Rare pathogenic variants in WNK3 cause X-linked intellectual disability

Area of Science:

• Neurogenetics
• Human Development
• Molecular Biology

Background:

• WNK3 kinase (PRKWNK3) is known to influence brain development and function through cation-chloride cotransporter regulation.
• The specific role of WNK3 in human developmental disorders remained largely uncharacterized.
• Intellectual disability (ID) encompasses a range of conditions affecting cognitive and adaptive functioning.

Purpose of the Study:

• To investigate the role of WNK3 in human development, particularly in cases of intellectual disability.
• To identify genetic variants in WNK3 associated with rare forms of intellectual disability.

Main Methods:

• Exome or genome sequencing was performed on individuals with rare familial or sporadic intellectual disability.
• Genetic variants in WNK3 were identified and analyzed for their inheritance patterns and pathogenicity.
• Functional impact of WNK3 variants on KCC2 phosphorylation was assessed.

Main Results:

• Six distinct maternally-inherited, hemizygous WNK3 variants (loss-of-function or missense) were identified in 14 male individuals across 6 families.
• Affected individuals presented with intellectual disability, variable epilepsy, and structural brain defects.
• Pathogenic WNK3 missense variants disrupted KCC2 phosphorylation at threonine 1007, impacting synaptic inhibition development.

Conclusions:

• Pathogenic WNK3 variants are a cause of a rare X-linked intellectual disability characterized by epilepsy and brain abnormalities.
• Impaired WNK3-mediated phospho-regulation of KCC2 represents a key pathogenic mechanism in these neurodevelopmental disorders.
• This study highlights WNK3 as a crucial gene for human brain development and synaptic function.