Cardio-facio-cutaneous syndrome-associated pathogenic MAP2K1 variants activate autophagy

Area of Science:

• Genetics and Molecular Biology
• Cellular Biology
• Developmental Biology

Background:

• Cardio-facio-cutaneous syndrome (CFCS) is a developmental disorder linked to mutations in the MAP2K1 gene, which encodes mitogen-activated protein kinase kinase 1 (MEK1).
• Constitutive activation of the MEK/ERK signaling pathway is the established mechanism underlying CFCS.
• The precise molecular mechanisms driving this aberrant signaling and the potential involvement of cellular processes like autophagy in CFCS pathogenesis remain incompletely understood.

Observation:

• This study reports on three Chinese children diagnosed with CFCS, all carrying pathogenic variants in the MAP2K1 gene identified through exome sequencing.
• Clinical manifestations included characteristic dysmorphic facial features, seizures, psychomotor retardation, and short stature. One child also presented with pulmonary valve stenosis, skeletal deformities, and osteoporosis.
• Exome sequencing identified known missense mutations (c.383G>T; p.Gly128Val and c.389A>G; p.Tyr130Cys) in exon 3 and a novel missense variant (c.170A>T; p.Lys57Met) in exon 2 of MAP2K1.

Findings:

• In vitro experiments using SH-SY5Y neuroblastoma cells demonstrated that MAP2K1 mutations activate ERK-dependent cell cycle progression.
• Crucially, these mutations were found to induce autophagy, a cellular self-degradation process.
• This is the first evidence linking MAP2K1 mutations to both cell cycle activation and autophagy induction in the context of CFCS.

Implications:

• The findings expand the known spectrum of MAP2K1 mutations associated with CFCS.
• This research elucidates the role of MEK1 protein in neuronal function and provides novel insights into CFCS.
• The study suggests that autophagy may play a significant role in mediating the pathological effects of altered MAP2K1 function, contributing to the diverse phenotypes observed in CFCS.