RESUMEN
Crigler-Najjar syndrome type I (CN-I) is a rare and severe metabolic disorder. A recurrent mutation - c.1070A>G in exon 3 - was identified in the Tunisian population, suggesting a founder effect. In 2004, the detection of this mutation in two Kuwaiti Bedouin families has called the Tunisian founder effect in question again. To determine the origin of this mutation, 21 Tunisian and 2 Kuwaiti Bedouin CN-I patients were screened using nine genetic markers. Haplotype analysis confirmed the founder effect hypothesis and dated the appearance of this mutation some 32 generations ago in the Tunisian population. Using the same genetic analysis, the ancestor haplotype was identified in these two families. This result genetically confirms the blending of the Bedouin nomads within today's Tunisian population. After population migration from east to west, this mutation was introduced into the Tunisian population, and then perpetuated, probably because of marriages in isolated communities.
Asunto(s)
Síndrome de Crigler-Najjar/genética , Estudios de Casos y Controles , Síndrome de Crigler-Najjar/enzimología , Frecuencia de los Genes , Marcadores Genéticos , Glucuronosiltransferasa/genética , Humanos , Desequilibrio de Ligamiento/genética , Mutación/genética , Mapeo Físico de Cromosoma , TúnezAsunto(s)
Albúminas/administración & dosificación , Síndrome de Crigler-Najjar/terapia , Fototerapia/métodos , Adulto , Albúminas/uso terapéutico , Bilirrubina/sangre , Síndrome de Crigler-Najjar/sangre , Femenino , Estudios de Seguimiento , Humanos , Recién Nacido , Infusiones Intravenosas , Embarazo , Resultado del EmbarazoRESUMEN
Crigler-Najjar syndrome type I (CN-I) is a rare and severe inherited disorder of bilirubin metabolism, caused by the total deficiency of bilirubin-UDP-glucuronosyltransferase (UGT) activity. Enzymatic diagnosis cannot be performed in chorionic villi or amniocytes as UGT is not active in these tissues. The cloning of the UGT1 gene and the identification of disease-causing mutations have led to the possibility of performing DNA-based diagnosis. Here we report DNA-based prenatal diagnosis of CN-I in two Tunisian families in whom CN-I patients were diagnosed. As we had previously shown that CN-I was, in Tunisia, associated with homozygosity for the Q357R mutation within the UGT1 gene, we were able to detect this mutation in both families and to show that it was easily recognized by single-strand conformation polymorphism (SSCP) analysis. In both cases, SSCP analysis of fetal DNA showed that the fetus was heterozygous for the Q357R mutation. In one family, the pregnancy was carried to term and a healthy baby was born, whereas, in the other family, the pregnancy is still continuing. Thus the prenatal diagnosis of CN-I is possible, provided disease-causing mutations have been identified. SSCP analysis of DNA prepared either from amniocytes or from chorionic villi is a simple, reliable and fast method for prenatal diagnosis.
Asunto(s)
Síndrome de Crigler-Najjar/diagnóstico , Síndrome de Crigler-Najjar/genética , Glucuronosiltransferasa/genética , Polimorfismo Conformacional Retorcido-Simple , Diagnóstico Prenatal/métodos , Muestra de la Vellosidad Coriónica , Femenino , Heterocigoto , Homocigoto , Humanos , Proteínas de Transporte de Monosacáridos/genética , Mutación , Embarazo , TúnezRESUMEN
OBJECTIVE: Apolipoprotein E (apo E) is pivotal in lipid metabolism. In women with preeclampsia, an atherogenic state is observed. We hypothesized that a particular genotype of apo E may be associated with preeclampsia. METHODS: Genomic DNA was extracted from 55 normotensive and 49 preeclamptic women (defined according to the American College of Obstetricians and Gynecologists criteria). DNA was amplified by PCR and digested simultaneously by AflIII and HaeII giving profiles identifying all the possible genotypes of apo E. RESULTS: The most common isoform apo E3 was found both for normotensive and preeclamptic women (76% and 85%, respectively). The frequency of apo E2 and E4, which are more atherogenic, was not higher in the preeclamptic population. CONCLUSION: We were unable to demonstrate that the "atherogenic state" of preeclampsia is associated with a particular genotype of apo E. Familial studies show that shared genetic and environmental factors are involved in lipid variability. However, owing to the diversity of factors contributing to the development of preeclampsia (fetal and paternal genotypes), these data do not allow to rule-out a possible contribution of maternal apo E to preeclampsia.
Asunto(s)
Apolipoproteínas E/genética , Fragmentos de Péptidos/genética , Polimorfismo Genético , Preeclampsia/genética , Adulto , Femenino , Genotipo , Humanos , Embarazo , Isoformas de ProteínasAsunto(s)
Sustitución de Aminoácidos/genética , Arginina/genética , Síndrome de Crigler-Najjar/genética , Efecto Fundador , Glutamina/genética , Proteínas de Transporte de Monosacáridos/genética , Mutación/genética , Síndrome de Crigler-Najjar/epidemiología , Humanos , Proteínas de Transporte de Monosacáridos/deficiencia , Túnez/epidemiologíaRESUMEN
OBJECTIVE: Preeclampsia is associated with an abnormal lipid profile and high apolipoprotein E (Apo E) levels. Apo E may favor lipid uptake by macrophages and is thought to increase triglycerides clearance. However, high Apo E levels may interfere with lipolysis by interacting with the lipoprotein lipase (LPL) activator, apolipoprotein C2 (Apo C2). LPL activity may also be impaired by high levels of the LPL inhibitor apolipoprotein C3 (Apo C3). Therefore, lipid profile depends on the balance between the opposing effects of Apo C2 and Apo C3 and on interference due to Apo E. We investigated the involvement of these three lipoproteins in lipid disorders associated with preeclampsia. METHODS: Blood samples were taken from 25 normotensive and 24 preeclamptic pregnant women after a 12-hr fasting period. These samples were analyzed for standard lipid profile and Apo E, C2, C3 concentrations. RESULTS: Concentrations of triglycerides, total cholesterol, LDL, HDL, and LDL cholesterol did not differ significantly between preeclamptic women and pregnant controls. Apo C2 concentration and Apo E/Apo C2 ratio did not differ between the two groups of women but Apo C3 and Apo E concentrations were higher in preeclamptic than in pregnant controls. The ratio of triglycerides to Apo E was similar in the two groups of women. In both groups, triglycerides levels were positively correlated with Apo E (p=0.0429), Apo C2 (p=0.0045) and Apo C3 (p=0.0004) concentrations, but not with Apo E/Apo C2 ratio (p=0.760). CONCLUSIONS: In preeclamptic women, the increase in Apo E concentration may not increase triglycerides clearance because LPL activity seems to be inhibited by high Apo C3 concentration.