UPF3B-related syndrome

It is estimated that intellectual disability (ID) affects approximately 2% of the global population. This broad collection of clinically variable and genetically heterogeneous brain disorders is primarily characterized by impaired ability to learn and remember. The socio-economic impact of ID is significant. Currently, more than 380 genes and hundreds of additional loci have been identified in which mutations (or copy number variations; CNVs) cause ID. It is estimated that 10–15% of ID genes are located on the X chromosome, also known as X-linked ID (XLID). Although identifying the full spectrum of genetic causes of ID remains a major challenge, a better understanding of the molecular pathways underlying ID is becoming increasingly crucial.

Mutations in the UPF3B gene have been found to cause XLID (MIM: 300676). To date, approximately 10 separate families with UPF3B mutations are known, including de novo mutations, all of which result in loss of UPF3B function. In addition to intellectual disability, patients with UPF3B mutations may also present with attention deficit hyperactivity disorder (ADHD), autism, and schizophrenia. The severity and type of clinical manifestations vary both within and between families. Molecular and whole-transcriptome analyses of patient UPF3B cells suggest that the UPF3B protein is critical for normal brain development and function. The underlying molecular mechanism, however, remains largely unknown.

 Patients with loss-of-function UPF3B mutations exhibit a highly variable neurological phenotype. This suggests that UPF3B function is important for normal brain development; however, our understanding of the underlying molecular processes remains limited. Overall, the data indicate that the Upf3b-mediated nonsense-mediated mRNA decay (Upf3b-NMD) pathway is a key regulator of multiple brain developmental processes, which likely underlie aspects of the clinical manifestations of variable intellectual disability, autism, ADHD, and childhood-onset schizophrenia in patients with UPF3B mutations. 

• rôzne stupne mentálneho postihnutia
• autizmus
• schizofrénia (niekedy začínajúca už v destve)
• porucha pozornosti
• hyperaktivita