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. 2010;1(5):223-230.
doi: 10.1159/000327156. Epub 2011 Apr 7.

CDH3-Related Syndromes: Report on a New Mutation and Overview of the Genotype-Phenotype Correlations

L Basel-Vanagaite  1 , M Pasmanik-Chor, R Lurie, A Yeheskel, K W Kjaer
Affiliations

CDH3-Related Syndromes: Report on a New Mutation and Overview of the Genotype-Phenotype Correlations

L Basel-Vanagaite et al. Mol Syndromol. 2010.

Abstract

Hypotrichosis with juvenile macular dystrophy (HJMD) and ectodermal dysplasia, ectrodactyly and macular dystrophy (EEM) are both caused by mutations in the CDH3 gene. In this report, we describe a family with EEM syndrome caused by a novel CDH3 gene mutation and review the mutation spectrum and limb abnormalities in both EEM and HJMD. A protein structure model showing the localization of different mutations causing both syndromes is presented. The CDH3 gene was sequenced and investigation of the mutations performed using a protein structure model. The conservation score was calculated by ConSurf. We identified a novel CDH3 gene mutation, p.G277V, which resides in a conserved residue located on a β-strand in the second cadherin domain. Review of the data on previously published mutations showed intra-familial and inter-familial variations in the severity of the limb abnormalities. Syndactyly was the most consistent clinical finding present in all the patients regardless of mutation type. The results of our study point to a phenotypic continuum between HJMD and EEM. It is important for genetic counseling to keep in mind the possible clinical/phenotypic overlap between these 2 syndromes and to be aware of the possible risk of limb abnormalities in future pregnancies in families with HJMD syndrome. CDH3 gene mutation screening is recommended in patients with both these syndromes as part of the work-up in order to offer appropriate genetic counseling.

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Figures

Fig. 1
Fig. 1
Clinical and radiographic features. A Right hand of patient 1 showing the hypoplastic distal phalanx of the second finger. B Anteroposterior radiograph of the right hand of patient 1 at the age of 12½ years showing the hypoplastic distal phalanx of the second finger. C Sparse and curly hair of patient 2. D Right hand of patient 2 showing a hypoplastic nail on the second finger with camptodactyly and the presence of scarring between the second and third fingers.
Fig. 2
Fig. 2
Scanning electron microscopy of the hair. Scanning electron microscopy of the hair of patient 1 with original magnification ×50 (A, B) and light microscopy with original magnification of ×40 (C, D), ×70 (E) and ×50 (F). A The periodic twists of the hair shaft (pili torti). B Hair shaft with sharp angle folding. C Flattening of the hair shaft and a straight band. D Flattening and angulations along a hair shaft. E Polarized light microscopy of pili torti and hair shaft twisting of 180°. F Flattening and angulations along a hair shaft.
Fig. 3
Fig. 3
CDH3 gene mutations. ACDH3 gene structure according to the UCSC genome browser. Splice-site variations are marked. B Enlargement of the region including exons 3–16, where most of the variations are located. Variations in bold mark EEM syndrome-causing mutations. Variations in plain text mark mutations causing HJMD syndrome. Asterisks mark the variations found in both syndromes.
Fig. 4
Fig. 4
A structure model of human cadherin 3. A The 5 cadherin domains are colored red, orange, yellow, green, and blue. Calcium ions, as found in EP-cadherin crystal, are shown as gray spheres. The missense mutations are shown as colored spheres and marked in the figure. B G277 is shown as sticks and colored according to the elements (oxygen in red, nitrogen in blue, carbon in green). It is located on a β-strand in the second cadherin domain. The residues of the second and fifth β-strands are shown as sticks. Three hydrogen bonds between the main chains of the 2 β-strands are shown as dashed yellow lines (T232–V278, S233–I279 and V238–G277). C N322 is shown as sticks and colored according to the elements (as described above). It is located close to a calcium ion (2.4 angstroms). D H575 is shown as sticks and colored according to the elements (as described above). It is located in the fifth domain, in close proximity to N542 in the fourth domain (3.5 angstroms). E van der Waals spheres representation of G277 and residues 5 angstroms away. G277 is shown in green. It is located on the second domain (orange). F E504 is shown as sticks and colored according to the elements (green carbons). It is located in the fourth domain. In the X-ray structure of EP-cadherin, this residue (shown in purple) is in close proximity to a calcium ion. G R503 is shown as sticks and colored according to the elements. It is located in the fourth domain, in close proximity to N512 (3 angstroms).
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