A Novel CDH1 Mutation Causing Reduced E-Cadherin Dimerization Is Associated with Nonsyndromic Cleft Lip With or...

Area of Science:

• Genetics
• Developmental Biology
• Molecular Biology

Background:

• Cleft lip with or without cleft palate (CL/P) is a common congenital anomaly, affecting 1 in 700 to 1000 newborns.
• Nonsyndromic CL/P (NSCL/P) accounts for approximately 70% of all CL/P cases, indicating a significant genetic component.
• Identifying the genetic underpinnings of NSCL/P is crucial for understanding its etiology and developing targeted interventions.

Observation:

• This study investigated a four-generation Chinese family exhibiting autosomal dominant NSCL/P.
• Whole-exome sequencing identified a novel missense mutation, c.468G>C (p.Trp156Cys), in the CDH1 gene within affected individuals.
• The mutation segregated with the NSCL/P phenotype throughout the family, confirmed by Sanger sequencing and PCR-RFLP.

Findings:

• The identified CDH1 p.Trp156Cys mutation impairs E-cadherin dimerization, a key process for cell-cell adhesion.
• Functional assays demonstrated reduced cell-cell adhesion ability in cells carrying the mutation.
• This suggests that compromised E-cadherin function due to the novel mutation is the molecular mechanism underlying NSCL/P in this family.

Implications:

• The discovery of this novel CDH1 variant expands the known spectrum of mutations associated with NSCL/P.
• This research contributes to a deeper understanding of the molecular basis of NSCL/P.
• Further investigation into CDH1's role in craniofacial development may reveal new therapeutic targets for CL/P.