RESUMEN
Unexpectedly low hemoglobin oxygen saturation as determined by pulse-oximeter analysis was observed in a patient who underwent an elective surgical procedure. Specific hemoglobin derivatives such as carboxyhemoglobin, methemoglobin, and reduced hemoglobin that have been described to lower pulse-oximetry determination of oxygenation were not detected. Absorbance spectra revealed the patient's hemoglobin to be different than that obtained from two normal volunteers. High-pressure liquid chromatographic analysis of the hemoglobin showed an unknown band that comprised 15% of the patient's hemoglobin. DNA sequence analysis showed a point mutation in the second nucleotide of the 45th codon of the beta-globin chain. This mutation encodes for an abnormal beta-chain (beta-45 Phe-->Ser) that has been described as hemoglobin Cheverly. Hemoglobin Cheverly is an unstable hemoglobin that has a similar mutation as the beta-42 Phe-->Ser mutation seen in hemoglobin Hammersmith. Hemoglobin Hammersmith and another unstable hemoglobin, hemoglobin Köln, have previously been described to have unexpectedly low pulse-oximeter-determined oxyhemoglobin levels. That we find hemoglobin Cheverly to result in a similar phenomenon suggests that pulse-oximeter monitoring of oxygenation status may not be appropriate for the unstable hemoglobins. Low pulse-oximeter oxygenation determinations for these hemoglobins do not appear to predict clinical hypoxemia.
Asunto(s)
Análisis de los Gases de la Sangre , Hemoglobinas Anormales/fisiología , Oximetría , Adulto , Femenino , Hemoglobinas Anormales/química , Humanos , Oxihemoglobinas/análisisRESUMEN
We have studied the relative levels of gamma-mRNA [%gamma/(gamma + beta)], Ggamma- and Agamma-mRNAs [%Ggamma/(Ggamma + Agamma)], hemoglobin (Hb) F, and the Ggamma and Agamma chains in some 50 patients with sickle cell anemia (SS) and with different haplotypes. As expected, the Hb F levels varied greatly and were high in patients with the Saudi Arabian-Indian haplotype. Similarly, the Ggamma values varied greatly (from 19.5 to 76.5%) and depended on the haplotypes. A rare haplotype, named Mor, was found in 3 SS patients, 1 of whom was a homozygote Mor/Mor; this haplotype is associated with the lowest Ggamma value (19.5% in the homozygote) and with a C-->T mutation at position -202 of the Agamma promoter. The levels of gamma-mRNA roughly parallel those of Hb F, but older patients have increased levels of mRNA, which appears not to be efficiently translated into Hb F. Similar observation have been reported for other hemoglobinopathies such as deltabeta-thalassemia heterozygotes and Hb Lepore heterozygotes. The relative quantity of Ggamma-mRNA was closely related to that of the Ggamma chain in the 15 patients who were studied; the Ggamma- to Agamma-mRNA ratio did not change with age.
Asunto(s)
Anemia de Células Falciformes/genética , Hemoglobina Fetal/genética , ARN Mensajero/genética , Adolescente , Adulto , Anemia de Células Falciformes/sangre , Niño , Femenino , Hemoglobina Fetal/biosíntesis , Haplotipos , Humanos , Masculino , ARN Mensajero/biosíntesisRESUMEN
The higher oxygen (O2) affinity of fetal blood compared to maternal blood has been considered advantageous for the survival of the fetus. However, there is little information on infants born to mothers who carry a hemoglobin (Hb) variant with altered O2 affinity. This report describes two mothers and their newborn infants, each with a different globin chain variant are identified as Hb Linköping, [beta36(C2)Pro-->Thr] and Hb Sunshine Seth [alpha94(G1)Asp-->His]. Hb Linkoping is a known high O2 affinity variant, while Hb Sunshine Seth was found to have a low affinity for O2. One mother and her newborn, both with a heterozygosity for Hb Linköping, had P50 values of 1.9 and 2.5 kPa, respectively, a reversal of the physiological maternal-infant gradient. The other mother and her newborn, who were heterozygous for Hb Sunshine Seth, had P50 values of 4.7 and 4.4 kPa, respectively, a minimal gradient. The Hb F, plasma erythropoietin, and 2,3-diphosphoglycerate (2,3-DPG) levels were normal in both infants. The newborns were clinically normal.
