Figure 2
From: Blepharocheilodontic syndrome is a CDH1 pathway–related disorder due to mutations in CDH1 and CTNND1
CDH1 mutations analysis. (A) (a) Structure of E-cadherin comprising protein signal peptide, precursor sequence, extracellular domain (EC), transmembrane domain (TM), and cytoplasmic domain. Exons and binding domain of p120ctn are indicated. E-cadherin extracellular domain is characterized by five repeats EC domains (EC1 to EC5). EC1–EC2 interconnection shows the conserved DQND sequence (surrounded) corresponding to the calcium ion–binding sites. Residues Asp254, Asp257, and Val454 show high conservation across vertebrates. Location of the missense germ-line E-cadherin mutations identified in BCD syndrome (indicated by asterisks), HDGC without or with cleft lip/palate (HDGC+CLP in blue), and NSCLP (in green). (A) (b) Structure of p120ctn. Four isoforms arise by alternative splicing from four start codons (M1 to M4). Isoforms 1 and 3 are the most abundantly expressed isoforms. Exons 18 (exon A), exon 20 (exon B), and exon 11 (exon C) undergo alternative splicing. CTNND1 mutations identified in our cohort, indicated by asterisks, affect isoforms 1 to 3. (B) (a) Three-dimensional predicted structure of the human native and mutated (Asp254Tyr and Asp257Val) E-cadherin proteins. EC1 and EC2 domains are colored orange, with residues 254 and 257 shown in CPK. Both substitutions possibly disrupt electrostatic interactions between calcium ions and mutated binding side. Substitution p.(Asp254Tyr) possibly further impairs interactions through modification of orientation of the side chain. (B) (b) Mutations c.1320G>T and c.1320G+1G>C disrupt the canonical consensus motif AGgt at the exon 9–intron 9 boundary. 3D structures are visualized with RasMol 2.7.5.1 (Herbert J. Bernstein). (c) RT-PCR on lymphocytes RNA from individual F5-I2 and healthy control. A shorter transcript was identified in patient F5-I2, corresponding to skipping of exon 9. Sequencing confirms exon skipping.
