F9-192 are 0.86 for A and 0.14 for G. For F9-Hha1, the gene frequencies are 0.69 for - and 0.31 for +. Haplotype analysis revealed that the two polymorphic sites are in linkage equilibrium and, thus, are useful markers for genetic counseling of Asian families in which hemophilia B exists.
Adults with CF followed in a university center were assessed for the presence of the most common CF gene mutation, delta-F508. Excluding one member of a sibling pair, 29 of 55 subjects had two copies of delta-F508 (homozygotes), 23 had one copy of delta-F508 with the other CF mutation not identified (complex heterozygotes) and three were lacking delta-F508. A wide range of clinical severity was seen among individuals carrying two copies of the delta-F508 gene, who are genetically identical at the CF gene locus. The number of individuals diagnosed with CF as adults was significantly lower in the homozygote group (1 of 29) as compared with the heterozygote group (7 of 24). No differences were detected between groups in pulmonary function, non-pulmonary complications or overall clinical severity. These results suggest that environmental or background genetic factors contribute significantly to the variability in pulmonary and other complications seen among individuals with CF.
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Hemophilia B is due to multiple molecular defects in the factor IX gene. Over 80% of mutations are single base substitutions. By amplification and direct sequencing, 51 single base substitutions were found in the transcribed sequence of the factor IX genes of patients from 50 distinct families with hemophilia B. These include 30 mutations in 29 families not previously reported by us; of these, 12 are novel, i.e., not previously published in other series. Of the 51 substitutions in our overall series 23 (45%) occurred as C-to-T or G-to-A transitions at 11 sites within CG dinucleotides. It is estimated that CG transitions occur from one to two orders of magnitude more frequently than mutations in nucleotides that are not within a CG pair. More than one family had identical defects for 6 of the CG mutations. At 4 of these sites, most patients had different haplotypes compatible with distinct mutations. Non-CG-type mutations occurred throughout the coding regions with only one mutation in more than one family. The latter included 7 families with a 397 Ile-to-Thr defect that all share a rare haplotype, suggesting a common ancestor.
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Factor IXSeattle 1 is a 10-kb intragenic deletion identified in a family that has hemophilia B. By sequencing across the site of the deletion, we discovered at the deletion junction a 13-bp sequence (5' . . . TAGAA-GTTCACTT . . . 3') that was homologous to two 14-bp sequences 10 kb apart in introns D and F of the normal factor IX gene. The presence of these homologous sequences in two different regions of the normal gene allows us to propose that genetic recombination has occurred between the sequences, resulting in the gene deletion. The precise recombination site was able to be localized to one of 5 bp (5' . . . AGTTC . . . 3') in the middle of the homologous sequences. The exact length of the deletion is 10,000 bp.
In a study undertaken to determine compliance with Universal Precautions, we observed 129 personnel performing 1,274 interventions on 151 consecutive critically ill and injured patients in an emergency department setting in July 1988. Barrier precautions were fully adhered to 44.0% of the time. During interventions in patients with profuse bleeding, adherence was only 19.5% in contrast to 44.7% for those who were not bleeding. Adherence was 56.4% during minor interventions but only 16.7% during major procedures. Adherence rates varied among health care providers: residents, 58%; emergency staff physicians, 38%; consultant physicians, 43%; emergency nursing staff, 44%; paramedics, 8%; radiology technicians, 14%; and housekeeping, 91%. In a follow up questionnaire that ascertained reasons for lack of compliance, 47% of providers indicated that there was not always sufficient time to put on protective material, 33% felt that precautions interfered with skillful performance of procedures, and 23% stated that materials were uncomfortable. Only 2.7% felt that Universal Precautions did not work. Since there is no proven postexposure prophylaxis for human immunodeficiency virus, Universal Precautions must be rigorously followed until such time as they are shown not to be effective or an alternate approach is developed. Strategies to improve compliance and improvements in barrier technology need to be developed.
The polymerase chain reaction (PCR) method was used to amplify a 356-bp DNA segment containing the suspected BamHI polymorphic site of the factor IX gene. Following the enzyme digestions and gel electrophoresis, polymorphic genotypes (-,+ and +/- types) were observed. The gene frequencies for the rare (+) allele are about 36% in blacks and 2% in Caucasians. The 356-bp DNA was further purified and sequenced. The sequencing gels revealed a single nucleotide substitution (T to G) at position -561 of the gene in blacks and Caucasians. The T-to-G transversion generated a new BamHI site (GGATCC,+type) from a nonenzymatic site, (TGATCC,-type).
In five patients with hemophilia B and detectable Factor IX antigen, altered reactivity to a specific polyclonal antibody fraction or monoclonal anti-Factor IX antibodies was noted. Amplification of selected portions of their Factor IX genes by polymerase chain reaction allowed rapid identification of a single base transition in each of the five families tested. In a patient with severe hemophilia and an altered calcium binding domain, a G to A transition in exon II changed the codon for Glu-27 to Lys (Factor IXSeattle 3). Patients from two families with mild hemophilia with decreased reactivity to a MAb that binds to a site within the sequence coded for by exon IV had a G to A transition changing the codon for Gly-60 to Ser (Factor IXDurham). Two unrelated patients with moderately severe hemophilia lacked reactivity to another murine monoclonal anti-Factor IX which binds to an epitope in the amino-terminal half of the heavy chain of Factor IXa. In these patients, exon VIII contained a G to A transition changing Arg-248 to Gln (Factor IXSeattle 4).