RESUMEN
GNB5 encodes the G protein ß subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision.
Asunto(s)
Bradicardia/genética , Bradicardia/fisiopatología , Discapacidades del Desarrollo/genética , Subunidades beta de la Proteína de Unión al GTP/genética , Genes Recesivos/genética , Mutación/genética , Nodo Sinoatrial/fisiopatología , Adolescente , Animales , Niño , Discapacidades del Desarrollo/fisiopatología , Femenino , Subunidades beta de la Proteína de Unión al GTP/deficiencia , Reflujo Gastroesofágico/genética , Reflujo Gastroesofágico/fisiopatología , Eliminación de Gen , Frecuencia Cardíaca/genética , Heterocigoto , Humanos , Masculino , Hipotonía Muscular/genética , Mutación Missense/genética , Linaje , Fenotipo , Enfermedades de la Retina/genética , Enfermedades de la Retina/fisiopatología , Convulsiones/genética , Síndrome , Adulto Joven , Pez Cebra/genética , Pez Cebra/fisiología , Proteínas de Pez CebraRESUMEN
INTRODUCTION: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder caused by deficiency of alanine glyoxylate aminotransferase, due to a defect in the AGXT gene. Several mutations in this gene have been reported and some of them have been observed in multiple populations. The aim of our study was to analyze the mutations causing PH1 in the Moroccan population and to estimate its prevalence in Morocco. METHODS: Molecular studies of 29 unrelated Moroccan patients with PH were performed by direct sequencing of all exons of the AGXT gene. In addition, to estimate the prevalence of PH1, we screened for the recurrent p.Ile244Thr mutation in 250 unrelated Moroccan newborns using real-time polymerase chain reaction. RESULTS: Four pathogenic mutations were detected in 25 unrelated patients. The c.731T>C (p.Ile244Thr) was the most frequent mutation with a frequency of 84%. The other three mutations were c.33delC, c.976delG, and c.331C>T. The prevalence of the PH1 mutation among Moroccans was then estimated to range from 1/7267 to 1/6264. CONCLUSION: PH1 is one of the most prevalent genetic diseases in the Moroccan population and is probably underdiagnosed. Front line genetic testing for PH1 in Morocco should be initiated using an assay for the recurrent p.Ile244Thr mutation. This strategy would provide a useful tool for precocious diagnosis of presymptomatic individuals and to prevent their rapid progression to renal failure.