RAP1-mediated MEK/ERK pathway defects in Kabuki syndrome.

Area of Science:

• Genetics and Molecular Biology
• Developmental Biology
• Cell Biology

Background:

• Kabuki syndrome (KS) is a genetic disorder characterized by developmental delay and congenital anomalies.
• Mutations in KMT2D and KDM6A are primary causes, but the regulated physiological systems remain largely unknown.
• Understanding the molecular pathways underlying KS is crucial for developing effective treatments.

Purpose of the Study:

• To identify novel genetic factors involved in Kabuki syndrome pathogenesis.
• To elucidate the functional interactions of these genes with known KS-associated genes.
• To explore potential therapeutic strategies targeting identified molecular pathways.

Main Methods:

• Whole-exome sequencing was employed to identify genetic mutations in patients with KS and KS-like phenotypes.
• Genetic and functional interactions were studied using zebrafish models and patient-derived cell lines.
• Analysis of MEK/ERK signaling and F-actin polymerization was performed.

Main Results:

• A homozygous mutation in RAP1A (due to uniparental isodisomy) and a de novo mutation in RAP1B were identified in KS patients.
• Dysfunction of identified genes and known KS genes led to aberrant MEK/ERK signaling and disrupted F-actin polymerization and cell intercalation.
• Phenotypes in zebrafish models were rescued by inhibiting MEK/ERK signaling.

Conclusions:

• The study identifies RAP1A and RAP1B as novel genes associated with KS and KS-like phenotypes.
• Kabuki syndrome pathophysiology shares mechanisms with RASopathies, involving MEK/ERK signaling and F-actin dynamics.
• Targeting MEK/ERK signaling presents a potential therapeutic avenue for Kabuki syndrome.