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Biomedical subjects

S A Berry

Publications and source records attributed to S A Berry.

At least 37 records · Page 2Linked to original sources
PubMed1997

Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations.

Inborn errors of the pyruvate dehydrogenase complex (PDC) are associated with lactic acidosis, neuroanatomic defects, developmental delay, and early death. PDC deficiency is a clinically heterogeneous disorder, with most mutations located in the coding region of the X-linked alpha subunit of the first catalytic component, pyruvate dehydrogenase (E1). Treatment of E1 deficiency hs included cofactor replacement, activation of PDC with dichloroacetate, and ketogenic diets. In this report, we describe the outcome of ketogenic diet treatment in seven boys with E1 deficiency. These patients were divided into two groups based on their mutations (R349H, three patients; and R234G, four patients, two sibling pairs). All seven patients received ketogenic diets with varying degrees of carbohydrate restriction. Clinical outcome was compared within each group and between siblings as related to the intensity and duration of dietary intervention. Subjects who either had the diet initiated earlier in life or who were placed on greater carbohydrate restriction had increased longevity and improved mental development. Based on the improved outcomes of patients with identical mutations, it appears that a nearly carbohydrate-free diet initiated shortly after birth may be useful in the treatment of E1 deficiency.

Child Development↗
PubMed1996

Clinical and biochemical heterogeneity in females of a large pedigree with ornithine transcarbamylase deficiency due to the R141Q mutation.

A large family with ornithine transcarbamylase deficiency due to mutation R141Q was ascertained through a propositus who presented with acute neonatal hyperammonemic coma. Of 13 females at risk, 11 were evaluated clinically and had laboratory studies performed. Seven were found to be heterozygous for the mutation. Of these seven, five had chronic clinical symptoms and two were asymptomatic. None of the heterozygotes had elevated plasma ammonia on random testing. Of the five symptomatic females, three had markedly elevated plasma glutamine levels on random testing, while two had levels in the upper range of normal. Plasma citrulline and arginine levels were somewhat lower in the symptomatic individuals but still within the normal range. Five heterozygotes who were tested had either spontaneous orotic aciduria or elevated orotic acid following ingestion of allopurinol, whereas one unaffected female and one unaffected male had normal allopurinol tests. A higher than expected proportion of female heterozygous for the R141Q mutation were clinically and biochemically symptomatic but remained undiagnosed for many years. Plasma glutamine determination and allopurinol testing should be performed in females who present with a combination of relatively non-specific symptoms detailed in this report.

Allopurinol↗
PubMed1996

Duplication of 7p: further delineation of the phenotype and restriction of the critical region to the distal part of the short arm.

We report on a patient with duplication of 7p15-->pter and review the literature. Patients with partial duplication of the distal 7p, including only the distal segment 7p15-->pter, have a syndrome comparable to that of patients with a larger or complete duplication of 7p. This suggests that the critical region for the dup(7p) phenotype is restricted to 7p15-->pter. The complete clinical phenotype of dup(7)(p15-->pter) includes mental retardation, skull anomalies, large anterior fontanel, cardiovascular defects, joint dislocation and contraction, and gastrointestinal and genital defects. Recognition of the clinical spectrum in patients with a smaller duplication of 7p, and the assignment of this critical region, should prove valuable for accurate counseling, prediction of outcome, and further gene mapping.

Abnormalities, Multiple↗
PubMed1996

Rapid agonist-induced internalization of the 5-hydroxytryptamine2A receptor occurs via the endosome pathway in vitro.

The mechanism by which agonists induce 5-hydroxytryptamine2A (5-HT2A) receptor internalization was investigated in a clonal cell line stably transfected with the 5-HT2A receptor cDNA. Confocal laser microscopy of immunolabeled 5-HT2A receptors in control (untreated) cells demonstrated that most of the immunoreactivity was associated with the cell surface. After quipazine administration, a significant increase in intracellular immunofluorescence was measured. Time course studies demonstrated rapid agonist-dependent internalization of 5-HT2A receptors, with significant internalization occurring as early as 5 min after agonist administration at 37 degrees. In GF-62 cells, agonist-induced internalization was blocked by preincubation with the 5-HT2A receptor antagonist ketanserin. Internalization was also temperature sensitive because agonist-induced internalization did not occur at 4 degrees. Dual-label experiments disclosed that 5-HT2A and transferrin receptors were internalized via the same endocytotic vesicles. These results suggest that 5-HT2A receptors and transferrin receptors are internalized via the endosomal pathway in GF-62 cells. Although 5-HT2A receptors were internalized, down-regulation, or loss of radioligand binding sites, did not occur. Our results demonstrate that agonists rapidly induce 5-HT2A receptor internalization via the endosomal pathway and that internalization can be dissociated from down-regulation.

