CTNND1 encodes the catenin delta-1 (alias p120ctn), an Armadillo repeat protein that interacts closely with the E-cadherin. The intracellular domain of E-cadherin binds to p120ctn, stabilizing the E-cadherin complex at the membrane and preventing its binding to the endocytosis machinery. The majority of the variants identified in BCD syndrome patients result in a premature stop codon (5/6). These protein-truncating variants probably lead to nonsense-mediated RNA decay (NMD), and thus to haploinsufficiency. Less likely, these variants lead to the production of a short protein lacking important functional domains. The sole missense variant identified in the condition, p.(Gly532Asp), involves an amino-acid located in the same ARM domain as residue Lys574, which directly interacts with E-cadherin. Thus, it is assumed that this variant disrupts p120ctn/E-cadherin interaction.
Unlike in Blepharocheilodontic (BCD) syndrome, variants identified in patients with Non-Syndromic Cleft Lip with or without Cleft Palate (NSCLP) mostly result in amino-acid substitution (5/9). Except variant p.(Gln19Glu), identified in a three-generation family, all other CTNND1-missense variants involve amino-acids located in p120ctn/E-cadherin interaction domains.