Heterozygous loss-of-function variant in METTL5 is associated with intellectual disability

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Biallelic pathogenic variants in METTL5 cause autosomal recessive intellectual disability (ID).
• The role of heterozygous METTL5 variants in ID is largely unknown.
• METTL5 is an RNA methyltransferase crucial for 18S rRNA m6A modification.

Purpose of the Study:

• To investigate the clinical relevance of heterozygous METTL5 variants in neurodevelopmental disorders.
• To explore the functional consequences of a specific heterozygous frameshift variant in METTL5.
• To expand the understanding of METTL5-related disorders.

Main Methods:

• Identified a heterozygous frameshift variant in METTL5 in an affected father-son pair with ID.
• Performed functional analyses to assess the variant's impact on protein expression and 18S rRNA m6A modification.
• Utilized proteomic profiling to identify downstream molecular changes.

Main Results:

• The identified variant abolished conserved domains and markedly reduced METTL5 protein expression.
• 18S rRNA m6A modification was impaired, leading to decreased global protein synthesis.
• Proteomic analysis revealed downregulation of neuronal proteins involved in neuron projection.

Conclusions:

• Heterozygous loss-of-function variants in METTL5, especially early frameshift mutations, may increase the risk of neurodevelopmental disorders.
• METTL5 haploinsufficiency can impact neurodevelopmental processes.
• This study broadens the known spectrum of METTL5-associated genetic conditions.