RESUMO
BACKGROUND/AIMS: Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. METHODS: We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing. RESULTS: All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified. CONCLUSIONS: This autosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis.
Assuntos
Amelogênese Imperfeita/genética , Proteínas do Esmalte Dentário/genética , Predisposição Genética para Doença/genética , Mutação , Nefrocalcinose/genética , Adolescente , Adulto , Amelogênese Imperfeita/complicações , Amelogênese Imperfeita/patologia , Criança , Consanguinidade , Exoma/genética , Saúde da Família , Feminino , Genes Recessivos/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Nefrocalcinose/complicações , Nefrocalcinose/patologia , Linhagem , Análise de Sequência de DNA/métodos , Síndrome , Adulto JovemRESUMO
Metachromatic Leukodystrophy (MLD) and Multiple Sulfatase Deficiency (MSD) are rare and ultra-rare lysosomal storage diseases. Due to enzyme defects, patients are unable to split the sulfategroup from the respective substrates. In MSD all sulfatases are affected due to a defect of the Sulfatase Modifying Factor 1 (SUMF1) gene coding for the formylglycine generating enzyme (FGE) necessary for the modification of the active site of sulfatases. In MLD mutations in the arylsulfatase A (ARSA) gene cause ARSA deficiency with subsequent accumulation of 3-sulfogalactocerebroside especially in oligodendrocytes. The clinical consequence is demyelination and a devastating neurological disease. Enzyme replacement therapy (ERT) with recombinant human arylsulfatase A (rhARSA), gene therapy, and stem cell transplantation are suggested as new therapeutic options. The aim of our study was to characterize rhARSA concerning its substrate specificity using analytical isotachophoresis (ITP). Substrate specificity could be demonstrated by sulfate splitting from the natural substrates 3-sulfogalactocerebroside and ascorbyl-2-sulfate and the artificial substrate p-nitrocatecholsulfate, whereas galactose-6-sulfate, a substrate of galactose-6sulfurylase, was totally resistant. In contrast, leukocyte extracts of healthy donors were able to split sulfate also from galactose-6-sulfate. The ITP method allows therefore a rapid and simple differentiation between samples of MLD and MSD patients and healthy donors. Therefore, the isotachophoretic diagnostic assay from leukocyte extracts described here provides a fast and efficient way for the diagnosis of MLD and MSD patients and an elegant system to differentiate between these diseases in one assay.
Assuntos
Cerebrosídeo Sulfatase/química , Ensaios Enzimáticos/métodos , Isotacoforese/métodos , Leucócitos/enzimologia , Leucodistrofia Metacromática/enzimologia , Doença da Deficiência de Múltiplas Sulfatases/enzimologia , Sulfatases/química , Cerebrosídeo Sulfatase/genética , Cerebrosídeo Sulfatase/metabolismo , Humanos , Cinética , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/genética , Doença da Deficiência de Múltiplas Sulfatases/diagnóstico , Doença da Deficiência de Múltiplas Sulfatases/genética , Proteínas Recombinantes/análise , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sulfatases/genética , Sulfatases/metabolismo , Sulfatos/química , Sulfatos/metabolismoRESUMO
The human genome consists of 23 pairs of chromosomes that contain 20 000-25 000 genes. Genetic disorders can be caused by different mechanisms, and therefore the confirmation of a suspected diagnosis requires knowledge of the underlying defect, so that the correct test can be applied. Monogenic diseases are caused by disturbances in a single gene, and currently only targeted diagnostic testing is available following a specific clinical suspicion. Chromosomal disorders usually involve multiple genes, so that the symptoms are often less specific. Specialists in Medical Genetics FMH are trained in creating a clinical genetic differential diagnosis, requesting the according laboratory test, interpretating the results and providing expert genetic counseling in presymptomatic and prenatal diagnosis. In Switzerland, specific legal principles and ethical guidelines must be taken into account.
Le génome humain est constitué de 23 paires de chromosomes et contient 20 000 à 25 000 gènes. Les maladies génétiques peuvent être causées par différents mécanismes, or pour confirmer un diagnostic présumé et utiliser le test adéquat, il est nécessaire de connaître le défaut génétique sous-jacent. Les maladies monogéniques sont causées par des perturbations dans un seul gène, et actuellement seul un test diagnostique ciblé peut être réalisé suite à une suspicion clinique spécifique. Les anomalies chromosomiques impliquent généralement plusieurs gènes, donc les symptômes sont souvent moins spécifiques. Les spécialistes en génétique médicale FMH sont formés à reconnaître cliniquement les diagnostics génétiques, à demander les analyses correspondantes, à en interpréter les résultats et à donner un conseil génétique adapté en diagnostic présymptomatique et prénatal. En Suisse, des principes juridiques et éthiques spécifiques doivent également être pris en compte.