Netrin-G2 dysfunction causes a Rett-like phenotype with areflexia.

Area of Science:

• Neurogenetics
• Developmental Neuroscience

Background:

• Rett syndrome (RTT) is a rare neurodevelopmental disorder.
• The methyl-CpG-binding protein 2 (MECP2) gene is the primary cause of typical RTT.
• Novel genetic etiologies for RTT-like phenotypes are actively sought.

Observation:

• Three individuals from two families presented with a novel Rett-like phenotype and areflexia, negative for MECP2 mutations.
• Whole-exome sequencing identified a shared homozygous frameshift mutation (c.376dupT) in the netrin-G2 (NTNG2) gene in all affected individuals.
• This NTNG2 mutation segregated with the disease in both families.

Findings:

• The identified NTNG2 mutation is predicted to cause nonsense-mediated decay.
• Functional studies involving NTNG2 knockdown in mouse neurons revealed severe defects in neuronal morphology and migration.
• NTNG1, a related netrin-G family member, has previously been associated with RTT-like phenotypes, but this is the first report implicating NTNG2.

Implications:

• This study identifies NTNG2 as a novel causative gene for a Rett-like neurodevelopmental disorder.
• Netrin-G proteins are crucial for axonal guidance and synaptic function, and their disruption leads to significant neurodevelopmental impairments.
• These findings expand the genetic landscape of RTT and related disorders, offering new avenues for research and potential therapeutic targets.