Phenotypic Diversity and Mutation Spectrum in Hypotrichosis with Juvenile Macular Dystrophy

Abstract

Hypotrichosis with juvenile macular dystrophy is a rare autosomal recessive disorder characterized by abnormal growth of scalp hair during infancy, and by the later occurrence of macular degeneration leading to blindness during the first to third decade of life. Hypotrichosis with juvenile macular dystrophy was recently shown to result from mutations in CDH3 encoding P-cadherin. In this study, we assessed 27 individuals, including nine patients, belonging to five families in an attempt to characterize further the CDH3 mutation spectrum and delineate possible phenotype-genotype correlations. Deleterious biallelic mutations, predicted to lead to the translation of a dysfunctional protein, were found in all affected individuals. Four of these mutations are novel. Affected individuals of two large separate apparently unrelated families of Arab Israeli origin were found to carry the same homozygous mis-sense mutation (R503H) in exon 11 of the CDH3 gene. This mutation, which alters a Ca2+-binding site in the fourth extracellular domain of P-cadherin, was previously described in a third unrelated Arab Israeli family. Using haplotype analysis for a series of polymorphic markers encompassing the CDH3 gene, we obtained evidence suggesting a founder effect for R503H in the Arab Israeli population. We also compared the dermatologic and ophthalmologic features of 22 hypotrichosis with juvenile macular dystrophy patients with known recessive mutations in CDH3. Whereas hair paucity and macular degeneration were found in all patients, we noticed significant interfamilial and intrafamilial differences in hair morphology, associated skin findings as well as severity and age of onset of visual disability. Altogether, our results obtained in a series of families of various ethnic origins firmly establish mutations in CDH3 as the proximal cause of hypotrichosis with juvenile macular dystrophy and demonstrate genetic homogeneity as well as phenotypic heterogeneity in this disorder.

P-Cadherin Promotes Cell-Cell Adhesion and Counteracts Invasion in Human Melanoma

“…This is an autosomal recessive disorder mainly characterized by hair loss and progressive macular degeneration leading to early blindness (52). The R503H mutation results in a single histidinefor-arginine substitution at position 503 (26,27), which is part of the highly conserved Ca 2+ -binding LDRE motif in the EC4 repeat of P-cadherin. As shown in cadherins related to P-cadherin, the LDRE motif is crucial for the proper folding of the extracellular domain of the cadherin molecule, enabling stable cis and trans cadherin interactions (25,53).…”

“…For the latter P-cadherin mutant, we mimicked the R503H mutation found in congenital hypotrichosis with juvenile macular dystrophy (HJMD) patients (26,27).…”

P-cadherin is a p63 target gene with a crucial role in the developing human limb bud and hair follicle

“…Paradoxically, previous reports have demonstrated that the identical mutation 829delG resulted in HJMD in one family (Indelman et al, 2003), while it led to EEM syndrome in another family (Kjaer et al, 2005), which suggests that an identical mutation can give rise to different phenotypes between families (Fig. 9).…”

“…9). Nevertheless, in HJMD families, all affected individuals have hair and eye involvement only (Sprecher et al, 2001;Indelman et al, 2002;Indelman et al, 2003;Indelman et al, 2005;Indelman et al, 2007). Similarly, in EEM families, all affected individuals show not only hair and eye phenotype but also hand/foot involvement (Kjaer et al, 2005).…”

“…Recessively inherited mutations in the human CDH3 gene were identified in affected individuals with hypotrichosis with juvenile macular dystrophy (HJMD) characterized by congenital sparse hair and early blindness due to macular dystrophy of the retina (Sprecher et al, 2001;Indelman et al, 2002;Indelman et al, 2003;Indelman et al, 2005;Indelman et al, 2007). More recently, mutations in the CDH3 were also reported to cause another autosomal recessive human disease in two families: ectodermal dysplasia, ectrodactyly and macular dystrophy (EEM syndrome) (Kjaer et al, 2005).…”