3T3 Cells↗
PubMed1995

Partial monosomy of chromosome 1p36.3: characterization of the critical region and delineation of a syndrome.

We describe 5 patients ranging in age from 3 to 47 years, with karyotypic abnormalities resulting in monosomy for portion of 1p36.3, microcephaly, mental retardation, prominent forehead, deep-set eyes, depressed nasal bridge, flat midface, relative prognathism, and abnormal ears. Four patients have small hands and feet. All exhibited self-abusive behavior. Additional findings in some of the patients include brain anomalies, optic atrophy, hearing loss and skeletal deformities. The breakpoints within chromosome 1 were designated at 1p36.33 (1 case). Thus, the smallest region of deletion overlap is 1p36.33-->1pter. Detection of the abnormal 1 relied on high resolution G-band analysis. Fluorescence in situ hybridization (FISH) utilizing a DNA probe (Oncor D1Z2) containing the repetitive sequences in distal 1p36, confirmed a deletion of one 1 homologue in all 5 cases. The abnormal 1 resulted from a de novo deletion in only one patient. The remaining patients were either confirmed (3 cases) or suspected (1 case) to have unbalanced translocations. Despite the additional genetic imbalance present in these four cases, monosomy of 1p36.33 appears to be responsible for a specific clinical phenotype. Characterization of this phenotype should assist in the clinical diagnosis of this chromosome abnormality.

Abnormalities, Multiple↗
PubMed1995

Growth hormone induction of hepatic serine protease inhibitor 2.1 transcription is mediated by a Stat5-related factor binding synergistically to two gamma-activated sites.

A growth hormone (GH)-inducible nuclear factor (GHINF) from rat liver has been purified to near homogeneity. On SDS-polyacrylamide gel electrophoresis and UV-cross-linking, a major band of mass approximately 93 kDa and a minor band of approximately 70 kDa are detected in the purified fraction. DNase I footprinting using purified GHINF yields a protected region of -149/-115 on the rat serine protease inhibitor 2.1 (Spi 2.1) promoter encompassed within the growth hormone response element (GHRE). Mutational analysis demonstrated that GHINF binds synergistically to two gamma-interferon-activated sites (GAS) within the GHRE, with the 3' element being the pivotal binding domain. Functional assays show that both GAS elements are necessary for full GH response. GHINF has no immunoreactivity with either a C-terminal Stat1 antibody or an N-terminal Stat3 antibody, while cross-reacting with a C-terminal Stat5 monoclonal antibody. GHINF will bind to two GAS elements from the Stat5 binding region of the beta-casein gene. These studies indicate that GHINF is a Stat5-related factor binding synergistically to two GAS elements to activate Spi 2.1 transcription.

Animals↗
PubMed1995

Growth hormone rapidly activates rat serine protease inhibitor 2.1 gene transcription and induces a DNA-binding activity distinct from those of Stat1, -3, and -4.

Transcriptional regulation by growth hormone (GH) represents the culmination of signal transduction pathways that are initiated by the cell surface GH receptor and are targeted to the nucleus. Recent studies have demonstrated that the activated GH receptor can stimulate Stat1, a cytoplasmic transcription factor that becomes tyrosine phosphorylated and translocates to the nucleus, where it can interact with specific DNA sequences to modulate gene expression. GH also has been found to induce protein binding to a portion of the rat serine protease inhibitor (Spi) 2.1 gene promoter that is required for GH-induced transcription of Spi 2.1. Using GH-deficient hypophysectomized rats as a model, we show that GH treatment rapidly and potently induces both nuclear Spi 2.1 mRNA expression in the liver and specific nuclear protein binding to a 45-bp segment of the Spi 2.1 gene promoter. A GH-inducible gel-shifted complex appears within 15 min of systemic hormone administration and can be inhibited by an antiphosphotyrosine monoclonal antibody but is not blocked by a polyclonal antiserum to Stat1, Stat3, or Stat4, even though the nucleotide sequence contains two gamma interferon-activated sequence-like elements that could interact with STAT proteins. By Southwestern (DNA-protein) blot analysis, approximately 41- and 35-kDa GH-inducible proteins were detected in hepatic nuclear extracts with the Spi 2.1 DNA probe. Thus, a GH-activated signaling pathway stimulates Spi 2.1 gene expression through a unique mechanism that does not appear to involve known members of the STAT family of transcription factors.

