Biomedical subjects
Publications and source records attributed to J A Phillips.
A genetic linkage group on the long arm of chromosome 17 is reported. A maximum likelihood of theta = 0.20 between the centromere-based locus D17Z1 and COL1A1 has been found, as well as a theta = 0.10 between COL1A1 and GH1. The most likely order of the three loci is D17Z1-COL1A1-GH1.
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Female green iguanas, Iguana iguana, were caught in Belize, Central America (17 degrees N), in December, at the onset of seasonal gonadal activity. The animals were immediately transferred to San Diego (32 degrees N). Ovarian follicular development continued, with peak plasma hormone levels measured in January and February; 200 pg/ml for progesterone (P) and 800 pg/ml for total estrogens (Et = estradiol [E2] + estrone [E1]). E2 was the predominant estrogen throughout the cycle. Follicular atrophy was indicated in April with circulating progesterone and estrogen levels decreasing to baseline (refractory phase) levels (P = 20 pg/ml; Et = 50 pg/ml). Approximately midway through the refractory phase of their annual reproductive cycle (late May), either the D-Arg6 analog of Chicken II or mammalian GnRH was administered via intraperitoneal osmotic pumps for 14 days to nine females. The analog of chicken II induced a fivefold increase in total circulating estrogens within 3-4 days after implantation. Both continuous and pulsatile delivery of the chicken II analog produced a similar pattern of steroidogenic response. A radical sham control animal showed no increase in steroidogenesis. Mammalian GnRH produced a pattern of similar duration, although the magnitude of the steroidogenic response was only half that produced by the chicken II analog. Estrogen titers approached baseline levels in all treatment groups two days after treatment ceased. Progesterone levels increased in all treatment groups during the delivery of exogenous GnRH, although the increases were not consistent. Untreated male cagemates housed with treated females exhibited increased territoriality, courtship behavior, and mating, which began on day 4 or 5 of the treatment period. The control female was not courted by its male cagemate.
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Multiple endocrine neoplasia type II (MEN-II or Sipple's syndrome) is an autosomal dominant disorder characterized by medullary thyroid cancers, pheochromocytomas, and parathyroid adenomas. A blind analysis of high resolution G-banded chromosomes was performed on blood specimens from eight MEN-II individuals from three unrelated families and six control subjects. Seven of eight MEN-II patients and one of six control subjects were determined to have a deletion at 20p12.2. These findings support the hypothesis that MEN-II patients have a 20p12.2 deletion (chi 2 = 6.99; p less than 0.01). Genomic DNA from seven of the eight MEN-II patients was studied using the DNA probe, D20S5, localized by in situ hybridization to 20p12. The probe binding site is not deleted in some MEN-II patients, as demonstrated by the presence of two alleles detected as restriction fragment length polymorphisms. Thus, D20S5 does not hybridize to DNA sequences that are deleted based on cytogenetic analysis in MEN-II patients.
We studied prospectively 26 young patients with achondroplasia to test two hypotheses: that respiratory problems may be the result of occult spinal cord compression, and that achondroplastic patients with cord compression might have occult respiratory abnormalities. Respiratory abnormalities were present in 85%, the majority caused by a primary problem of the pulmonary system, such as small thoracic cage or obstructed airway. Three patients had hypoxemia, recurrent cyanotic spells, and episodes of respiratory distress explainable only by cervicomedullary cord compression; in each patient, respiratory problems were alleviated by decompressive surgery. Another six patients with cervicomedullary compression had, in addition, at least one primary pulmonary cause of respiratory problems. After decompressive surgery the respiratory problems improved in three and were unchanged in three. Reconstructed sagittal CT images proved the most sensitive technique for detecting craniocervical stenosis as a cause of cervicomedullary cord compression, although some degree of stenosis was present in nearly all of the patients.
