How a rare skin disease links South Africa to an 18th Century French seaman

5 June 2017 - Michèle Ramsay and Thandiswa Ngcungcu

Keratolytic Winter Erythema – more commonly referred to as KWE – is a genetic skin disease affecting the palms and the soles.

It¡¯s also colloquially known as ¡°Oudtshoorn skin¡± because many people with the condition were living in this rural town in South Africa¡¯s Western Cape when it was first described.

The condition doesn¡¯t affect the whole body but results in redness followed by peeling of thick pieces of skin on the palms and soles.

There¡¯s no effective treatment. Although not medically severely debilitating it can be socially uncomfortable and may be a disadvantage to people working in specific professions. The severity of the condition varies in different people and in most cases it¡¯s a recurrent cycle of redness and peeling.

A study done in the mid-1980s suggested that one in every 7200 Afrikaans people in South Africa is affected by the condition. But it¡¯s more likely that the prevalence is uneven across South Africa. It also occurs in about one in every 90000 coloured people (people of mixed racial descent).

Cases of KWE have also been described in German and Norwegian families. We suspect the harsh South African climate has exacerbated the condition making it easier to diagnose. Dermatologists across the world have picked up cases of KWE among South Africans in the diaspora, particularly the UK and Canada.

In research we¡¯ve done on the condition we have made new important findings that can help with diagnosis. This in turn can help us establish its true prevalence and opens the door to research about possible treatment.

We anticipate that our findings could also contribute to understanding how this particular mutation affects a gene that may play a role in other skin diseases and peeling disorders.

Tracing the history

The condition was first named by George Findlay, a South African dermatologist based at the University of Witwatersrand in the 1970s, who had seen many patients and their families.

Findlay found that if one parent had KWE, there was a 50% chance that the trait would manifest in a child. This indicated that it was a dominant genetic condition.

In the early 1980s Peter Hull, another dermatologist, did a genealogical study and traced the South African founder of the condition to a ship captain, Captain Francois Renier Duminy, who settled in South Africa in the late 1700s. His research involved visiting the families of people who had the condition and then doing extensive investigations into their roots.

All families linked back to the captain who was originally from Laurent, France, and travelled to the Cape of Good Hope where he settled. Hull established that the disease spread from the Frenchman to his children (one of whom was illegitimate and born in South Africa).

Everyone in South Africa who has the disease can trace their lineage back to the French seaman and his offspring.

The disease¡¯s presence in South Africa is the result of what¡¯s known in genetics as a ¡°founder effect¡± ¨C when a new population is established by a very small number of individuals, they contribute a large proportion to the population gene pool. The genes from those people are over represented in the resulting population, in this case the Afrikaners. This is the reason why KWE is more common in South Africa than elsewhere in the world.

The struggle to find the gene

It has taken us 32 years to find the mutation that¡¯s responsible for the condition. But our latest discovery explains why we struggled to find the gene in the first place.

Twenty years ago we did a study on people with the condition. We discovered the region in which the mutation was located: the short arm of chromosome 8. For many years after that study we analysed the genes in that region. But we could not find which gene was causing the disease.

As a result of genomic technology we were able to take the next steps by analysing the entire region that was identified on chromosome 8, including regions that did not have genes.

We initially performed conventional analysis of prioritising genes but we didn¡¯t find anything. But when we looked at the areas between genes, we found the first part of the answer to the cause of KWE. A large region between the genes was duplicated (present in two copies). This could be the cause, we thought.

While we were doing our work a researcher in Norway found a different mutation in the same region of the chromosome. There was, however, a duplicated section that overlapped with ours.

This meant that by joining forces we could strengthen our research to understand how the mutations in the two different families caused the same condition. Skin biopsies were taken from a few people with KWE and some unaffected volunteers. The epidermis samples from affected individuals and the volunteers were analysed to identify the gene that¡¯s influenced by the mutation in the region between the genes. We tested three candidate genes that were in close proximity to the mutation.

We discovered that one of the genes, cathepsin B, was being over produced in people with KWE, which is what caused the peeling.

Next steps

The discovery is important on two fronts. Firstly, it may help scientists understand other skin diseases and peeling disorders. It¡¯s possible that this gene could play a role in them too.

Secondly, it will help dermatologists make the correct diagnosis of the condition, as a DNA test can identify the mutation.

But several parts of the puzzle still remain. One, for example, is why it comes and goes in some people. Another is why the symptoms only affect the palms and the soles of the feet.

The next move is for scientists to culture skin cells to establish what triggers the condition. Anecdotal evidence suggests the condition is exacerbated when people are stressed or have an infection.

The end result would be to establish how to treat it. But we are a long way to translating our findings into something useful for people with KWE.

Mich¨¨le Ramsay, Director of the Sydney Brenner Institute for Molecular Bioscience, Professor in the Division of Human Genetics , University of the Witwatersrand and Thandiswa Ngcungcu, PhD candidate in the Division of Human Genetics, Faculty of Health Sciences, University of the Witwatersrand. This article was originally published on The Conversation. Read the original article.