Mutations in the human homologue of mouse dl cause autosomal recessive anddominant hypohidrotic ectodermal dysplasia

X-linked hypohidrotic ectodermal dysplasia results in abnormal morphogenesi s of teeth, hair and eccrine sweat glands(1). The gene (ED1) responsible fo r the disorder has been identified(2-4), as well as the analogous X-linked gene (Ta) in the mouse(5,6). Autosomal recessive disorders, phenotypically indistinguishable from the X-linked forms, exist in humans(7) and at two se parate loci (crinkled, cr, and downless, dl) in mice(8). Dominant disorders , possibly allelic to the recessive loci, are seen in both species(9,10) (E D3, Dl(slk)). A candidate gene has recently been identified at the dl locus (11) that is mutated in both dl and Dl(slk) mutant alleles. We isolated and characterized its human DL homologue, and identified mutations in three fa milies displaying recessive inheritance and two with dominant inheritance. The disorder does not map to the candidate gene locus in all autosomal rece ssive families, implying the existence of at least one additional human loc us. The putative protein is predicted to have a single transmembrane domain , and shows similarity to two separate domains of the tumour necrosis facto r receptor (TNFR) family(12,13).