Animals↗
PubMed1995

Tyrosinase inhibition due to interaction of homocyst(e)ine with copper: the mechanism for reversible hypopigmentation in homocystinuria due to cystathionine beta-synthase deficiency.

Deficiency of cystathionine beta-synthase (CBS) is a genetic disorder of transsulfuration resulting in elevated plasma homocyst(e)ine and methionine and decreased cysteine. Affected patients have multisystem involvement, which may include light skin and hair. Reversible hypopigmentation in treated homocystinuric patients has been infrequently reported, and the mechanism is undefined. Two CBS-deficient homocystinuric patients manifested darkening of their hypopigmented hair following treatment that decreased plasma homocyst(e)ine. We hypothesized that homocyst(e)ine inhibits tyrosinase, the major pigment enzyme. The activity of tyrosinase extracted from pigmented human melanoma cells (MNT-1) that were grown in the presence of homocysteine was reduced in comparison to that extracted from cells grown without homocysteine. Copper sulfate restored homocyst(e)ine-inhibited tyrosinase activity when added to the culture cell media at a proportion of 1.25 mol of copper sulfate per 1 mol of DL-homocysteine. Holo-tyrosinase activity was inhibited by adding DL-homocysteine to the assay reaction mixture, and the addition of copper sulfate to the reaction mixture prevented this inhibition. Other tested compounds, L-cystine and betaine did not affect tyrosinase activity. Our data suggest that reversible hypopigmentation in homocystinuria is the result of tyrosinase inhibition by homocyst(e)ine and that the probable mechanism of this inhibition is the interaction of homocyst(e)ine with copper at the active site of tyrosinase.

Adolescent↗
PubMed1994

Infant with multiple congenital anomalies and deletion (9)(q34.3).

We report on a male infant with developmental delay, growth failure, hypotonia, dolichocephaly, hypoplastic midface, epicanthal folds, down-slanting palpebral fissures, foveal hypoplasia, tracheomalacia, pectus excavatum, supraventricular tachycardia, gut malrotation, hypospadias, talipes equinovarus, short third metatarsals, capillary hemangiomata, and a de novo terminal deletion at 9q34.3.

Abnormalities, Multiple↗
PubMed1994

Binding of a growth hormone-inducible nuclear factor is mediated by tyrosine phosphorylation.

The nuclear mechanism by which GH acts to induce gene expression after binding to its receptor on the cell surface is not defined. We have characterized an element in the 5'-flanking region of the rat GH-responsive serine protease inhibitor (Spi) 2.1 gene responsible for its induction by GH. This element binds a hepatic nuclear protein(s) in a GH state-specific manner. Activation of binding by GH does not require de novo protein synthesis, suggesting that a reversible posttranslational process is required for binding to the element. To define the mechanism of this process, hepatic nuclear extracts were analyzed by electrophoretic mobility shift assays using a DNA fragment (-147 to -103) of the Spi 2.1 gene. Treatment of extracts with phosphatases resulted in a marked reduction of GH state-specific binding. Addition of phosphatase inhibitors antagonized the reduction in binding after phosphatase treatment. The specific nature of the phosphorylation event involved in binding was explored using phosphotyrosine antibodies and a protein tyrosine phosphatase. Treatment of nuclear extracts with either of these reagents ablated binding to the response element. Because the tyrosine-phosphorylated transcription factor protein p91 has recently been implicated in cytokine signal transduction mediated by JAK2, we sought evidence that p91 was part of the GH-responsive binding complex. Analysis of an enriched preparation of GH-inducible binding complexes by Western blots using anti-p91 demonstrated no immunoreactivity. We conclude that tyrosine phosphorylation of a nuclear factor is required for GH state-specific binding to this GH response element in vivo, but that p91 is not present in the binding complex.

Animals↗
PubMed1993

Hepatic fatty acid-binding protein mRNA is regulated by growth hormone.

