A Missense Mutation in CDH3, Encoding P-Cadherin, Causes Hypotrichosis with Juvenile Macular Dystrophy

Abstract

Hypotrichosis with juvenile macular dystrophy is a rare autosomal recessive disorder characterized by early hair loss heralding severe degenerative changes of the retinal macula and culminating in blindness during the second to third decade of life. Recently, we identified a frameshift mutation in the CDH3 gene encoding P-cadherin as the proximal cause of hypotrichosis with juvenile macular dystrophy in four families. We report here another consanguineous family in which four members were diagnosed with hypotrichosis with juvenile macular dystrophy. Light and scanning electron microscopy revealed in all patients morphologic hair shaft abnormalities consistent with pili torti. Ocular fundus examination disclosed marked degeneration of the macular pigment epithelium. Electrophysiologic studies were diagnostic for severe retinal dysfunction. DNA sequence analysis of the entire coding sequence of CDH3 revealed in all affected individuals a homozygous missense mutation resulting in a single amino acid substitution at position 503 of P-cadherin sequence (R503H). The mutation completely segregated with the hypotrichosis with juvenile macular dystrophy phenotype in the family but was not detectable in 83 healthy, unrelated controls. The amino acid substitution affects a highly conserved residue and is predicted to alter a Ca2+ binding domain of P-cadherin. This is the first pathogenic missense mutation reported in CDH3 and the second mutation found to underlie hypotrichosis with juvenile macular dystrophy. Our data establish recessive mutations in CDH3 as the molecular cause of hypotrichosis with juvenile macular dystrophy and expand our understanding of the pathophysiology of this intriguing disorder.

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

“…They are highly conserved among various cadherins. Substitutions of these residues may prevent the protein from binding the Ca 2+ ions due to the change in charge [Indelman et al, 2002;Kjaer et al, 2005]. H575 is located in the fifth domain, in close proximity to D542 in the fourth angstroms).…”

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

“…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).…”