Asunto(s)
Hemoglobinopatías/metabolismo , Intercambio Materno-Fetal , Oxígeno/metabolismo , Adulto , Diagnóstico Diferencial , Femenino , Hemoglobinopatías/diagnóstico , Humanos , Recién Nacido , Embarazo , Factores de TiempoAsunto(s)
Cromatografía Líquida de Alta Presión , Cromatografía por Intercambio Iónico , Globinas/aislamiento & purificación , Hemoglobinas Anormales/aislamiento & purificación , Sustitución de Aminoácidos/genética , Cromatografía Líquida de Alta Presión/métodos , Cromatografía por Intercambio Iónico/métodos , Globinas/genética , Hemoglobinas Anormales/genética , Humanos , Sensibilidad y Especificidad , Temperatura , Factores de TiempoAsunto(s)
Alelos , Codón Iniciador/genética , Personajes , Mutación Puntual , Talasemia beta/genética , Talasemia beta/historia , Adulto , Anciano , Anciano de 80 o más Años , Preescolar , Femenino , Historia del Siglo XVII , Historia del Siglo XVIII , Historia del Siglo XIX , Historia del Siglo XX , Humanos , Masculino , Moscú , Linaje , Polimorfismo GenéticoAsunto(s)
Globinas/genética , Hemoglobinas Anormales/genética , Mutagénesis Sitio-Dirigida , Proteínas Recombinantes de Fusión/genética , Escherichia coli , Globinas/química , Hemoglobinas Anormales/química , Humanos , Modelos Moleculares , Mutación Puntual , Proteínas Recombinantes de Fusión/química , Saccharomyces cerevisiaeRESUMEN
Information on mutations in human hemoglobin is important in many efforts, including understanding the pathophysiology of hemoglobin diseases, developing therapies, elucidating the dynamics of sequence alterations inhuman populations, and dissecting the details of protein structure/function relationships. Currently, information is available on a large number of mutations and variants, but is distributed among thousands of papers. In an effort to organize this voluminous data set, two Syllabi have been prepared compiling succinct information on human hemoglobin abnormalities. In both of these, each entry provides amino acid and/or DNA sequence alterations, hematological and clinical data, methodology used for characterization, ethnic distribution, and functional properties and stability of the hemoglobin, together with appropriate literature references. A Syllabus of Human Hemoglobin Variants (1996) describes 693 abnormal hemoglobins resulting from alterations in the alpha-, beta-, gamma-, and delta-globin chains, including special abnormalities such as double mutations, hybrid chains, elongated chains, deletions, and insertions. We have converted this resource to an electronic form that is accessible via the World Wide Web at the Globin Gene Server (http://globin.cse.psu.edu). Hyperlinks are provided from each entry in the tables of variants to the corresponding full description. In addition, a simple query interface allows the user to find all entries containing a designated word or phrase. We are in the process of converting A Syllabus of Thalassemia Mutations (1997) to a similar electronic format.
Asunto(s)
Redes de Comunicación de Computadores , Bases de Datos Factuales , Variación Genética , Globinas/genética , Hemoglobinas Anormales/genética , Globinas/química , Hemoglobinopatías/genética , Hemoglobinas Anormales/química , Humanos , Mutación PuntualAsunto(s)
Regulación de la Expresión Génica , Globinas/genética , Mutación , Alineación de Secuencia/métodos , Animales , Secuencia de Bases , Biología Computacional/métodos , Análisis Mutacional de ADN/métodos , Bases de Datos Factuales , Galago , Cabras , Hemoglobinopatías/genética , Humanos , Ratones , Datos de Secuencia Molecular , Conejos , Homología de Secuencia de Ácido Nucleico , Programas InformáticosRESUMEN
We describe a Black female who has suffered for many years from an (often) severe anemia (Hb 5-9 g/dl) with iron deficiency (serum Fe 8 microg/dl; TIBC 462 microg/dl; ferritin 7 ng/ml or less) and folate deficiency. The patient had hypermenorrhea which was appropriately treated resulting in an increase in hemoglobin level but not affecting the Fe deficiency. Splenomegaly was present, perhaps resulting from a clay-eating habit, although this was consistently denied. The patient had an alpha-thalassemia-2 (-3.7 kb) trait and a deletional hereditary persistence of fetal hemoglobin (HPFH) (type II) which were inherited from her father. Over the last six years the level of Hb F varied between 8.5 and 16% (25-29% in the father), while the G gamma value was also low (15-22% versus 32-34% in the father). Comparable reductions were seen in the relative levels of gamma-mRNA and G gamma-mRNA. These data support results published by Adams et al who showed a severe reduction in Hb F level in another HPFH heterozygote with Fe deficiency; these investigations suggested that a reduction in alpha-globin synthesis resulted in preferential formation of alpha beta dimers rather than alpha gamma dimers. Our data suggest that the decrease of Hb F and G gamma levels is due to a reduction in gamma-mRNA formation, mainly of the G gamma type, rather than through a posttranslational mechanism alone.
