Researchers piece together the puzzle of Hailey-Hailey skin disease

Hailey-Hailey disease is a blistering skin disorder, usually inherited, and is characterized by a painful erosive skin rash that appears on the body in an unusual pattern of lines. The rash appears in a linear pattern on the extremities, S-shaped on the chest and abdomen, and V-shaped on the back. These lines are thought to trace the pathway of development of the ectoderm, one of the three layers of cells of the early human embryo and that which gives rise to skin and neural tissue.

It has been thought that individuals with Hailey-Hailey disease possess not one, but two or more genetically different populations of cells that originate from the one fertilized cell after fusion of the sperm and ovum during fertilization. This condition is known as mosaicism. In most cases of clinical mosaicism, the linear patterns of abnormal skin are surrounded by normal skin – termed type 1 mosacism. Several patients have been described whom experience both patterned lesions and, in remaining areas of skin, also show a milder form of the disorder – termed type 2 mosaicism.

In the November 15 issue of the Journal of Clinical Investigation, German researcher Jorge Frank and colleagues reveal the molecular basis of type 2 mosaicism in Hailey-Hailey disease. The authors isolated skin cells from severely affected areas of a female patient and found that skin cells from patterned skins lesions possessed a defect in the gene ATP2C1, which encodes a calcium pump protein, present on the chromosome derived from the patients mother. Normally, the chromosome obtained from the father and presumably containing a normal form of this gene, would compensate for this defect and result in the remaining skin cells being normal. However, in this case, the chromosome obtained from the father had been lost. Therefore, skin cells isolated from other areas of the skin possessed the same defect and in effect the patient had received a "double dose" of the mutant gene in severely affected areas.

In an accompanying commentary, Amy S. Paller, from the Department of Dermatology at Northwestern University discusses this novel genetic concept and asserts that "the discovery of the basis for type 2 mosaicism contributes to our understanding of gene mosaicism as well as of embryologic development of the ectoderm." This study will prompt further examination of the mechanisms of embryologic development of the ectoderm and the causes of other patterned epidermal and dermal disorders.

TITLE: Allelic loss underlies type 2 segmental Hailey-Hailey disease, proving molecular confirmation of a novel genetic concept.

AUTHOR CONTACT: Jorge Frank
Department of Dermatology and Allergology, University Clinic of the RWTH, Aachen, Germany.
Phone: 49-241-808-9162; Fax: 49-241-808-2413; E-mail: jfrank@ukaachen.de.

View the PDF of this article at: http://www.jci.org/cgi/content/full/114/10/1467

ACCOMPANYING COMMENTARY:
TITLE: Piecing together the puzzle of cutaneous mosaicism.

AUTHOR CONTACT: Amy S. Paller
Department of Dermatology. Northwestern University, Chicago, Illinois, USA.
Phone: 312-695-0197; Fax: 312-695-0664; E-mail: apaller@northwestern.edu.

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