2002 Bill Reed
International Travel Fellowship

Eli Sprecher, M.D., 5th year resident in the Department of Dermatology at Rambam Medical Center, Technion - Israel Institute of Technology, was the winner of the Everett C. Fox Residents/Fellows Award at the 60th Annual American Academy of Dermatology Meeting.  He was awarded the International Travel Fellowship from the Friends of Bill Reed Club and will give the Bill Reed Lecture at the European Society of Dermatologic Research Meeting.
 

Hypotrichosis With Juvenile Macular Dystrophy Is Caused By A Mutation In The CDH3 Gene Encoding P-Cadherin
Eli Sprecher, Reuven Bergman, Gabriele Richard, Raziel Lurie, Stavit Shalev, Dan Petronius, Adel Shalata, Yefim Anbinder, Leena Manov, Rina Leibu, Ido Perlman, Nadine Cohen, Raymonde Szargel
Departments of Dermatology, Pediatric Surgery and Pathology, Rambam Medical Center, Haifa, Israel; Departments of Human Genetics and Physiology and Biophysics, Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel; Department of Dermatology and Cutaneous Biology, Thomas Jefferson Institute of Molecular Medicine, Thomas Jefferson Medical College, Philadelphia, Pennsylvania, United States of Americal; Pediatric Dermatology Unit, Schneider Children's Hospital, Petach-Tikva, Israel; Institute of Human Genetics, Haemek Medical Center, Afula, Israel.

Introduction:  Congenital hypotrichosis with juvenile macular dystrophy (HJMD; MIM 601553) is an autosomal recessive disorder characterized by hair loss at an early age followed by macular dystrophy eventually leading to blindness during the second decade of life.  Although the disorder has often been described, the small size of the families reported so far has precluded further investigation of the genetic basis of this syndrome. 
Methods:  We have recently identified 5 multiplex families comprising a total of 14 patients affected by HJMD.  The present study was aimed at investigating the molecular basis of HJMD in these families in 3 stages: (1) Clinical characterization of the syndrome; (2) Localization of the HJMD gene locus using homozygosity mapping; (3) Identification of the defective gene in HJMD using candidate gene positional cloning. 
Results:  All patients were born with normal hair at birth; hair loss occurred at the age of 3 months and partial regrowth of sparse and short hair was observed during puberty.  Light and scanning electron microscopy revealed unique and previously unreported structural abnormalities of the hair shaft.  Eye fundus examination showed different degrees of macular changes from fine pigmentary dispersion to prominent atrophic scars.  Electrophysiological evaluation of the visual system indicated impaired macular function.  A genome-wide screening was performed using 202 microsatellite markers.  The disease phenotype demonstrated linkage to a novel locus on 16q22.1 with a maximal LOD score of 10.4 at marker D16S2624.  Through further haplotype analysis, we identified a 5 cM critical interval for the disease gene.  We characterized three contigs linked to this region and containing approximately 45 genes.  One of these contigs harbored the CDH3 gene encoding P-cadherin, which is expressed in retinal pigment epithelium and hair follicles and mediates cell-cell adhesion at the adherens junction.  Mutation analysis revealed in all families a common homozygous deletion in exon 8 of the CDH3 gene, resulting in the translation of a markedly truncated protein.  The fact that patients of apparently unrelated families shared an ancestral haplotype suggests a founder effect for this mutation. 
Conclusions:  The present results establish the molecular etiology of HJMD.  They implicate for the first time a member of the cadherin family in the pathogenesis of a hair disorder, reveal an hitherto unrecognized functional/developmental link between hair follicle and retinal pigment epithelia and point to a novel therapeutic target for more common inherited and acquired hair and retinal disorders. 

A missense mutation in CDH3, encoding P-cadherin, causes hypotrichosis with juvenile macular dystrophy.
E Sprecher¹, M Indelman¹, R Lurie², G Richard³, B Miller⁴, D Petronius¹, R Leibu⁴, I Perlman⁵, R Bergman¹. Departments of ¹Dermatology, and ⁴Ophtalmology, Rambam Medical Center, Haifa, Israel; ²Pediatric Dermatology Unit, Schneider Children’s Hospital, Petach-Tikva, Israel; ³Department of Dermatology and Cutaneous Biology, Thomas Jefferson Institute of Molecular Medicine, Thomas Jefferson Medical College, Philadelphia, Pennsylvania, United States of America; Department ⁵Physiology and Biophysics, Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel.

Hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive disorder characterized by early hair loss heralding the occurrence of severe degenerative changes affecting the retinal macula and culminating in blindness during the second to third decade of life. We recently reported a frameshift mutation in the CDH3 gene encoding P-cadherin, as the proximal cause of HJMD in 4 families. We identified an additional consanguineous family affected with HJMD and comprising 4 affected individuals. Light and scanning electron microscopy revealed morphological hair abnormalities consistent with pili torti in all patients. Fundus examination disclosed in all patients marked degenerative changes in the macular pigment epithelium. Electrophysiological studies were diagnostic of severe retinal dysfunction.  Using haplotype analysis, we found out that all affected family members were homozygous for a polymorphic marker located in the vicinity of the CDH3 gene. We establish the entire coding sequence of CDH3 in a patient and identified a missense mutation in this gene resulting in a substitution at position 503 of P-cadherin amino acid sequence (R503H). The mutation was found in an homozygous state in all affected individuals, in an heterozygous state in obligatory carriers and in none of 83 healthy unrelated individuals. The mutation was shown to affect a highly conserved residue, considered to be involved in Ca⁺² binding. This is the first missense mutation reported in CDH3 and the second mutation found to underlie HJMD. These findings establish mutations in CDH3 as the cause of HJMD and expand our understanding of the pathophysiology of this fascinating disorder.