Asunto(s)
Anemia Ferropénica/genética , Hemoglobina Fetal/genética , Deficiencia de Ácido Fólico/genética , Eliminación de Gen , Globinas/genética , ARN Mensajero/metabolismo , Adulto , Anemia Ferropénica/sangre , Femenino , Hemoglobina Fetal/metabolismo , Deficiencia de Ácido Fólico/sangre , Tamización de Portadores Genéticos , Globinas/metabolismo , Humanos , Pica , ARN Mensajero/sangre , Talasemia alfa/sangre , Talasemia alfa/genéticaRESUMEN
During the past decade new procedures have been developed for the isolation of RNA from a few mL of freshly collected blood. This material is reverse transcribed and the resulting cDNA can be used for the determination of the ratios between different types of globin mRNA, namely alpha 2/alpha 1, alpha/zeta, alpha/beta, gamma/beta, beta A/beta X, delta beta Lep/beta, and G gamma/A gamma. Details about these polymerase chain reaction-based methods are reviewed, and information about their usefulness in studying alpha-thalassemia, beta-thalassemia, sickle cell anemia and other beta-globin gene abnormalities, Hb Lepore heterozygosity, and heterozygosity for alpha 2- or alpha 1-globin gene mutations will be provided. The methods are also most useful in characterizing the mRNA types in single, in vitro cultured, BFU-E colonies; in colonies derived from cells of a Hb S heterozygote; for instance, the beta A- and beta(S)-mRNAs were present in all colonies and in about equal quantities, while many of those cells from a subject with a somatic cell mutant (Hb Costa Rica) contained beta A-mRNA and no beta-Costa Rica mRNA, and only a few had both types. The techniques described have considerable diagnostic value and offer a rather simple approach to the study of some of the listed diseases.
Asunto(s)
Eritrocitos/química , Variación Genética , Hemoglobinas/genética , ARN Mensajero/biosíntesis , Talasemia alfa/genética , Talasemia beta/genética , Anemia de Células Falciformes/genética , Globinas/genética , Hemoglobina Falciforme/genética , Hemoglobinas Anormales/genética , Heterocigoto , Humanos , Talasemia alfa/sangre , Talasemia beta/sangreRESUMEN
Hematological and hemoglobin (Hb) data are presented for numerous patients with compound heterozygosities for different beta chain variants and for a beta chain variant with different beta-thalassemia (beta-thal) alleles. Considerable variations, which result from the type of beta chain variant and beta-thal mutation, can be noted. The comparison again emphasizes the importance of determining the diagnoses at the molecular level to aid the physician in the management of patients with different combinations of abnormalities. Simplification and commercialization of modern technology may make the introduction of this approach in some clinical chemistry laboratories possible.
Asunto(s)
Hemoglobinas Anormales/genética , Mutación , Talasemia beta/sangre , Adolescente , Adulto , Niño , Preescolar , Heterocigoto , Humanos , Lactante , Persona de Mediana Edad , Fenotipo , Talasemia beta/genéticaRESUMEN
Two Mexican mestizo families with Hb Lepore Washington-Boston are described. One family is from Cordova, in the State of Veracruz, in the East coast of Mexico: the proband is a 44-year old asymptomatic male with italian ancestors; the other family is from the city of Durango, State of Durango, in the northwestern part of the country: the propositus is a 32-year old pregnant female with French ancestors. In both cases the Hb Lepore was identified by alkaline electrophoresis and characterized by high performance liquid chromatography and PCR with specific probes flanking the deletion frame. The beta-haplotype in both families was +(-)-(-)-(++), the commonest beta-haplotype reported with this mutation. This paper describes the first cases of this entity in Mexico.
