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P Goodyer

Publications and source records attributed to P Goodyer.

At least 37 records · Page 2Linked to original sources
PubMed1996

A common molecular basis for three inherited kidney stone diseases.

Kidney stones (nephrolithiasis), which affect 12% of males and 5% of females in the western world, are familial in 45% of patients and are most commonly associated with hypercalciuria. Three disorders of hypercalciuric nephrolithiasis (Dent's disease, X-linked recessive nephrolithiasis (XRN), and X-linked recessive hypophosphataemic rickets (XLRH)) have been mapped to Xp11.22 (refs 5-7). A microdeletion in one Dent's disease kindred allowed the identification of a candidate gene, CLCN5 (refs 8,9) which encodes a putative renal chloride channel. Here we report the investigation of 11 kindreds with these renal tubular disorders for CLCN5 abnormalities; this identified three nonsense, four missense and two donor splice site mutations, together with one intragenic deletion and one microdeletion encompassing the entire gene. Heterologous expression of wild-type CLCN5 in Xenopus oocytes yielded outwardly rectifying chloride currents, which were either abolished or markedly reduced by the mutations. The common aetiology for Dent's disease, XRN and XLRH indicates that CLCN5 may be involved in other renal tubular disorders associated with kidney stones.

Amino Acid Sequence↗
PubMed1996

The pathogenesis of multicystic dysplastic kidney disease: insights from the study of fetal kidneys.

The pathogenesis of multicystic dysplastic kidney disease (MCDKD) is unknown. Most morphologic studies of MCDKD kidneys have been performed when the kidneys are resected postnatally, when their architecture has been distorted by massive cyst enlargement. We obtained two MCDKD kidneys at an early stage of development (14 and 19 weeks' gestation) and examined the pattern of nephrogenesis in detail. In both affected kidneys, we identified islands of spatially dislocated metanephric blastema adjacent to zones containing all the normal structural elements of nephrogenesis, including aggregates of induced mesenchyme, S-shaped bodies and maturing glomerull, and proximal and distal tubules. Metanephric blastemal cells displayed characteristic vimentin and smooth muscle actin immunoreactivity and insulin-like growth factor II gene expression, whereas induced elements exhibited appropriate cytokeratin immunoreactivity and Wilms' tumor gene expression. In most other zones, renal cysts were lined with epithelia varying from a flattened squamous to a cuboidal morphology and expression of markers suggested their origin to be from all portions of the nephron including Bowman's space, proximal tubule, and collecting duct. In some cysts, small clusters of epithelial cells were identified within the cyst lumen. These studies suggest that in the early stages of MCDKD, normal nephrogenesis occurs in what seems to be a normal metanephric blastema; however, an intrinsic abnormality in the branching morphogenesis of the ureteric duct might be responsible for the development of the histopathologic changes described.

Actins↗
PubMed1995

Repression of the retinoic acid receptor-alpha gene by the Wilms' tumor suppressor gene product, wt1.

The Wilms' tumor (WT) suppressor gene, WT1, encodes a zinc finger DNA binding protein (wt1) which functions as a transcriptional regulator. Germline WT1 mutations predispose to WTs and in many cases are associated with urogenital anomalies. Identification of wt1 downstream targets is essential to understanding regulatory processes involved in development of this system. In this study, we demonstrate that wt1 can repress transcription of the retinoic acid receptor-alpha 1 (RAR-alpha 1) promoter. Transient transfection, deletion mutagenesis, and mobility shift assays suggest that wt1 mediates repression of the human RAR-alpha 1 promoter through a GC-rich DNA binding motif (5'-GCGGGGGCG-3'), at positions -111 to -120 bp (relative to the transcription initiation site). In contrast, the murine RAR-alpha 1 promoter contains a cryptic binding motif and is not responsive to wt1. These results indicate that some wt1-regulatory pathways are not conserved across species, suggesting a molecular basis for differences in phenotypes between humans and mice harboring WT1 lesions.

Base Sequence↗
PubMed1995

A phase I study of chemically synthesized verotoxin (Shiga-like toxin) Pk-trisaccharide receptors attached to chromosorb for preventing hemolytic-uremic syndrome.

A double-blind, placebo-controlled study was conducted to document possible side effects associated with oral consumption of synthetic verotoxin (VT, shiga-like toxin) Pk-trisaccharide receptor sequences attached to Chromosorb (Synsorb-Pk) by healthy adult volunteers. Synsorb-Pk reclaimed from volunteer stool samples was also analyzed to determine if its VT-binding activity was affected by exposure to the pH extremes and digestive processes of the human gastrointestinal tract. No participant reported any Synsorb-Pk-related adverse reactions, and no clinically important trends in laboratory data were evident. Synsorb-Pk recovered from stools retained its ability to absorb VT in polymyxin extracts of VT-producing Escherichia coli and also neutralized VT when mixed in vitro with VT-positive stools from children with hemorrhagic colitis or hemolytic-uremic syndrome (HUS). These results suggest a potential use for Synsorb-Pk in preventing HUS in patients infected with VT-producing E. coli.

Absorption↗
PubMed1994

Nature and recurrence of AVPR2 mutations in X-linked nephrogenic diabetes insipidus.

