Genomic Duplication Responsible for Rare Skin Disease

Through data analysis, ancestry mapping, genomic comparison, and international collaboration, researchers have identified the genetic mutation that causes the rare skin disease keratolytic winter erythema (KWE), or “Oudtshoorn skin,” in South African and Norwegian families.

Researchers at University of the Witwatersrand led the study in collaboration with peers in Europe, the USA, and Canada. KWE causes a redness of the palms and soles with consecutive cycles of peeling of large sections of thick skin, often exacerbated during winter months. Oudtshoorn is a town in the Western Cape province of South Africa where the disorder was present in large families.

Afrikaners, the Afrikaans-language speakers descended from predominantly Dutch, German, and French settlers in South Africa, have a high risk for several genetic disorders (e.g. familial hypercholesterolaemia, porphyria, and the lesser known KWE) because of founder mutations brought by small groups who settled in the Cape of Good Hope and whose descendants are now spread throughout South Africa.

In 1977 KWE was found to occur with a dominant mode of inheritance (so, on average, if a parent has the condition about half the children inherit it in every generation). This early research has enabled dermatologists to make a definitive diagnosis and helped researchers better understand similar skin disorders.

In 1997, student Michelle Starfield guided by Michèle Ramsay, professor at Witz, and a group in Germany mapped the KWE trait to a region on the short arm of chromosome 8. The researchers showed that it was likely that the South African families all had the same mutation but that the German family had a different mutation. Later research focused on characterizing this region of the genome and examining good candidate genes. The KWE mutation remained elusive.

Subsequently, Wits student Thandiswa Ngcungcu, supervised by Prof. Ramsay, investigated KWE with large-scale DNA sequencing during an internship in Novartis, Basel. The mutation was not detected by conventional data analysis so copy-number variants (duplications or deletions) were investigated. Ngcungcu and colleagues discovered a duplication mutation in a genomic region between genes that was present in all South African KWE-affected individuals studied.

During this time Dr Torunn Fiskerstrand, University of Bergen, Norway, independently discovered a genomic duplication as the cause KWE in Norwegians. Ramsay and Fiskerstrand collaborated. The different DNA duplications in the South African and Norwegian families overlapped at a critical enhancer region, providing strong evidence that this was the KWE-causing mutation.

The scientists researched how this duplicated enhancer caused KWE and discovered that the mutation causes a nearby gene, CTSB, to produce more protein than normal and that this abnormal expression was the likely cause of the skin peeling disorder.

The study, by Ngcungcu T et al, was published in the May 2017 issue of the American Journal of Human Genetics.