X-linked hypohidrotic ectodermal dysplasia results in abnormal morphogenesis of teeth, hair and eccrine sweat glands. The gene (ED1) responsible for the disorder has been identified, as well as the analogous X-linked gene (Ta) in the mouse. Autosomal recessive disorders, phenotypically indistinguishable from the X-linked forms, exist in humans and at two separate loci (crinkled, cr, and downless, dl) in mice. Dominant disorders, possibly allelic to the recessive loci, are seen in both species (ED3, Dlslk). A candidate gene has recently been identified at the dl locus that is mutated in both dl and Dlslk mutant alleles. We isolated and characterized its human DL homologue, and identified mutations in three families displaying recessive inheritance and two with dominant inheritance. The disorder does not map to the candidate gene locus in all autosomal recessive families, implying the existence of at least one additional human locus. The putative protein is predicted to have a single transmembrane domain, and shows similarity to two separate domains of the tumour necrosis factor receptor (TNFR) family.

Mutations in the epithelial morphogen ectodysplasin-A (EDA), a member of the tumor necrosis factor (TNF) family, are responsible for the human disorder X-linked hypohidrotic ectodermal dysplasia (XLHED) characterized by impaired development of hair, eccrine sweat glands, and teeth. EDA-A1 and EDA-A2 are two splice variants of EDA, which bind distinct EDA-A1 and X-linked EDA-A2 receptors. We identified a series of novel EDA mutations in families with XLHED, allowing the identification of the following three functionally important regions in EDA: a C-terminal TNF homology domain, a collagen domain, and a furin protease recognition sequence. Mutations in the TNF homology domain impair binding of both splice variants to their receptors. Mutations in the collagen domain can inhibit multimerization of the TNF homology region, whereas those in the consensus furin recognition sequence prevent proteolytic cleavage of EDA. Finally, a mutation affecting an intron splice donor site is predicted to eliminate specifically the EDA-A1 but not the EDA-A2 splice variant. Thus a proteolytically processed, oligomeric form of EDA-A1 is required in vivo for proper morphogenesis.The ED1 gene encodes a protein, ectodysplasin-A (EDA), 1 recently recognized to be a member of the tumor necrosis factor (TNF) superfamily of ligands. Mutations within the ED1 gene cause an X-linked recessive disorder, hypohidrotic or anhidrotic ectodermal dysplasia (ED1, XLHED) (Mendelian inheritance in man 305100), involving abnormal morphogenesis of teeth, hair, and eccrine sweat glands. Various splice forms of the ED1 transcript have been detected, but two isoforms differing only by two amino acids, EDA-A1 (391 aa) and EDA-A2 (389 aa), contain a TNF homology domain (1-3). EDA is a type II transmembrane protein with a small N-terminal intracellular domain and a larger C-terminal extracellular domain containing a (Gly-X-Y) 19 collagen-like repeat with a single interruption and a C-terminal TNF homology domain (Fig. 1A). The TNF homology domain is similar to other members of the TNF family, consisting of 10 predicted anti-parallel ␤-sheets linked by variable loops (Fig. 1A). TNF family ligands homotrimerize to form a pear-shaped quaternary structure able to bind a receptor molecule at each monomer-monomer interface (4, 5). The closest EDA homologues in the TNF family are BAFF/ BLyS, APRIL, and TWEAK, although none of them contains collagen-like repeats (6 -9). All four ligands contain consensus sequences for proteolytic cleavage by furin within their extracellular domain. In the case of EDA, two overlapping consensus sites are located between the transmembrane and the collagenlike domains (Fig. 1A). EDA-A1, but not EDA-A2, has been shown to specifically bind to EDAR, a member of the TNF receptor superfamily that, like most members of the TNF receptor family, activates the NF-B and c-Jun N-terminal kinase pathways (3, 10). Mutations in DL (EDAR), the human homologue of the murine downless locus, produce an identical phenotype to loss of function of EDA (11,12)...

Background: Macaca fascicularis (cynomolgus or longtail macaques) is the most commonly used nonhuman primate in biomedical research. Little is known about the genomic variation in cynomolgus macaques or how the sequence variants compare to those of the well-studied related species, Macaca mulatta (rhesus macaque). Previously we identified single nucleotide polymorphisms (SNPs) in portions of 94 rhesus macaque genes and reported that Indian and Chinese rhesus had largely different SNPs. Here we identify SNPs from some of the same genomic regions of cynomolgus macaques (from Indochina, Indonesia, Mauritius and the Philippines) and compare them to the SNPs found in rhesus.