A novel PAK1 variant causative of neurodevelopmental disorder with postnatal macrocephaly
Sachiko Ohori1, Satomi Mitsuhashi2, Revital Ben-Haim3
1Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
Abstract:
p21-activated kinases (PAKs) are protein serine/threonine kinases stimulated by Rho-family p21 GTPases such as CDC42 and RAC. PAKs have been implicated in several human disorders, with pathogenic variants in PAK3 associated with intellectual disability and several PAK members, especially PAK1 and PAK4, overexpressed in human cancer. Recently, de novo PAK1 variants were reported to be causative of neurodevelopmental disorder (ND) with secondary macrocephaly in three patients. We herein report a fourth patient with ND, epilepsy, and macrocephaly caused by a de novo PAK1 missense variant. Two previously reported missense PAK1 variants functioned as activating alleles by reducing PAK1 homodimerization. To examine the pathogenicity of the identified novel p.Ser110Thr variant, we carried out in silico structural analysis. Our findings suggest that this variant also prevents PAK1 homodimerization, leading to constitutive PAK1 activation.
Insights
Pathogenic variants in PAK1 (p21-activated kinase 1) cause neurodevelopmental disorders. A novel de novo variant in PAK1 leads to constitutive activation, suggesting a mechanism for this disorder.
Area of Science:
- Molecular Biology
- Genetics
- Neuroscience
Background:
- p21-activated kinases (PAKs) are serine/threonine kinases regulated by Rho GTPases.
- PAKs are implicated in human disorders, including intellectual disability (PAK3 variants) and cancer (PAK1, PAK4 overexpression).
- De novo PAK1 variants have been identified as a cause of neurodevelopmental disorder (ND) with macrocephaly.
Observation:
- A fourth patient with ND, epilepsy, and macrocephaly was identified.
- This patient harbors a de novo missense variant in PAK1 (p.Ser110Thr).
- Previous pathogenic PAK1 variants were shown to reduce homodimerization, leading to activation.
Findings:
- In silico structural analysis of the novel p.Ser110Thr variant suggests it also disrupts PAK1 homodimerization.
- This disruption results in constitutive activation of PAK1.
- The findings support a mechanism where PAK1 overactivation underlies ND with macrocephaly.
Implications:
- This study expands the known genetic causes of neurodevelopmental disorders.
- Understanding the mechanism of PAK1 activation provides insights into ND pathogenesis.
- Further research into PAK1 signaling pathways may reveal therapeutic targets for related disorders.
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