Asunto(s)
Globinas/genética , Hemoglobinas Anormales/análisis , Talasemia beta/genética , Adulto , Electroforesis de las Proteínas Sanguíneas , Niño , Femenino , Francia/etnología , Frecuencia de los Genes , Haplotipos/genética , Hemoglobinas Anormales/genética , Heterocigoto , Humanos , Indígenas Norteamericanos/genética , Italia/etnología , Masculino , México/epidemiología , Persona de Mediana Edad , Embarazo , Complicaciones Hematológicas del Embarazo , Eliminación de Secuencia , Población Blanca/genética , Talasemia beta/sangre , Talasemia beta/etnologíaRESUMEN
Hb Lepore is one of the most common abnormal haemoglobins in Caucasians in Central Portugal and in the Spanish Alta Extremadura (0.28% in a survey of school children). A group of 19 Portuguese and 14 Spanish Hb Lepore carriers (all unrelated) was characterised at the molecular level by the polymerase chain reaction, sequencing and restriction enzyme analysis. The Portuguese and one Spanish carrier were heterozygous for Hb Lepore-Baltimore, whereas all other Spanish subjects were Hb Lepore-Washington-Boston carriers. Sequencing of the Hb Lepore-Baltimore gene further established the crossover at delta 68-beta 84, a region two codons (CDs) shorter than that previously described and easily confirmed by digestion with MaeI and BanI. Data from haplotype analysis suggest that this crossover occurred as an independent event on the Iberian Peninsula. The haematological data were similar in both groups except for the levels of Hb F and the G gamma chain, which were significantly higher in the Hb Lepore-Baltimore heterozygotes. Quantification of the globin chains and the mRNA transcripts showed that the delta beta gene is transcribed at a higher level than the delta gene with levels of translation giving rise to 10%-15% of Hb Lepore. The different levels of Hb F observed in the two groups are the results of the higher transcription rate of the gamma genes in Hb Lepore-Baltimore heterozygotes and an apparently less efficient translation of G gamma genes in Hb Lepore-Washington-Boston heterozygotes.
Asunto(s)
Hemoglobinas Anormales/genética , Secuencia de Bases , Cartilla de ADN , Tamización de Portadores Genéticos , Hemoglobinas Anormales/biosíntesis , Humanos , Reacción en Cadena de la Polimerasa , Portugal , ARN Mensajero/biosíntesis , Análisis de Regresión , Mapeo Restrictivo , España , Transcripción GenéticaRESUMEN
The level of Hb E (including Hb A2) was quantitated in 30 adult Hb E heterozygotes by cation exchange high performance liquid chromatography; in 20 subjects the alpha-globin gene status was determined by gene mapping and polymerase chain reaction methodology. A decrease in Hb E level was observed which was directly related to the type of alpha-thalassemia that was present; the lowest percentage of Hb E (and Hb A2) was 10.2%, seen in two persons with Hb Constant Spring (CS)-Hb H disease (alpha CS alpha/--). Similar analyses were made for several newborn babies with a Hb E heterozygosity, the Hb E level was determined as beta E by a reversed phase high performance liquid chromatographic procedure. One baby with Hb E trait and Hb H disease (-alpha/--) had a beta E level of 17.7% (as % of beta A + beta E) comparable to that seen for adults with an identical genotype. One fetus with hydrops fetalis (--/--) and Hb E trait had low beta E and beta A levels which, however, were nearly identical (1.5 and 1.3% of the total hemoglobin). These beta chains apparently combine with the embryonic zeta chain to form Hb Portland-II (zeta 2 beta 2A) and a variant of this hemoglobin (zeta 2 beta 2 E). The affinity of the two beta chains for the zeta chain must be the same and quite different from that for the alpha chain. Moreover, this single observation suggests an equal synthesis of beta A and beta E chains, the low level of Hb E in adult heterozygotes being primarily the result of a greatly decreased rate of assembly of alpha beta E dimers.