Abstract
Indirect molecular diagnosis of X linked hypohidrotic ectodermal dysplasia (XLHED), a congenital disorder of hair, teeth, and eccrine sweat glands, has been possible by linkage analysis. Direct mutation detection would enable carrier detection in female relatives of sporadic cases, as well as help distinguish XLHED from the rarer, clinically indistinguishable, autosomal recessive disorder ARHED. Recently, a candidate gene for XLHED has been identified. Genomic DNA from 162 affected males and 21 females, who were either obligate carriers or had manifestations of the disorder, were screened by SSCP analysis. A subset of the patients had been previously screened for large genomic deletions and had limited screening of a single exon by SSCP analysis. The two known exons were amplified using flanking primers. Approximately 7% of patients, all males, had putative mutations identified within exon 1, but no variants were found within exon 2. Ten different putative mutations and four probable polymorphisms were identified. Both of the known exons were sequenced in 10 patients who had no detectable SSCP changes, but no additional mutations were found. No correlation between phenotype and genotype was evident between either affected subjects or subjects with or without detectable mutations. The results of the study indicate that only a small minority of affected males can be diagnosed by direct mutation analysis, and that the remainder of the patients are likely to have mutations in as yet unidentified exons of the EDA gene. Linkage analysis, in informative situations, therefore remains the only practical diagnostic option available.
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- Antonarakis S. E., Rossiter J. P., Young M., Horst J., de Moerloose P., Sommer S. S., Ketterling R. P., Kazazian H. H., Jr, Négrier C., Vinciguerra C. Factor VIII gene inversions in severe hemophilia A: results of an international consortium study. Blood. 1995 Sep 15;86(6):2206–2212. [PubMed] [Google Scholar]
- Arte S., Nieminen P., Pirinen S., Thesleff I., Peltonen L. Gene defect in hypodontia: exclusion of EGF, EGFR, and FGF-3 as candidate genes. J Dent Res. 1996 Jun;75(6):1346–1352. doi: 10.1177/00220345960750060401. [DOI] [PubMed] [Google Scholar]
- Bartstra H. L., Hulsmans R. F., Steijlen P. M., Ruige M., de Die-Smulders C. E., Cassiman J. J. Mosaic expression of hypohidrotic ectodermal dysplasia in an isolated affected female child. Arch Dermatol. 1994 Nov;130(11):1421–1424. [PubMed] [Google Scholar]
- Clarke A., Phillips D. I., Brown R., Harper P. S. Clinical aspects of X-linked hypohidrotic ectodermal dysplasia. Arch Dis Child. 1987 Oct;62(10):989–996. doi: 10.1136/adc.62.10.989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Crawford P. J., Aldred M. J., Clarke A. Clinical and radiographic dental findings in X linked hypohidrotic ectodermal dysplasia. J Med Genet. 1991 Mar;28(3):181–185. doi: 10.1136/jmg.28.3.181. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fan E., Levin D. B., Glickman B. W., Logan D. M. Limitations in the use of SSCP analysis. Mutat Res. 1993 Jul;288(1):85–92. doi: 10.1016/0027-5107(93)90210-7. [DOI] [PubMed] [Google Scholar]
- Freire-Maia N., Pinheiro M. Carrier detection in Christ-Siemens-Touraine syndrome (X-linked hypohidrotic ectodermal dysplasia) Am J Hum Genet. 1982 Jul;34(4):672–674. [PMC free article] [PubMed] [Google Scholar]
- Hayashi K., Yandell D. W. How sensitive is PCR-SSCP? Hum Mutat. 1993;2(5):338–346. doi: 10.1002/humu.1380020503. [DOI] [PubMed] [Google Scholar]
- Kere J., Srivastava A. K., Montonen O., Zonana J., Thomas N., Ferguson B., Munoz F., Morgan D., Clarke A., Baybayan P. X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet. 1996 Aug;13(4):409–416. doi: 10.1038/ng0895-409. [DOI] [PubMed] [Google Scholar]
- Munoz F., Lestringant G., Sybert V., Frydman M., Alswaini A., Frossard P. M., Jorgenson R., Zonana J. Definitive evidence for an autosomal recessive form of hypohidrotic ectodermal dysplasia clinically indistinguishable from the more common X-linked disorder. Am J Hum Genet. 1997 Jul;61(1):94–100. doi: 10.1086/513905. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thomas N. S., Chelly J., Zonana J., Davies K. J., Morgan S., Gault J., Rack K. A., Buckle V. J., Brockdorff N., Clarke A. Characterisation of molecular DNA rearrangements within the Xq12-q13.1 region, in three patients with X-linked hypohidrotic ectodermal dysplasia (EDA). Hum Mol Genet. 1993 Oct;2(10):1679–1685. doi: 10.1093/hmg/2.10.1679. [DOI] [PubMed] [Google Scholar]
- Zonana J., Clarke A., Sarfarazi M., Thomas N. S., Roberts K., Marymee K., Harper P. S. X-linked hypohidrotic ectodermal dysplasia: localization within the region Xq11-21.1 by linkage analysis and implications for carrier detection and prenatal diagnosis. Am J Hum Genet. 1988 Jul;43(1):75–85. [PMC free article] [PubMed] [Google Scholar]
- Zonana J. Hypohidrotic (anhidrotic) ectodermal dysplasia: molecular genetic research and its clinical applications. Semin Dermatol. 1993 Sep;12(3):241–246. [PubMed] [Google Scholar]
- Zonana J., Jones M., Browne D., Litt M., Kramer P., Becker H. W., Brockdorff N., Rastan S., Davies K. P., Clarke A. High-resolution mapping of the X-linked hypohidrotic ectodermal dysplasia (EDA) locus. Am J Hum Genet. 1992 Nov;51(5):1036–1046. [PMC free article] [PubMed] [Google Scholar]
- Zonana J., Jones M., Clarke A., Gault J., Muller B., Thomas N. S. Detection of de novo mutations and analysis of their origin in families with X linked hypohidrotic ectodermal dysplasia. J Med Genet. 1994 Apr;31(4):287–292. doi: 10.1136/jmg.31.4.287. [DOI] [PMC free article] [PubMed] [Google Scholar]