title: 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.
authors.affiliation: Department of Dermatology and Laboratory of Molecular Dermatology, Rambam Medical Center, Haifa, Israel.
authors.forename: Margarita
authors.initials: M
authors.lastname: Indelman
authors.forename: Reuven
authors.initials: R
authors.lastname: Bergman
authors.forename: Raziel
authors.initials: R
authors.lastname: Lurie
authors.forename: Gabriele
authors.initials: G
authors.lastname: Richard
authors.forename: Benjamin
authors.initials: B
authors.lastname: Miller
authors.forename: Danny
authors.initials: D
authors.lastname: Petronius
authors.forename: Dan
authors.initials: D
authors.lastname: Ciubutaro
authors.forename: Rina
authors.initials: R
authors.lastname: Leibu
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
mesh_terms: D000595:Amino Acid Sequence; D015820:Cadherins / Q000235:genetics*; D002648:Child; D003241:Consanguinity; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007039:Hypotrichosis / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense
chemical_list: D015820:Cadherins