RESUMEN
Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650-85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy.
Asunto(s)
Alcaptonuria/genética , Enfermedades Óseas Metabólicas/genética , Huesos/enzimología , Homogentisato 1,2-Dioxigenasa/genética , Mutación Missense , Polimorfismo de Nucleótido Simple , Alcaptonuria/diagnóstico , Alcaptonuria/enzimología , Alcaptonuria/patología , Secuencia de Bases , Enfermedades Óseas Metabólicas/diagnóstico , Enfermedades Óseas Metabólicas/enzimología , Enfermedades Óseas Metabólicas/patología , Huesos/patología , Dominio Catalítico , Bases de Datos Genéticas , Exones , Femenino , Expresión Génica , Heterogeneidad Genética , Homogentisato 1,2-Dioxigenasa/química , Humanos , Intrones , Italia , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Linaje , Fenotipo , Estructura Secundaria de Proteína , Análisis de Secuencia de ADNRESUMEN
AIM AND OBJECTIVES: 1. To assess the iodine nutritional status in patients with goiter by measuring urinary iodine excretion. 2. To compare the iodine nutritional status with the thyroid function and correlate with the type of thyroid disease. STUDY DESIGN: Case control study. MATERIALS AND METHODS: Three hundred patients with goiter and one hundred euthyroid healthy non-goitrous volunteers were included in this study. RESULTS AND CONCLUSIONS: All patients had elevated urinary iodine suggesting excess iodine intake and absence of iodine deficiency. Complications known to be associated with excess iodine, viz., benign goiter (35%), iodine-induced hyperthyroidism or thyrotoxicosis (34%), thyroiditis (16%) and cancer of thyroid (15%) have been observed in this study. Therefore, continued supplementation of edible salt fortified with iodine should be monitored carefully, and supplementation programs should be tailored to the particular region.
