14 research outputs found
Expression of Human Globin Genes in Transgenic Mice Carrying the Β-Globin Gene Cluster with a Mutation Causing G ΓΒ + Hereditary Persistence of Fetal Hemoglobin a
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73405/1/j.1749-6632.1990.tb24303.x.pd
Kidney disease in adults with Prader-Willi syndrome:international cohort study and systematic literature review
BACKGROUND: Prader-Willi syndrome (PWS) is a rare, complex, genetic disorder characterized by hyperphagia, hypotonia, delayed psychomotor development, low muscle mass and hypothalamic dysfunction. Adults with PWS often have obesity, hypertension and type 2 diabetes mellitus (DM2), known risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD). Early symptoms of CVD and CKD may be masked by intellectual disability and inability to express physical complaints. Furthermore, kidney diseases are often asymptomatic. Therefore, renal and cardiovascular disease might be missed in patients with PWS. Microalbuminuria is an early sign of microvascular damage in the kidneys and other vascular beds. Therefore, we screened our adult PWS cohort for the presence of elevated urinary albumin and (micro)albuminuria.METHODS: We retrospectively collected anthropometric measurements, blood pressure, medical history, medication use, urine dipstick and biochemical measurements form electronic patient files. In addition, we performed a systematic literature review on kidney disease in PWS.RESULTS: We included 162 adults with genetically confirmed PWS (56% male, median age 28 years), of whom 44 (27%) had DM2. None had known CVD. All subjects had normal estimated glomerular filtration rate (eGFR) according to non-PWS reference intervals. Elevated urinary albumin or (micro)albuminuria was present in 28 (18%); 19 out of 75 (25%) had an increased urinary albumin-to-creatinine ratio (UACR) and 10 out of 57 (18%) had an increased urinary protein-to-creatinine ratio. Elevated urinary albumin was present at a young age (median age 26 (IQR 24-32) years) and was associated with an significantly higher BMI and LDL-cholesterol levels and higher prevalence of DM2, hypertension and dyslipidemia than those with normal UACR (p=0.027, p=0.019, p<0.001, p<0.001, p=0.011 and respectively).CONCLUSION: Upon screening, one in every five adults with PWS had increased urinary albumin or (micro)albuminuria, early signs of microvascular disease. All had normal eGFR, according to non-PWS reference intervals, and none had a formal diagnosis of CVD. As muscle mass is low in PWS, creatinine levels and eGFR may be spuriously normal. Urinalysis in this patient group can be used as a screening tool for microvascular (kidney) disease. We propose an algorithm for the detection and management of microvascular disease in adults with PWS.</p
Corrigendum: Kidney disease in adults with Prader-Willi syndrome: international cohort study and systematic literature review
Kidney disease in adults with Prader-Willi syndrome: international cohort study and systematic literature review
BackgroundPrader-Willi syndrome (PWS) is a rare, complex, genetic disorder characterized by hyperphagia, hypotonia, delayed psychomotor development, low muscle mass and hypothalamic dysfunction. Adults with PWS often have obesity, hypertension and type 2 diabetes mellitus (DM2), known risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD). Early symptoms of CVD and CKD may be masked by intellectual disability and inability to express physical complaints. Furthermore, kidney diseases are often asymptomatic. Therefore, renal and cardiovascular disease might be missed in patients with PWS. Microalbuminuria is an early sign of microvascular damage in the kidneys and other vascular beds. Therefore, we screened our adult PWS cohort for the presence of elevated urinary albumin and (micro)albuminuria.MethodsWe retrospectively collected anthropometric measurements, blood pressure, medical history, medication use, urine dipstick and biochemical measurements form electronic patient files. In addition, we performed a systematic literature review on kidney disease in PWS.ResultsWe included 162 adults with genetically confirmed PWS (56% male, median age 28 years), of whom 44 (27%) had DM2. None had known CVD. All subjects had normal estimated glomerular filtration rate (eGFR) according to non-PWS reference intervals. Elevated urinary albumin or (micro)albuminuria was present in 28 (18%); 19 out of 75 (25%) had an increased urinary albumin-to-creatinine ratio (UACR) and 10 out of 57 (18%) had an increased urinary protein-to-creatinine ratio. Elevated urinary albumin was present at a young age (median age 26 (IQR 24-32) years) and was associated with an significantly higher BMI and LDL-cholesterol levels and higher prevalence of DM2, hypertension and dyslipidemia than those with normal UACR (p=0.027, p=0.019, p<0.001, p<0.001, p=0.011 and respectively).ConclusionUpon screening, one in every five adults with PWS had increased urinary albumin or (micro)albuminuria, early signs of microvascular disease. All had normal eGFR, according to non-PWS reference intervals, and none had a formal diagnosis of CVD. As muscle mass is low in PWS, creatinine levels and eGFR may be spuriously normal. Urinalysis in this patient group can be used as a screening tool for microvascular (kidney) disease. We propose an algorithm for the detection and management of microvascular disease in adults with PWS
Regulation of the human fetal gamma globin genes.
