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

Nature Genetics volume 22, pages 366–369 (1999)Cite this article

Abstract

X-linked hypohidrotic ectodermal dysplasia results in abnormal morphogenesis of teeth, hair and eccrine sweat glands1. The gene (ED1) responsible for the disorder has been identified2,3,4, as well as the analogous X-linked gene (Ta) in the mouse5,6. Autosomal recessive disorders, phenotypically indistinguishable from the X-linked forms, exist in humans7 and at two separate loci (crinkled, cr, and downless, dl) in mice8. Dominant disorders, possibly allelic to the recessive loci, are seen in both species9,10 (ED3, Dlslk). A candidate gene has recently been identified at the dl locus11 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) family12,13.

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Figure 1: DL transcript, physical map, genomic organization and putative protein product.
Figure 2: Expression analyses.
Figure 3: Family ED1237.
Figure 4: Sequence comparison of the proposed central β sheet of the ED1 protein (aa 293-309) and five members of the human TNF ligand superfamily.

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Acknowledgements

We thank the families for participation; referring clinicians Z. Borochowitz, C. McKeown, C. DeLozier-Blanchet, R. Jorgensen and D. Bixler; J. Zeltinger and K. Holbrook for RNA from human fetal skin; J. Murray for the human embryonic craniofacial library; and J. Hejna and M. Litt for assistance in BAC screening and radiation hybrid mapping. This work was supported by NIH grants DE11311 (J.Z.) and AR45316 (P.A.O.), as well as by a grant from the National Foundation for Ectodermal Dysplasia (J.Z.).

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Authors and Affiliations

  1. Department of Molecular and Medical Genetics, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, 97201, Oregon, USA

    Alex W. Monreal, Betsy M. Ferguson, Summer L. Street & Jonathan Zonana

  2. Departments of Cell Biology and Molecular and Human Genetics, Baylor College of Medicine, Houston, 77030, Texas , USA

    Denis J. Headon & Paul A. Overbeek

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  1. Alex W. Monreal
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  4. Summer L. Street
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  6. Jonathan Zonana
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Correspondence to Betsy M. Ferguson.

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Monreal, A., Ferguson, B., Headon, D. et al. Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat Genet 22, 366–369 (1999). https://doi.org/10.1038/11937

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