Congenital adrenal hyperplasia (CAH) is a common genetic disorder due to defective 21-hydroxylation of steroid hormones. The human P450XXIA2 gene encodes cytochrome P450c21 [steroid 21-monooxygenase (steroid 21-hydroxylase), EC 1.14.99.10], which mediates 21-hydroxylation. The P450XXIA2 gene may be distinguished from the duplicated P450XXIA1 pseudogene by cleavage with the restriction endonuclease Taq I, with the XXIA2 gene characterized by a 3.7-kilobase (kb) fragment and the XXIA1 pseudogene characterized by a 3.2-kb fragment. Restriction endonuclease mapping by several laboratories has suggested that deletion of the P450XXIA2 gene occurs in about 25% of patients with CAH, as their genomic DNA lacks detectable 3.7-kb Taq I fragments. We have cloned human P450c21 cDNA and used it to study genomic DNA prepared from 51 persons in 10 families, each of which includes 2 or more persons with CAH. After Taq I digestion, apparent deletions are seen in 7 of the 20 alleles of the probands; using EcoRI, apparent deletions are seen in 9 of the 20 alleles. However, the apparently deleted alleles seen with Taq I do not coincide with those seen with EcoRI. Furthermore, studies with Bgl II, EcoRI, Kpn I, and Xba I yield normal patterns with at least two enzymes in all cases. Since all probands yielded normal patterns with at least two of the five enzymes used, we conclude that the P450XXIA2 gene "deletions" widely reported in CAH patients probably represent gene conversions, unequal crossovers, or polymorphisms rather than simple gene deletions.
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We present another patient with the rare disorder of isolated GH deficiency (IGHD) type 1A. The diagnosis was confirmed by the clinical course, serology and genetic structure. Analysis of the post GH treatment serum of this patient with several thoroughly characterized monoclonal antibodies against GH established the presence of polyclonal, high titre and high avidity IgG-class antibodies against GH. These had the ability to neutralize GH as they could inhibit the binding of radiolabelled GH to GH-receptors on IM9 lymphoblastoid cells. DNA restriction mapping indicated a deletion of the GH-N gene and a family DNA pattern that was consistent with the proposed autosomal recessive aetiology of this disorder. These findings explain the inability of this patient to synthesize GH and his total immunological intolerance to GH replacement therapy.
A DNA polymorphism for an Xbal site in intron 22 of the human factor VIII:C gene extends the utility of DNA methods for carrier detection in families segregating for hemophilia A. While the DNA polymorphism detected by a BclI site in intron 18 of the factor VIII:C gene was informative for 41% of females studied, the BglI/intron 25 polymorphism provided no additional information because of apparent linkage disequilibrium. In contrast, the Xbal intron 22 polymorphism was useful in 53% of women who were uninformative (homozygous) for either the BclI or BglI polymorphisms. Using the BclI/intron 18 and Xbal/intron 22 intragenic polymorphisms, we could provide highly accurate information for 68% of women we studied who were at risk for carriership. The carrier status of the remaining 32% could be determined utilizing the closely linked Taql/St14 DNA polymorphism.
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Some tests to study the growth hormone secretion have been analysed. According to our own experience and to the present criteria the physiologic tests seem to be more suitable than the pharmacologic ones. In case of discordant results, those obtained in physiologic tests completed with the clinical data and if necessary with biologic probes are conclusive. The availability of GRF will allow the treatment of some cases of dwarfism of hypothalamic origin, that in our opinion are more frequent than those of pituitary origin. Otherwise the gene studies will contribute to the understanding of some cases of genetic dwarfism and make possible an appropriate genetic counseling.
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We report on two sibs with familial isolated growth hormone deficiency (IGHD) resulting from homozygosity for a 7.6 kb deletion within the growth hormone gene cluster. The deletion not only affects the structural gene for growth hormone (GH-N) but also alters sequences adjacent to the chorionic somatomammotropin-like (CS-L) gene. In contrast to previously reported cases with IGHD type IA, our two patients responded well to growth hormone substitution and formation of blocking antibodies did not occur.
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