Ectodysplasin-A1 is sufficient to rescue both hair growth and sweat glands in Tabby mice.

Mutations in the human ectodysplasin-A (EDA) are responsible for the most common form of the ectodermal dysplasia and the defective orthologous gene in mice produces the tabby phenotype, suggesting its vital role in the development of hair, sweat glands and teeth. Among several EDA splice isoforms, the most common and the longest EDA splice isoforms, EDA-A1 and EDA-A2, differing by only two amino acids, activate NF-kappaB-promoted transcription by binding to distinct receptors, EDAR and XEDAR. The extent to which any particular isoform is sufficient for the formation of hair, sweat glands or teeth has remained unclear. Here we report that transgenic expression of the mouse EDA-A1 isoform in tabby (EDA-less) males rescued development of several skin appendages. The transgenic tabby mice showed almost complete restoration of hair growth, dermal ridges, sweat glands and molars. The number of hair follicles in the transgenic mice is the same as in wild-type; though the development of follicles and associated glands varies from indistinguishable from wild-type to smaller and/or only partially formed. These results suggest that the other EDA isoforms may not be absolutely required for skin appendage formation, but consistent with distinctive temporal and spatial expression of the EDA-A2 isoform, are likely required for appropriate timing and completeness of development. Our data provide the first direct physiological evidence that EDA-A1 is a key regulator of hair follicle and sweat gland initiation; its soluble ligand form could aid in deriving therapeutic reagents for conditions affecting hair and sweat gland formation.

The mutation spectrum of the EDA gene in X-linked anhidrotic ectodermal dysplasia.

Mutations in ectodysplasin, the protein product of the EDA or ED1 gene, cause X-linked anhidrotic ectodermal dysplasia. From sixteen families we have identified thirteen mutations, of which nine were novel: a deletion of the entire exon 1, altered splicing site in intron 7 (IVS-2A-->G) and in intron 9 (IVS9+8 C-->G), deletion of 8 bp (1967-1974 nt), four missense mutations (G255C, G255D, W274G, C332Y) and nonsense mutation W274X. Previously identified and the novel mutations form four clusters: 1) at the junction of the transmembrane and extracellular domains, 2) at a putative protease recognition site, possibly affecting cleavage of ectodysplasin, 3) at the trimerizing collagen-like domain, and 4) at regions of high homology to tumor necrosis factor domains. Truncating and splice site mutations occur within the proximal two-thirds of the protein. Our data suggest the functional importance of specific ectodysplasin domains. Hum Mutat 17:349, 2001.

X-linked mental retardation with variable stature, head circumference, and testicular volume linked to Xq12-q21.

Clinical and molecular studies are reported on a family with X-linked mental retardation (XLMR) in which there are eight affected males in three generations. Although the males have somatic manifestations, these are variable and in most cases do not allow clear distinction of affected and unaffected males. Affected males are shorter and have a smaller head circumference. Several also have a sloping forehead (5/8), hearing loss (3/8), cupped ears (2/8), and small testes (4/6). An LOD score of 4.41 with zero recombination was obtained at locus DXS1166 in Xq13.2. This family highlights the difficulty in classifying XLMR conditions as either nonsyndromic or syndromic because of the variable somatic manifestations observed in the affected males.