PDGFRa mutations in humans with isolated cleft palate

Area of Science:

• Genetics
• Developmental Biology
• Human Disease

Background:

• Isolated cleft palate (CP) is a common birth defect with complex genetic underpinnings.
• While numerous genes are implicated, the complete genetic landscape of CP remains incompletely understood.

Purpose of the Study:

• To investigate the role of platelet-derived growth factor receptor alpha (PDGFRa) and miR-140 in the etiology of isolated cleft palate.
• To identify novel genetic variants in PDGFRa associated with CP.

Main Methods:

• PCR-sequencing of PDGFRa coding and 3' untranslated regions (UTR) in CP patients and controls.
• Statistical analysis of variant frequencies between cases and controls.
• Luciferase assays to assess the functional impact of identified variants on miR-140 binding.

Main Results:

• Seven novel single base-pair substitutions in PDGFRa were identified in 8.8% of CP patients versus 1% of controls (P<0.0001).
• Four missense mutations and three 3'UTR variants showed statistically significant differences in frequency compared to controls (P<0.05).
• A specific variant (c.*34G>A) near a miR-140 binding site significantly repressed luciferase activity in the presence of miR-140, indicating functional relevance.

Conclusions:

• This study presents the first genetic evidence implicating PDGFRa in the pathogenesis of human isolated cleft palate.
• Specific PDGFRa variants, particularly those affecting miR-140 regulation, may contribute to CP development.