Distinct CDH3 mutations cause ectodermal dysplasia, ectrodactyly, macular dystrophy (EEM syndrome)

Background: EEM syndrome is the rare association of ectodermal dysplasia, ectrodactyly, and macular dystrophy (OMIM 225280). Methods: We here demonstrate through molecular analysis that EEM is caused by distinct homozygous CDH3 mutations in two previously published families. Results: In family 1, a missense mutation (c. 965A -> T) causes a change of amino acid 322 from asparagine to isoleucine; this amino acid is located in a highly conserved motif likely to affect Ca2+ binding affecting specificity of the cell-cell binding function. In family 2, a homozygous frameshift deletion (c.829delG) introduces a truncated fusion protein with a premature stop codon at amino acid residue 295, expected to cause a non-functional protein lacking both its intracellular and membrane spanning domains and its extracellular cadherin repeats 3-5. Our mouse in situ expression data demonstrate that Cdh3 is expressed in the apical ectodermal ridge from E10.5 to E12.5, and later in the interdigital mesenchyme, a pattern compatible with the EEM phenotype. Furthermore, we discuss possible explanations for the phenotypic differences between EEM and congenital hypotrichosis with juvenile macular dystrophy (HJMD), which is also caused by CDH3 mutations. Conclusions: In summary, we have ascertained a third gene associated with ectrodactyly and have demonstrated a hitherto unrecognised role of CDH3 in shaping the human hand.