Hepatic fatty acid-binding protein (FABP) is one of several abundant proteins which may participate in fatty acid uptake and utilization. Using differential hybridization to screen for growth hormone-responsive gene products, a complementary deoxyribonucleic acid (cDNA) was isolated which proved to be a hepatic FABP cDNA fragment. Hypophysectomy caused a 60% reduction in hepatic FABP messenger ribonucleic acid (mRNA) levels in rat liver, and growth hormone administration to hypophysectomized rats resulted in restoration of the expression of hepatic FABP mRNA. Other pituitary hormones did not alter these changes in expression. The response to growth hormone occurred within 4 hours of administration. During development, expression of hepatic FABP mRNA in rat liver was low in late fetal life, with increases to 40% of adult values by day 2 of life. Significant increases to adult levels did not occur until after day 25, when weaning is essentially completed. Alteration of hepatic FABP mRNA expression by growth hormone in rat liver may be important in the complex regulation of fatty acid uptake and metabolism.

Animals↗
PubMed1993

Expression of growth hormone-responsive serpin mRNAs in perinatal rat liver.

Hormonal mechanisms controlling growth of the fetus are poorly understood, and generally growth hormone (GH) is not thought to influence perinatal growth. To examine the influence of GH in the expression of genes in perinatal rat liver, we measured RNA levels of several GH responsive and growth axis genes. Spi 2.1, Spi 2.2, Spi 2.3, insulin-like growth factors (IGF) I and II, and GH receptor mRNAs were measured in rat liver total RNA from gestational days 19, 20, 21, and postnatal day 2. Spi 2.1 and 2.3 genes were faintly expressed on day 20, 6% and 13 +/- 1% of adult levels on gestation day 21, and 6% and 31 +/- 6% of adult levels on day 2. Deoxyribonuclease I (DNase I)-hypersensitive sites in the 5' flanking region of the Spi 2.1 gene, which are concordant with GH response, were not present in DNA extracted from livers at gestation day 19 but were present at days 20, 21, and 2, suggesting the gene is transcriptionally competent after day 19 and that the areas of chromatin vulnerable to DNase I digestion are the same in pre- and postnatal life. Low levels of GH receptor mRNAs (approximately 10% of adult) were present on all measured days. IGF-I mRNA was below quantitatable levels in day 19 or 20 fetal samples and was only 2.7 +/- 0.1% of adult levels on day 21. Levels on day 2 were 9.6 +/- 1.9% of adult. IGF-II mRNA was essentially constant throughout this period, with a minimal increase at day 21 of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Germ cell localization of a testicular growth hormone-releasing hormone-like factor.

GH-releasing hormone (GHRH)-like mRNA and immunoreactivity (t-GHRH-li) are present in the testes of rats and humans. To learn more about the physiology of t-GHRH-li mRNA, we performed a series of experiments that disrupted various testicular functions. We employed ethylene dimethanesulfonate, a Leydig cell toxin, to assess the effects of Leydig cell ablation on t-GHRH-li mRNA and protein levels in prepubertal and postpubertal male rats. The ethylene dimethanesulfonate treatment resulted in decreases in serum testosterone, but had no effect on t-GHRH-li mRNA or peptide levels. To assess the effect of GHRH on Leydig cell steroidogenesis, Leydig cells were isolated by Percoll gradient centrifugation and cultured in the presence or absence of hCG, GHRH, or hCG plus GHRH. GHRH had no effect on steroidogenesis by Leydig cells, either alone or in combination with hCG. To localize t-GHRH-li mRNA within rat testis, in situ hybridization analysis was performed on testicular sections from normal rats, using a [35S]GHRH riboprobe. Grains were detected in spermatogenic cells with the antisense probe, whereas none was detected with the sense strand (control) probe. To verify these results, Northern blot analysis of RNA from separated testicular cells was performed. t-GHRH-li mRNA was detected in spermatocytes and round spermatids and to a lesser extent in Sertoli cells, but not in elongating spermatids, Leydig cells, or peritubular myoid cells. t-GHRH-li mRNA was also not found in epididymis. Since our experiments localized t-GHRH-li mRNA to spermatogenic cells, methoxyacetic acid (MAA), a pachytene spermatocyte toxin, was administered to postpubertal rats to determine whether t-GHRH-li is expressed primarily in pachytene spermatocytes. MAA treatment caused a decrease in testicular weight, which gradually returned to control levels by 42 days. Serum FSH levels in the treated animals fluctuated over the course of the experiment, while those in control animals remained steady. However, there was no difference in testicular GHRH-li mRNA levels between control and treated animals at any treatment time. Insulin-like growth factor-I and -II mRNA levels were also unaltered by the MAA treatment. We conclude from these results that t-GHRH-li is synthesized in early spermatogenic cells, but not in mature sperm, and that testicular GHRH-li does not play a major role in steroidogenesis by the Leydig cell.

Animals↗