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.