Haplotype-specific MAPK3 expression in 16p11.2 deletion contributes to variable neurodevelopment.

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Recurrent proximal 16p11.2 deletion (16p11.2del) is linked to neurodevelopmental disorders but shows incomplete penetrance and variable expressivity.
• Previous studies using human induced pluripotent stem cells confirmed neuronal development disruption in 16p11.2del cells, yet responsible genes and penetrance determinants remained unknown.

Purpose of the Study:

• To identify genes contributing to abnormal cellular phenotypes in 16p11.2del and understand factors influencing neurodevelopmental disorder penetrance.
• To investigate the role of residual haplotypes in MAPK3 expression and its association with neurodevelopmental phenotypes.

Main Methods:

• Haplotype phasing of the 16p11.2 region in a neurodevelopmental disorders cohort.
• Generation of human induced pluripotent stem cells from 16p11.2del families with distinct residual haplotypes.
• Transcriptomic profiling and cellular phenotyping of differentiated neuronal cells, including luciferase assays for SNP validation.

Main Results:

• MAPK3 was identified as a contributor to neuronal development dysfunction, affecting soma and electrophysiological properties.
• MAPK3 expression varied based on a 132 kb 58 single nucleotide polymorphism (SNP) residual haplotype, with a minor allele haplotype linked to reduced expression.
• Ten SNPs on the residual haplotype were mapped to MAPK3 enhancers, with six validated to influence MAPK3 expression via cis-regulation.

Conclusions:

• MAPK3 dysfunction, modulated by specific residual haplotypes, contributes to neurodevelopmental abnormalities in 16p11.2del carriers.
• The identified minor residual haplotype is associated with increased risk and severity of neurodevelopmental disorder phenotypes in 16p11.2del subjects.