What Is The Skin Disorder Known As Hailey-Hailey Disease And What Is Known About Its Underlying Genetic Cause?

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What Is Hailey-Hailey Disease?

Hailey-Hailey disease (HHD) is very rare autosomal dominant genetic disorder that predominantly affects the skin. Those who have HHD experience skin problems, such as blisters, erosions, plaques, fissures and lesions, that can be very painful. These problems are caused by the body’s failure to maintain cell-to-cell adhesion between cells that are part of the epidermal layer of the skin. Specifically, the failure to maintain cell-to-cell contact is a condition that is known as “acantholysis”. Areas of the body that are most commonly affected include the neck, the armpits and the groin region.

HHD symptoms are not typically seen in children. Rather, its lesion and blister symptoms usually manifest in affected individuals within a decade or two after they reach adulthood. Interestingly, in many HHD individuals, symptoms last for months or years and then go into remission for similar periods of time before returning again.

There is no known cure for HHD. However, the severity of symptoms can be somewhat reduced by ingesting, or applying topically, corticosteroids and antibiotics.

Genetic Causes

In 2000, a predominantly European team of molecular geneticists reported their analysis of the genomes of several HHD patients which led to their discovery that these individuals, collectively, harbored several different mutations in a gene that is known as ATP2C1. The ATP2C1 gene is predicted to encode a protein which belongs to the P-type ion-transport ATPase family of proteins.

Specifically, it is believed that the protein that is encoded by the ATP2C1 gene is required for the transport of calcium ions from the cytoplasm of keratinocytes, which are cells found in the epidermal layer of the skin, to the golgi apparatus in those cells. (A main function of the golgi apparatus is to process and package intracellular proteins for export outside the cell, where they are needed for any one of many different extracellular purposes.) Therefore, if this hypothesis is true, the protein product of the ATP2C1 gene likely plays an important role in maintaining calcium concentrations inside the golgi apparatus. Further, it would mean that a defective version of this protein, such as is made in individuals who are affected with HHD, may be insufficient for maintaining calcium concentrations inside the golgi apparatus, which is a phenomenon that likely would impair the ability of the golgi apparatus to properly process and package proteins for extracellular export (or to perform some other important golgi apparatus function). It therefore is speculated that this deficiency in the golgi apparatus is specifically what leads to the skin defects that are typically seen in HHD patients.


CIGNA, Hailey-Hailey Disease: https://www.cigna.com/healthinfo/nord1223.html

Hailey-Hailey Disease Society, What Is Hailey-Hailey Disease?: https://haileyhailey.com/WhatIsHHD.htm

R.J. Fairclough et al., Hailey-Hailey Disease: Identification of Novel Mutations in ATPC1 and Effect of Missense Mutation A528P on Protein Expression Levels, Journal of Investigative Dermatology 123:67-71 (2004). https://www.nature.com/jid/journal/v123/n1/full/5602393a.html

R. Sudbrak et al., Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca2+ pump, Human Molecular Genetics 9:1131-1140 (2000). https://hmg.oxfordjournals.org/content/9/7/1131.full

Z. Hu et al., Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey Disease, Nature Genetics 24:61-65 (2000). https://www.nature.com/ng/journal/v24/n1/full/ng0100_61.html