X-linked nephrogenic diabetes insipidus (NDI) is a rare disease with defective renal and extrarenal arginine-vaso-pressin V2 receptor responses due to mutations in the AVPR2 gene in Xq28. We analyzed 31 independent NDI families to determine the nature and recurrence of AVPR2 mutations. Twenty-one new putative disease-causing mutations were identified: 113delCT, 253del35, 255de19, 274insG, V88M, R106C, 402delCT, C112R, Y124X, S126F, W164S, S167L, 684delTA, 804insG, W284X, A285P, W293X, R337X, and three large deletions or gene rearrangements. Five other mutations--R113W, Y128S, R137H, R181C, and R202C--that previously had been reported in other families were detected. There was evidence for recurrent mutation for four mutations (R113W, R137H, S167L, and R337X). Eight de novo mutation events were detected (274insG, R106C, Y128S, 167L [twice], R202C, 684delTA, and R337X). The origins were maternal (one), grandmaternal (one), and grandpaternal (six). In the 31 NDI families and 6 families previously reported by us, there is evidence both for mutation hot spots for nucleotide substitutions and for small deletions and insertions. More than half (58%) of the nucleotide substitutions in 26 families could be a consequence of 5-methyl-cytosine deamination at a CpG dinucleotide. Most of the small deletions and insertions could be attributed to slipped mispairing during DNA replication.

Amino Acid Sequence↗
PubMed1993

Relief of sickle cell priapism by hydralazine. Report of a case.

We report a 16-year-old Tanner IV male with homozygous hemoglobin S who presented with recurrent episodes of priapism unresponsive to standard therapy with hydration, analgesia, and exchange transfusion. He had a complete resolution of his symptoms with hydralazine therapy. We therefore suggest a trial of vasodilator therapy for recurrent sickle cell priapism before attempting surgical therapy.

Adolescent↗
PubMed1986

Renal ultrasound in metabolic bone disease.

Fifty-one patients aged 1 year to 56 years with metabolic bone disease underwent renal ultrasound. Medullary nephrocalcinosis was found in nine of 24 patients with X-linked hypophosphatemic rickets and is considered to be iatrogenic, related to vitamin D therapy. Another three in this group of 24 with both medullary and cortical increased renal echogenicity had suffered from repeated episodes of vitamin D intoxication and had secondary hyperparathyroidism. Nephrocalcinosis was less frequent in patients with treated vitamin D-dependent rickets or hypophosphatemic bone disease where generally smaller doses of vitamin D are given. Patients with pseudohypoparathyroidism, on small doses of vitamin D, had a normal renal ultrasound. In cystinosis and Fanconi's syndrome, the kidneys are small, echodense (both the cortex and medulla) with a tendency to cyst formation.

Adolescent↗
PubMed1986

Respiratory chain defects in the mitochondria of cultured skin fibroblasts from three patients with lacticacidemia.

The cultured skin fibroblasts from three patients with lacticacidemia were found to have low rates of 1-[14C]pyruvate oxidation in the face of normal pyruvate dehydrogenase activity. After incubation with 1 mM glucose, these three cell strains also exhibited lactate/pyruvate ratios which were three times greater than those of controls. In two of the patients, both ATP and oxygen consumption in fibroblast mitochondrial preparations was deficient with NAD-linked substrates but normal with succinate and ascorbate/N'N'N'N' tetramethyl phenylene diamine. In the third patient, ATP synthesis in mitochondrial preparations was deficient with all substrates tested. Measurement of Rotenone-sensitive NADH-cytochrome c reductase in mitochondrial preparations from skin fibroblasts showed that two of the patients had 14 and 18%, respectively, of control activity. In the third patient, cytochrome oxidase activity was 15% of that in controls. We conclude that respiratory chain defects can be demonstrated in cultured skin fibroblasts with consistency using a number of different techniques.

Adenosine Triphosphate↗
PubMed1985

Ontogeny modifies manifestations of cystinuria genes: implications for counseling.

Among 339,868 newborn infants screened at 3 weeks of age (91% compliance rate), 730 had elevated rates of excretion of cystine and the dibasic amino acids lysine, ornithine, and arginine; 191 infants had persistent "infantile cystinuria" on follow-up screening (100% compliance). Apparent incidence of the phenotype was 562 per million infants; this rate is seven times higher than for classic cystinuria in the adult segment of the Quebec population. We studied longitudinally 26 probands 2 to 4 months of age. Initially, each excreted cystine and dibasic amino acids at much higher levels than did normal infants or either parent. From parental phenotypes (heterozygous or homozygous normal) and urine amino acid excretion values at 6 months of age in probands, the infants were classified as either heterozygous for the various classic cystinuria genotypes--type I ("silent"), eight infants; type II (high excretor), three; type III (moderate excretor), nine--or homozygous (and genetic compound), six. Urine amino acid excretion diminished steadily with age, to reach the variant parental value in heterozygous infants but not in homozygotes. Cystinuria heterozygotes, with the possible exception of some type I individuals, could not be distinguished reliably from homozygotes in early infancy, although homozygotes had significantly higher excretion values as a group. We deduce that renal ontogeny amplifies phenotypic expression of cystinuria alleles, thus influencing correct classification of genotype (heterozygote vs homozygote, and type of allele). These findings have implications for counseling and the need for follow-up of infantile cystinuria.

