Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype.

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Intellectual disability (ID) and autism spectrum disorder (ASD) are common neurodevelopmental disorders with unknown genetic causes.
• The Elongator complex is involved in gene expression, but its role in neurodevelopment is unclear.

Purpose of the Study:

• To investigate the genetic basis of ID and ASD.
• To identify novel genes associated with neurodevelopmental disorders.
• To elucidate the molecular mechanisms underlying ID and ASD pathogenesis.

Main Methods:

• Identified biallelic variants in the ELP2 gene in patients with ID and ASD.
• Generated and analyzed Elp2-mutant mouse models.
• Performed brain imaging, tractography, and molecular analyses.

Main Results:

• Elp2 variants cause microcephaly, white matter abnormalities, and altered brain connectivity in mice.
• Mutations impair Elp2 complex activity, tRNA modification, and protein homeostasis.
• Observed impaired neurogenesis, myelin loss, and neurodegeneration in mutant mice.

Conclusions:

• Biallelic variants in ELP2 are associated with ID and ASD.
• ELP2 mutations disrupt neurodevelopment through impaired tRNA modification and protein homeostasis.
• This study highlights tRNA modification as a key factor in monogenic ID and ASD pathogenesis.