RESUMO
Variants of unknown significance (VUS) remain a constant challenge in the diagnosis of hereditary cancer and the counseling of patients with pedigrees suggestive of such a syndrome. In order to assess some of this limitation, several variants in the DNA repair gene ATM were selected from a cohort of high risk individuals with negative genetic diagnoses. ATM has proven a challenge in the counseling of patients due to its nature as a moderate penetrance gene. In this study, six ATM missense mutations with a high likelihood for pathogenicity were assessed through a battery of experiments to yield high fidelity information on their biochemical effect on ATM activity. We report that several of these variants show signs of reduced ATM function indicative of likely pathogenicity. With further study, this data may be used in clinic, improving diagnosis, surveillance, and outcome for patients carrying these mutations.
Assuntos
Neoplasias da Mama , Neoplasias , Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Mutação/genética , Neoplasias/genética , Linhagem , PenetrânciaRESUMO
The HECT-type E3 ligase Itch is increasingly being shown to have a vital role in immune regulation. Itch deficiency leads to deleterious inflammatory disorders both in mice and humans. By adding ubiquitin to the key signaling intermediates, Itch functions as a critical regulator of lymphocyte-cell activation, differentiation and immune tolerance. Also, Itch cooperates with deubiquitinating enzymes such as A20 and Cyld to terminate NF-κB signaling and prevent chronic inflammation. This review summarizes recent advances that highlight Itch's role in lymphocyte function and explores recent insights regarding its role as a regulator of inflammatory signaling.
