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A Novel Arginine→Serine Mutation in EDA1 in a Japanese Family with X-Linked Anhidrotic Ectodermal Dysplasia

2000; Elsevier BV; Volume: 115; Issue: 2 Linguagem: Inglês

10.1046/j.1523-1747.2000.00065-1.x

1523-1747

Noriaki Aoki, Kaoru Ito, Toshiaki Tachibana, Masaaki Ito,

dental development and anomalies

To the Editor: X-linked hypohidrotic ectodermal dysplasia (EDA; MIM 305100), the most common form of the ectodermal dysplasias, is characterized by the absence or hypoplasia of hair, teeth, and sweat glands (Muksickva, 1994Muksickva Mendelian Inheritance in Man. 11th edn. Baltimore, Johns Hopkins University Press1994Google Scholar. Heterozygous carriers of EDA may have minor or moderate degrees of hypotrichosis, hypodontia, and hypohidrosis, although many show no obvious clinical manifestations. The trait had been mapped to Xq12-q13 and a part of the gene responsible for the disease, EDA1, was isolated by positional cloning (Kere et al., 1996Kere J. Srivastava A.K. Montonen O. et al.X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein.Nature Genet. 1996; 13: 409-416Crossref PubMed Scopus (560) Google Scholar). The full-length sequence of EDA1 transcript has recently been published (Bayés et al., 1998Bayés M. Hartung A.J. Ezer S. et al.The anhidrotic ectodermal dysplasia gene (EDA) undergoes alternative splicing and encodes ectodysplasin-A with deletion mutations in collagenous repeats.Hum Mol Genet. 1998; 7: 1661-1669Crossref PubMed Scopus (173) Google Scholar;Monreal et al., 1998Monreal A.W. Zonana J. Ferguson B. Identification of a new splice form of the EDA1 gene permits detection of nearly all X-linked hypohidrotic ectodermal dysplasia mutations.Am J Hum Genet. 1998; 60: 380-389Abstract Full Text Full Text PDF Scopus (171) Google Scholar). It consists of eight exons, resulting in a cDNA of 5307 bp, which is translated into a protein with 391 amino acids. Here we report a novel amino acid substitution mutation (arginine→serine) in codon 156 in EDA1 and show the successful DNA diagnosis in a family to detect carrier status. A 2-y-old boy was referred to our department, in September 1999, suffering from recurrent fever and inability to sweat. His scalp hair and eyelashes were normal, and eyebrows were sparse. The face showed the characteristic features: mild frontal bossing, saddle nose, and bilateral epicanthus. An orthopantography revealed the presence of only one canine at right mandible. Histologic examination showed complete absence of eccrine sweat glands and ducts in the dermis. His parents were not relatives and both of them were healthy. After informed consent, genomic DNA was isolated from peripheral blood. A 254-bp polymerase chain reaction fragment containing exon 3 of the EDA1 gene was amplified using primers described earlier (Monreal et al., 1998Monreal A.W. Zonana J. Ferguson B. Identification of a new splice form of the EDA1 gene permits detection of nearly all X-linked hypohidrotic ectodermal dysplasia mutations.Am J Hum Genet. 1998; 60: 380-389Abstract Full Text Full Text PDF Scopus (171) Google Scholar). The patient's amplified fragment as well as that from the father and the mother was directly sequenced by using the ABI-PRISM dye terminator and the 373 sequencer (Applied Biosystems, Foster City, CA). The sequence from the patient revealed a point mutation (708C→A) in exon 3 of the EDA1 gene, which changes codon 156 from arginine to serine (R156S). The heterozygosity was demonstrated in his mother Figure 1. This mutation was not detected in his father and 50 normal unrelated individuals. In 1996, the EDA1 gene composed of two exons was identified from an adult sweat gland cDNA library, while the mutations of its gene were detected in only one-tenth of the patients (Kere et al., 1996Kere J. Srivastava A.K. Montonen O. et al.X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein.Nature Genet. 1996; 13: 409-416Crossref PubMed Scopus (560) Google Scholar), indicating the presence of alternative gene products including segments from uncovered exons. Subsequently, two groups identified the complete EDA1 gene encoding 391 amino acid protein using cDNA sequence from the homologous mouse gene, Tabby (Ta), and described that its mutations were detected in approximately 90% of the patients, which allowed mutation diagnostics in the majority of patients (Bayés et al., 1998Bayés M. Hartung A.J. Ezer S. et al.The anhidrotic ectodermal dysplasia gene (EDA) undergoes alternative splicing and encodes ectodysplasin-A with deletion mutations in collagenous repeats.Hum Mol Genet. 1998; 7: 1661-1669Crossref PubMed Scopus (173) Google Scholar;Monreal et al., 1998Monreal A.W. Zonana J. Ferguson B. Identification of a new splice form of the EDA1 gene permits detection of nearly all X-linked hypohidrotic ectodermal dysplasia mutations.Am J Hum Genet. 1998; 60: 380-389Abstract Full Text Full Text PDF Scopus (171) Google Scholar). On the basis of the deduced amino acid sequence, EDA1 was predicted to possess at least three functional domains; transmembrane domain, TNF-like domain, and positively charged domain (Copley, 1999Copley R.R. The gene for X-linked anhidrotic ectodermal dysplasia encodes a TNF-like domain.J Mol Med. 1999; 77: 361-363Crossref PubMed Scopus (12) Google Scholar). So far, 37 different pathogenic mutations have been identified, four with small deletions, five with gross deletions, four with insertions, one with deletion/insertion, one with altered splicing, and 22 with point mutations. In addition, a number of missense mutations reported to date have been detected predominantly on three domains. Based on these mutation data, one can assume that the domains are likely to play the important role in the involvement of EDA1 in the epithelial-mesenchymal signaling pathway. The present mutation R156S is located on the positively charged domain, which is conserved highly between mouse Ta and human EDA1, with a high content of arginines and lysines ranging between amino acids 152 and 178. Interestingly, the missense mutation of the same codon by a different amino acid (R156H and R156C) has been reported in three EDA families (Bayés et al., 1998Bayés M. Hartung A.J. Ezer S. et al.The anhidrotic ectodermal dysplasia gene (EDA) undergoes alternative splicing and encodes ectodysplasin-A with deletion mutations in collagenous repeats.Hum Mol Genet. 1998; 7: 1661-1669Crossref PubMed Scopus (173) Google Scholar;Monreal et al., 1998Monreal A.W. Zonana J. Ferguson B. Identification of a new splice form of the EDA1 gene permits detection of nearly all X-linked hypohidrotic ectodermal dysplasia mutations.Am J Hum Genet. 1998; 60: 380-389Abstract Full Text Full Text PDF Scopus (171) Google Scholar). Therefore, this arginine may be a hotspot in this gene since arginine residues often are encoded across CpG islands and actually codon 156 contains CpG sequence, which is known to have a higher mutation rate than other dinucleotides. Our data further support the hypothesis that serine substitution in codon 156 in the positively charged domain is indeed pathogenic and leads to EDA, and add to the expanding database on EDA1 mutations in EDA.