RESUMO
Introduction: Wilms tumor (WT) is the most common renal malignancy of children and can be seen in WAGR syndrome (WT, aniridia, genitourinary anomalies, and intellectual disability). WAGR results from a contiguous gene deletion within the 11p13 region, encompassing the WT1 gene, often responsible for WT development, and the PAX6 gene, responsible for aniridia. Aniridia, a pan-ocular disease resulting from iris hypoplasia, is thought to increase the risk for WT development if their genetic alteration spans both the WT1 and the PAX6 genes on 11p13.Case Description: We describe a unique case of a patient with aniridia secondary to a heterozygous PAX6 nonsense mutation who developed WT despite no additional identifiable germline genetic drivers for this disease.Discussion: Isolated mutations in PAX6 previously have not been associated with increased risk of WT development case raises the question of if surveillance for WT should be continued in patients with aniridia with an isolated PAX6 mutation identified.
Assuntos
Aniridia/patologia , Códon sem Sentido , Proteínas do Olho/genética , Neoplasias Renais/patologia , Fator de Transcrição PAX6/genética , Tumor de Wilms/patologia , Aniridia/complicações , Aniridia/genética , Pré-Escolar , Humanos , Neoplasias Renais/complicações , Neoplasias Renais/genética , Masculino , Prognóstico , Tumor de Wilms/complicações , Tumor de Wilms/genéticaRESUMO
DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.