RESUMO
We report the results of the first epidemiological study investigating glucose 6-phosphate dehydrogenase (G6PD) deficiency among the heterogenous Mauritian population. Mauritius has a population of approximately 1 million, and of these 66.8% are Indo-Mauritian (of Indian origin), 27.9% are Creoles (of African ancestry) and 2.1% are Sino-Mauritian, predominantly of Chinese origin. Of the 1435 Mauritian males tested, 73 (5.1%) were G6PD deficient. However, the prevalence varied considerably between the two major ethnic groups: 35/1157 (3.0%) for Indo-Mauritians and 37/267 (13.9%) for Creoles. Molecular analysis revealed three major deficient polymorphic variants; G6PD Orissa, G6PD Mediterranean and G6PD A-. G6PD Orissa (nt 131 G-->C; residue 44 Ala-->Gly) was found to be the most common variant among Indo-Mauritians: this deficient variant was recently identified to be highly characteristic of the tribal groups in central India. In Creoles the most common deficient variant was G6PD A- (27/37). These data are consistent with the different ancestral contributions to the present gene pool of the Mauritian population. This study has provided further information as to the precise nature of G6PD deficiency at the molecular level among Indians, about whom previously there was scant information. The data presented suggest that G6PD Orissa is widespread in central and southern states of India. Additionally, the identification and frequency of G6PD-deficient alleles in Mauritius is of public-health importance.
Assuntos
Doença de Depósito de Glicogênio Tipo I/genética , Eletroforese , Doença de Depósito de Glicogênio Tipo I/epidemiologia , Humanos , Índia/epidemiologia , Masculino , Maurício/etnologia , Mutação/genética , Polimorfismo GenéticoRESUMO
We have determined the causative mutation in 12 cases of glucose-6-phosphate dehydrogenase deficiency associated with chronic non-spherocytic haemolytic anaemia. In 11 of them the mutation we found had been previously reported in unrelated individuals. These mutations comprise seven different missense mutations and a 24 base pair deletion. G6PD Nara, previously found in a Japanese boy. Repeated findings of the same mutations suggests that a limited number of amino acid changes can produce the CNSHA phenotype and be compatible with normal development. The one new mutation we have found, G6PD Serres, is 1082 C-->T causing a 361 Ala-->Val substitution in the dimer interface where most other severe G6PD mutations are found. Now that several patients with the same mutation have been reported we can compare the resulting clinical phenotypes. For each mutation we find a reasonably consistent clinical picture, ranging from mild (G6PD Clinic) through moderate (G6PD Nashville) to severe (G6PD Beverly Hills and G6PD Nara).
Assuntos
Anemia Hemolítica/genética , Glucosefosfato Desidrogenase/genética , Doença de Depósito de Glicogênio Tipo I/genética , Mutação , Adolescente , Anemia Hemolítica/complicações , Criança , Pré-Escolar , Doença Crônica , Deleção de Genes , Doença de Depósito de Glicogênio Tipo I/complicações , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação PuntualRESUMO
Deficiency of glucose-6-phosphate dehydrogenase (G6PD) is usually found at high frequencies in areas of the world where malaria has been endemic. The frequency and genetic basis of G6PD deficiency have been studied in Africa, around the Mediterranean, and in the Far East, but little such information is available about the situation in India. To determine the extent of heterogeneity of G6PD, we have studied several different Indian populations by screening for G6PD deficiency, followed by molecular analysis of deficient alleles. The frequency of G6PD deficiency varies between 3% and 15% in different tribal and urban groups. Remarkably, a previously unreported deficient variant, G6PD Orissa (44 Ala-->Gly), is responsible for most of the G6PD deficiency in tribal Indian populations but is not found in urban populations, where most of the G6PD deficiency is due to the G6PD Mediterranean (188 Ser-->Phe) variant. The KmNADP of G6PD Orissa is fivefold higher than that of the normal enzyme. This may be due to the fact that the alanine residue that is replaced by glycine is part of a putative coenzyme-binding site.
Assuntos
Variação Genética , Deficiência de Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/genética , Polimorfismo Genético , Sequência de Bases , Mapeamento Cromossômico , Humanos , Índia , Cinética , Masculino , Dados de Sequência Molecular , Reação em Cadeia da PolimeraseRESUMO
We have investigated a 13-year-old girl from first cousin parents who presented with severe hemolytic anemia. Hematologic studies showed unstable hemoglobin (Hb) disease (chronic Heinz body anemia), and DNA analysis showed that the patient was homozygous for the previously reported abnormal Hb called Hb Bushwick (beta 74E18 gly-->val). Hb Bushwick is unstable in vitro and in vivo. In addition, using globin chain biosynthetic studies, we show that the beta (Bushwick) chains are unstable. Six members of the patient's family were heterozygous for Hb Bushwick and had a compensated hemolytic disorder. By contrast, the homozygous patient had chronic anemia caused by a combination of hemolysis and ineffective erythropoiesis that was subject to severe exacerbation concomitant with infection. Thus, although unstable Hb disease is correctly regarded as dominant, we clearly see a dosage effect in its expression, whereby the homozygous state is still compatible with life although the red blood cells contain nearly 100% unstable Hb.
Assuntos
Anemia Hemolítica/genética , Variação Genética , Hemoglobinas Anormais/genética , Homozigoto , Adolescente , Adulto , Idoso , Anemia Hemolítica/sangue , Sequência de Bases , Basófilos/patologia , Criança , Consanguinidade , Primers do DNA , Éxons , Feminino , Globinas/genética , Glicina , Humanos , Íntrons , Masculino , Dados de Sequência Molecular , Linhagem , Mutação Puntual , Reação em Cadeia da Polimerase , ValinaRESUMO
We have identified the glucose-6-phosphate dehydrogenase mutations responsible for enzyme deficiency in nine individuals with chronic nonspherocytic hemolytic anemia. We found the variants Tokyo, Iowa, Shinshu, and Guadalajara in British subjects and Kobe in an Italian. In addition we have determined the variant Corum has the mutation 820 G-->A and have found in British subjects the mis-sense mutations 224 T-->C, 488 G-->A and 833 C-->T which have not been described before. Some, but not all, of the mutations involve amino acids located near putative substrate binding sites.
Assuntos
Anemia Hemolítica/genética , Deficiência de Glucosefosfato Desidrogenase/complicações , Glucosefosfato Desidrogenase/genética , Mutação Puntual , Sítios de Ligação , Evolução Biológica , Doença Crônica , Códon/genética , Análise Mutacional de DNA , Éxons , Humanos , Masculino , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Especificidade da EspécieRESUMO
Fetal blood normally has a higher oxygen affinity than maternal blood because of the predominance of haemoglobin (Hb) F in the former and of Hb A in the latter; this predominance facilitates the transfer of oxygen from maternal to fetal blood. We report two patients who had exclusively or predominantly Hb F in their blood and were managed differently. When patient 1 became pregnant she had regular exchange blood transfusions in order to reduce her Hb F from 80% to below 50%; patient 2, who had 100% Hb F, was not transfused before, during or after her pregnancy. Each patient delivered a normal healthy baby. We conclude that the differential oxygen affinity produced by the combination of Hb A in the maternal blood and Hb F in the fetal blood is not indispensable to ensure an oxygen supply adequate for normal fetal development and growth.