Gene For Anhidrotic Ectodermal Dysplasia Identified

July 29, 1996

Gene for Anhidrotic Ectodermal Dysplasia Identified
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July 29, 1996

Contact: Wayne Little
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Gene for Anhidrotic Ectodermal Dysplasia Identified

In 1875, Charles Darwin described a peculiar disorder that appeared in each generation of one family's male members, affecting some, sparing others. The mysterious condition became apparent in the very young, manifesting itself with "...small and weak incisor teeth...very little hair on the body...excessive dryness of the skin..." In addition to the obvious symptoms, Darwin also noted that "Though the daughters in the above family were never affected, they transmit the tendency to their sons; and no case has occurred of a son transmitting it to his sons." With a few simple observations, Darwin launched a scientific inquiry that has finally led to the discovery of the gene for anhidrotic ectodermal dysplasia (EDA).

In the early 1970s, a little less than 100 years after Darwin's description, the EDA gene became the first gene mapped to the X chromosome. It has taken roughly two more decades, but an international team of scientists, led by Dr. Juha Kere of the University of Helsinki and Dr. Anand Srivastava from the University of Washington in St. Louis, has pinpointed the location and identified the structure of the gene. This work, sponsored in part by the National Institute of Dental Research and the National Center for Human Genome Research at the National Institutes of Health, is published in the August issue of Nature Genetics. With this discovery, scientists have provided a molecular marker to identify female carriers of the disorder, and are a step closer to developing therapeutic interventions to prevent or alleviate symptoms in affected individuals.

Still, little is known about what occurs at the molecular level to ultimately produce the unique clinical features of EDA. The name itself refers to the abnormal development (dysplasia) of tissues that are derived from ectoderm, the outermost of the three primary layers of the embryo from which is derived, among other structures, the skin, hair, nails, sweat glands, and teeth. The term "anhidrotic" refers to the underdevelopment or absence of sweat glands, a condition that can be life threatening because it prevents the body from cooling down during fevers or periods of excessive heat. Other features that affect the quality of life for these young children include baldness and often the need for dentures or dental implants to compensate for the absence of teeth.

Of the more than 150 different forms of ectodermal dysplasia, mutations in the X chromosome account for about half of all cases. As was noted by Darwin, the "X-linked" form of ectodermal dysplasia is associated with male children. Males have but a single X chromosome inherited from the mother, along with a Y chromosome from the father. Females inherit an X from each parent. When a male inherits a mutated EDA gene from the mother, he has no back-up normal gene on a second X chromosome, as is the case with females. Males with the mutation come down with ectodermal dysplasia, females may have mild symptoms but mainly act as carriers, transmitting either a normal or mutated X chromosome to their offspring.

Interestingly, it was two female patients with all the symptoms of X-linked EDA that led Drs. Kere, Srivastava, and colleagues to the discovery of the gene. Earlier work by NIDR grantee and co-author Jonathan Zonana had identified an unusual chromosomal rearrangement in one of the girls. The X chromosome had been sheared in two, with one piece sticking to the end of chromosome 9 and the remainder forming a truncated X. A similar X translocation was identified by other investigators in the second girl. Although the break points occurred in slightly different locations, both destroyed the function of the EDA gene, indicating that the breaks occurred within the region of the chromosome that contains the gene. In other disorders where X translocations have been identified as the cause, the normal X chromosome is inactivated, leaving no functional copy of the gene. The disorder manifests itself as it would in males.

The breakpoint information, coupled with several studies that followed the inheritance pattern of known genetic markers on the X chromosome, narrowed the position of the gene to a region known as Xq12-q13.1 Once this region had been identified, it became a painstaking task of identifying the telltale DNA sequences that are characteristic of a gene, and looking for a matching gene product in the cell types that are affected by EDA.

The investigators identified a gene within this region of the X chromosome that contains the molecular code to produce a 135-amino acid protein. This novel protein has a predicted structure compatible with a transmembrane molecule, a protein that is part of the cell membrane and falls within the category of receptors, growth factors, or adherence molecules. The protein was detected in fetal tissues and certain types of adult skin cells that are consistent with the pathology of EDA.

The function of the protein remains unknown, but some exciting hints are provided by a strain of mouse called Tabby, named for its unusual pattern of hair markings. The mice have a mutation in the X chromosome region that is the mouse equivalent of the human EDA gene location. The mice are afflicted with some of the same symptoms that appear in humans, including missing sweat glands and abnormally shaped and/or missing teeth.

When newborn mice are injected with a protein called epidermal growth factor, the developmental defects are partially reversed. The product of the Tabby gene appears to be involved in molecular signaling events that affect the development of ectodermal tissues. Future studies will determine if the mouse and human genes are comparable, and will pursue the function of the human EDA protein and the role it plays in the formation and growth of hair, sweat glands, and teeth.

The investigators participating in this international collaborative effort were Juha Kere, Outi Montonen, Sini Ezer, Albert de la Chapelle, and Ulpu Saarialho-Kere, University of Helsinki; Anand K. Srivastava and David Schlessinger, Washington University School of Medicine; Jonathan Zonana, Betsy Ferguson, and Felix Munoz, Oregon Health Sciences University; Nick Thomas, Delyth Morgan, and Angus Clarke, University of Wales College of Medicine; and Ellison Y. Chen, Advanced Center for Genetic Technology, Foster City, California.

The study was supported by grants from the Sigrid Juselius Foundation, the Academy of Finland, Finska Läkaresällskapet, the Folkhälsan Institute of Genetics, the National Institute of Dental Research and National Center for Human Genome Research at the National Institutes of Health, the National Foundation for Ectodermal Dysplasias, and the Wellcome Trust.

NIH/National Institute of Dental and Craniofacial Research

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