The purpose of this report was to study fetal gamma globin gene regulation. In the non-deletion form of hereditary persistence of fetal hemoglobin (HPFH), point mutations occur within the promoter regions of the paired gamma globin genes. Since individuals with HPFH continue to express fetal globin in adult life, these point mutations may highlight sequences which contribute to the fetal to adult hemoglobin switch. Five HPFH mutations occur within seven base pairs in the 200 region of the gamma globin promoters. By gel retardation and footprinting assays, several proteins were shown to bind this region; at least one of the DNA-protein complexes results from Sp1 protein binding. Experiments with purified Sp1 protein and Sp1 antibody identified three regions within the gamma globin promoters which bind to Sp1. The transcriptionally important CACCC site at 140 has a high affinity for Sp1. The 50 and 200 regions constitute weak Sp1 binding sites. Additional proteins also bind to each of these sites. Expression studies in Drosophila SL2 cells demonstrated that these Sp1 binding sites allow Sp1 mediated transactivation of the gamma globin promoter. The Sp1-dependent promoter strength was reduced 57% by a point mutation within the CACCC sequence. The HPFH point mutation at 198 dramatically increases the binding of Sp1. As a result of this increased affinity, the 198 HPFH promoter is transactivated to a greater extent than the wild type promoter. Finally, transient expression assays were done in an attempt to demonstrate that the point mutations are responsible for the overproduction of gamma globin in adult cells. However, the constructs used failed to recapitulate the overexpression seen in vivo. This may be due to the need for additional cis sequences in the construct or the need to conduct these experiments in a cell line which can be induced to switch. In conclusion, the data presented here increases the understanding of the trans-factors which interact with the gamma globin promoters and suggests that Sp1 may play an important role in the regulation of the fetal gamma globin genes.Ph.D.Cellular and Molecular BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/105774/1/9208637.pdfDescription of 9208637.pdf : Restricted to UM users only
Specific in Vitro Interaction between Recombinant Strongylocentrotus purpuratus Bindin and a Recombinant 45A Fragment of the Putative Bindin Receptor
The interaction between recombinant Strongylocentrotus purpuratus sperm bindin and a recombinant fragment of the putative egg bindin receptor of the same species was measured in vitro. In solution these molecules interact with simple bimolecular kinetics, displaying an equilibrium dissociation constant of about 0.1 μM. Thus, as implied by many observations in vivo and in vitro, bindin and the putative egg receptor display a specific affinity for one another
Mercapturate pathway metabolites of sotorasib, a covalent inhibitor of KRASG12C, are associated with renal toxicity in the Sprague Dawley rat
Gene expression and lymphocyte population at the fetal-maternal interface in sheep pregnancies established by somatic cell nuclear transfer
Immunogenetic factors in the selection of cord blood units for transplantation: current search strategies and future perspectives
Gene Expression and Lymphocyte Population at the Fetal-maternal Interface in Sheep Pregnancies Established by Somatic Cell Nuclear Transfer
The hypothesis of this study was that the leukocyte populations and expression levels of genes related to immune response, growth factors and apoptosis would be altered at the fetal-maternal interface in somatic cell nuclear transfer (SCNT)-generated sheep pregnancies. Placental and endometrial samples from sheep pregnancies established by SCNT and natural breeding (control) were collected at 45 days and at term. Expression of genes related to growth factors, apoptosis and immune response was examined using quantitative reverse transcription polymerase chain reaction. Endometrial leukocyte populations and major histocompatibility class I (MHC-I) protein expression were examined by immunohistochemistry. At term we observed altered expression of genes related to apoptosis, growth factors and immune response in placental and endometrial tissue of SCNT pregnancies. In Day-45 pregnancies there was less-pronounced abnormal expression and only genes related to apoptosis and growth factors were abnormal in the placenta. Endometrial gene expression profiles were similar to age-matched controls. Placental MHC-I protein expression was similar in SCNT and controls at 45 days but increased in the SCNT at term. The altered gene expression at the fetal-maternal interface likely contributes to the placental dysfunction and overgrowth observed in sheep SCNT pregnancies