Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic...

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Ubiquitination is a critical posttranslational modification regulating cellular processes.
• Deubiquitinating enzymes (DUBs) are key regulators of the ubiquitin system.
• OTUD6B encodes an ovarian tumor domain (OTU)-containing DUB.

Purpose of the Study:

• To identify the genetic cause of an intellectual disability syndrome.
• To investigate the function of OTUD6B in human disease.
• To explore the link between OTUD6B, the ubiquitin system, and proteasome function.

Main Methods:

• Genetic analysis of affected individuals and families.
• Clinical evaluation of patients with OTUD6B variants.
• Generation and analysis of Otud6b knockout mice.
• Biochemical analysis of proteasome function in patient cells.

Main Results:

• Biallelic pathogenic variants in OTUD6B were identified in 12 individuals with intellectual disability, seizures, and dysmorphic features.
• Loss-of-function OTUD6B variants are associated with global developmental delay, microcephaly, absent speech, hypotonia, growth retardation, and congenital malformations.
• Otud6b knockout mice exhibit subviability, smaller size, and congenital heart defects.
• Patient cells show impaired proteasome function, including reduced 19S subunit incorporation and increased ubiquitin-protein conjugates.

Conclusions:

• Defective OTUD6B function underlies a multisystemic human disorder.
• OTUD6B plays a crucial role in proteasome function.
• This study highlights the connection between the ubiquitin system and human disease, particularly neurodevelopmental disorders.