Aging↗
PubMed1985

Defective intramitochondrial NADH oxidation in skin fibroblasts from an infant with fatal neonatal lacticacidemia.

A small-for-gestational-age female infant born at term developed severe lactic acidosis and died on day 13 of life. Two previous sibs had also died of overwhelming lactic acidosis in the neonatal period. The lactate-to-pyruvate and 3-hydroxybutyrate-to-acetoacetate ratios were elevated at 136 and 42 to one, respectively. The activities of the pyruvate dehydrogenase complex and pyruvate carboxylase in cultured skin fibroblasts were normal but a defect in respiration was indicated by the low rates of conversion of 1-[14C]pyruvate, glutamate, and lactate to 14CO2 in these cells. Skin fibroblast cultures also displayed an elevated lactate-to-pyruvate ratio (72:1) when incubated with glucose as substrate compared to control cell cultures (20:1). When mitochondrial preparations of skin fibroblasts (prepared by digitonin extraction) were tested for their ability to synthesize ATP from a variety of substrates, it was found that those of the patient made adequate amounts of ATP with either succinate or ascorbate/tetramethyl-phenylenediamine as substrate but not with the NAD-linked substrates pyruvate, isocitrate, and palmitoyl carnitine. We propose that this is indicative of a defect in the respiratory chain between NADH and coenzyme Q, for the first time demonstrable in cultured skin fibroblasts.

Acidosis↗
PubMed1984

The molecular basis for the two different clinical presentations of classical pyruvate carboxylase deficiency.

Eight cases of isolated human pyruvate carboxylase deficiency were examined from seven families. Although all patients presented with a chronic lacticacidemia, two particular patients presented with the added features of hyperammonemia, citrullinemia, and hyperlysinemia. When cultured skin fibroblasts from these patients were examined for their ability to synthesize [3H]biotin-containing proteins, it was found that the two patients who presented with hyperammonemia, citrullinemia, and hyperlysinemia did not synthesise a protein of the correct subunit molecular weight (Mr = 125 K daltons) corresponding to pyruvate carboxylase. In addition, when skin fibroblast proteins were labeled with [35S]methionine, cross-reacting material (CRM) corresponding to pyruvate carboxylase was immunoprecipitated by antipyruvate carboxylase antiserum in most patients, but again the two patients with the atypical presentation showed no CRM. We propose that the different clinical presentation of human pyruvate carboxylase deficiency is a manifestation of two different mutations in the pyruvate carboxylase gene, one that results in the synthesis of a relatively inactive pyruvate carboxylase protein CRM(+ve) and one that results in the lack of expression of the gene in the form of a recognizable protein CRM(-ve).

Biotin↗
PubMedDate not supplied

What PAX genes do in the kidney.

Of the nine known PAX genes, only two (PAX2 and PAX8) are expressed in the developing kidney. Genetic evidence in mice and humans indicates that PAX2 plays a critical role in normal renal development and may sit atop a molecular cascade which unfolds during the transition from undifferentiated mesenchyme to the early stages of nephrogenesis. Less is known about the role of PAX8 in kidney development; although PAX8 is expressed in the S-shaped body and early proximal tubule, preliminary data suggest that renal morphogenesis is unaffected by its absence. In this review, we discuss the basic aspects of PAX gene structure and function and how mutations of PAX2 might interfere with structure of the developing nephron.

Animals↗
PubMedDate not supplied

The molecular basis of cystinuria: an update.

Cystinuria is a hereditary disorder of cystine and dibasic amino acid transport across the luminal membrane of renal proximal tubule and small intestine. In 1992, a cDNA (rBAT) was isolated from kidney which induced high-affinity, sodium-independent uptake of cystine and dibasic amino acids when expressed in Xenopus oocytes. The rBAT gene was mapped to a region of chromosome 2p known to contain a cystinuria locus, and rBAT expression was demonstrated in the straight (S3) portion of renal proximal tubule and small intestine. Over 30 distinct rBAT mutations have been described in patients who inherit two fully recessive (type I) cystinuria genes. Recently, the second cystinuria gene (SLC7A9) on chromosome 19q was identified; SLC7A9 mutations were shown to cause the incompletely recessive form of cystinuria (types II and III). Patients who inherit two mutant SLC7A9 genes have recurrent nephrolithiasis comparable to those with two rBAT mutations. In some cystinuria families, patients inherit a fully recessive allele from one parent and an incompletely recessive allele from the other parent; patients with this 'mixed type' of cystinuria have somewhat milder disease. It is not yet clear whether this form of cystinuria involves rBAT as well as SLC7A9 mutations. Current evidence suggests that the transmembrane channel mediating uptake of cystine and dibasic amino acids at the luminal surface is encoded by SLC7A9; the smaller rBAT protein forms a heterodimeric complex with this channel and is critical for its targetting to the luminal membrane.

Amino Acid Transport Systems, Basic↗