NIH News Release
National Institute of Dental
and Craniofacial Research

Monday, August 2, 1999
5:00 p.m. EST

Contact: Wayne Little

Scientists Discover Second Gene for Disorder Described by Darwin

Today, it is difficult to imagine surviving the sweltering heat of summer without a decent cooling system. Inadequate production of sweat, nature's built-in coolant, is just one of the maladies endured by individuals who inherit a rare disorder called hypohidrotic ectodermal dysplasia. Affected children often have very little hair and usually require dentures during early childhood to help them eat normally.

First described by Charles Darwin, it has taken over a century for the genetic basis of this affliction to begin to fall into place. On the heels of the discovery of a mutated X-chromosome gene, researchers at Oregon Health Sciences University (OHSU) and the Baylor College of Medicine have now found another aberrant gene that produces identical symptoms, this one located on chromosome 2. The discovery of a second gene for this disorder improves the prospects for genetic diagnosis, and new insights into gene function may help in developing future therapies.

Dr. Jonathan Zonana from OHSU was a member of the international research team that tracked down the X-chromosome gene, and he is also an integral part of the group that identified the gene on chromosome 2. Zonana, along with Dr. Alex Monreal and colleagues, report their latest discovery in the August issue of Nature Genetics. The research was supported in part by the National Institutes of Health.

The hypohidrotic ectodermal dysplasia story dates back to 1875, when Darwin described a peculiar disorder that appeared in each generation of one family's male members. The mysterious condition became apparent in the very young, manifesting itself with poorly developed teeth, sparse hair on the head and body, and excessively dry skin due to underdeveloped sweat glands. These characteristics were the origin of the disorder's tongue-twister name--"hypohidrotic" referring to low levels of perspiration, and "ectodermal dysplasia" meaning abnormal development of certain tissues derived from embryonic ectoderm (teeth, hair, nails, glands). The individuals observed by Darwin were exclusively males and their symptoms resulted from a mutated gene, called ED1, recently identified on the X-chromosome. Females rarely get this form of ectodermal dysplasia because, unlike males who have one X and one Y chromosome, females have two X's and therefore carry a backup gene that can compensate for the mutation. However, there are families where children of both sexes are affected, with no evidence of X-chromosome involvement.

It was readily apparent to scientists like Zonana and Monreal that other gene defects could also produce hypohidrotic ectodermal dysplasia. Their group was able to identify the chromosome 2 gene, named DL, with the help of "downless" mice. These animals derive their name from a sparseness of hair as well as other features that mimic the human disorder. The researchers used DNA sequence information for the mouse gene to find the equivalent human gene on chromosome 2.

Once the gene was located and sequenced, the investigators examined families that had affected male and female members, yet no linkage with the X-chromosome. Five families had members with abnormalities in the DL gene, with each family having a unique mutation. The gene could be dominant (a defective gene from one parent was sufficient to cause the disorder) or recessive (both parents had to contribute a mutated gene.)

A possible explanation for this observation, according to Zonana, lies in the part of the gene affected by the mutation and in the predicted structure of the gene's protein product. The gene sequence is characteristic of a class of proteins that span the cell membrane and act as chemical receptors. Each receptor molecule binds with a signaling molecule and, as a result, causes a message to be sent to the cell nucleus. The part of the receptor molecule outside of the cell membrane acts "one on one" to bind a complementary signaling molecule. However, the protein component inside the cell must crosslink with two identical sister molecules in order to throw the switch that relays the message.

According to Zonana's hypothesis, a mutation affecting the external portion of the protein would wipe out the signal-binding activity of one gene product, but the presence of a second normal gene could compensate for the loss. This type of mutation would require a defective gene from each parent in order to produce abnormal development. However, if the mutation affects the internal portion, the result is similar to the "one bad apple spoiling the barrel" phenomenon. The defective piece of protein inside the cell could bind up functional sister molecules, essentially short-circuiting the switch mechanism and aborting the message to the nucleus. In this scenario, the mutated gene dominates the role of the normal gene.

This is not the only interesting genetic aspect of hypohidrotic ectodermal dysplasia. How can the ED1 gene on the X-chromosome and the DL gene on chromosome 2 produce essentially the same disorder? Again, says Zonana, the answer may lie in the projected structures of the protein products. The proteins coded by the ED1 and DL genes bear similarities to a signaling molecule (the ED1 protein) and its receptor (the DL protein). The researchers propose that both proteins may interact with one another as part of a continuous molecular pathway--a mutation affecting either protein interrupts the pathway, leading to the same developmental abnormalities.

Yet, even with the discovery of the DL gene, the hypohidrotic ectodermal dysplasia story is still evolving. Not all of the families screened for a defective DL gene had mutations, therefore it appears that additional gene(s) await discovery. Zonana and other researchers are presently hot on the trail of a human gene that is the equivalent of the mouse "crinkled" gene, which lies on mouse chromosome 13 and also produces ectodermal dysplasia-like symptoms.

In addition to Drs. Zonana and Monreal, the research team included Drs. Betsy Ferguson and Summer Street from Oregon Health Sciences University, and Drs. Denis Headon and Paul Overbeek from the Baylor College of Medicine, Houston, Texas. The research was supported by grants from the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and the National Foundation for Ectodermal Dysplasias. NIDCR and NIAMS are components of the National Institutes of Health in Bethesda, Maryland.