Heterozygous variants disrupting the interaction of ERF with activated ERK1/2 cause microcephaly, developmental...

Area of Science:

• Genetics and Molecular Biology
• Developmental Biology
• Human Disease Pathogenesis

Background:

• Mutations in the ETS2 repressor factor (ERF) gene are linked to craniosynostosis and Chitayat syndrome.
• The FSF motif within ERF is crucial for its interaction with extracellular signal-regulated kinases (ERKs).

Purpose of the Study:

• To investigate the role of a novel ERF de novo in-frame indel (c.911_913del) in a patient with microcephaly and congenital anomalies.
• To characterize the molecular mechanisms underlying ERF variants affecting the FSF motif and their contribution to human disease.

Main Methods:

• Exome and whole transcriptome sequencing were employed to identify genetic variants.
• Protein affinity mapping, co-immunoprecipitation, and subcellular localization studies were performed.
• Functional assays assessed the impact of variants on ERF-ERK interaction and ERF activity.

Main Results:

• A de novo ERF indel (c.911_913del) was identified in a patient with microcephaly, joint dislocations, and Pierre-Robin sequence.
• Three additional patients with developmental delay, microcephaly, Pierre-Robin sequence, and skeletal anomalies carried de novo ERF variants in the FSF motif.
• ERF variants impair ERF interaction with activated ERK1/2, increase nuclear localization, and affect repressor activity.

Conclusions:

• The study expands the phenotypic spectrum of ERF-related disorders to include MIDES syndrome, characterized by microcephaly, developmental delay, and skeletal anomalies.
• Disruption of the ERF-ERK interaction is implicated in the pathogenesis of MIDES syndrome and highlights its importance in human development.