Mason Freeman, MD,
Michael Fitzgerald, PhD

Harvard Medical School, Boston, MA

Dr. Mason Freeman

In our laboratory at the Massachusetts General Hospital, we have spent most of the past twenty years studying the role of cellular proteins that move lipids into or out of cells. Lipids are fats and are not dissolvable in water, so cells have developed special mechanisms for moving them around inside cells, as well as from inside a cell to outside a cell. One of the mechanisms cells use for this activity is a class of proteins called ABC transporters. ABC stands for ATP Binding Cassette. These transporters are proteins that bind the energy molecule of all cells, called ATP, and use its energy to move lipid molecules wherever the cell wants them to go. Both Lamellar Ichthyosis and Harlequin ichthyosis have been associated with alterations in the gene encoding one of these ABC transporters, ABCA12. We recently generated mice in which the ABCA12 gene was deleted, and these mice share many of the same features that children with Harlequin Ichthyosis have. The mice have thickened skin and water evaporates through this skin much faster than normal. We used our many years of experience measuring different lipids to identify a defect in the skin of these mice and we discovered a very unusual and specific lipid to be missing. This result makes us think that the activity of ABCA12 that is missing, in children with the scaly skin problems linked to the ABCA12 transporter, must cause the special lipid we identified not to get to its appropriate location in the cell. This failure means that it does not get processed to the final, correct form needed to make the skin look and work normally. In the work that F.I.R.S.T. is funding us to perform, we will try to understand if this idea is correct and if there are any ways to correct the defect or re-supply the missing critical lipid. We are very excited about this work and grateful for the support of the Foundation. Most importantly, we want to help find better ways to treat those who have developed these very serious skin disorders.

UPDATE:  2009

The project, Analysis of a Mouse Gene Deletion Model for the Lamellar/Harlequin Ichthyosis ABCA12 Transporter is in the second year of funding. In humans, mutation of the ABCA12 transporter has been associated with ichthyotic skin diseases including the most severe of these, harlequin ichthyosis (HI). However, little is known regarding the activity of ABCA12 and its relation to the loss of skin barrier function and the hyperkeratosis seen in patients carrying ABCA12 mutations. Using funds provided by FIRST and the National Institutes of Health investigators have developed a mouse model with a targeted deletion of the Abca12 gene and have shown this animal model reproduces the major features of the HI condition including a loss of the lipids that keep the skin from drying out. Like HI patients these mice also have a dramatic expansion and scaling of the outermost layer of the skin. Using mass spectrometry, a physical method that accurately measures the mass of molecules, they have profiled the lipids in the skin of the mice lacking ABCA12 and have found they have a profound reduction in linoleic esters of long chain omega-hydroxy-ceramides. Because these lipids are required for the barrier function of the skin, this result has given important insight into how ABCA12 functions to allow normal development of the skin and how loss of ABCA12 activity causes harlequin ichthyosis. Excitingly, during the second year of funding and during this time results will be extending. In particular, in collaboration with Dr. Leonard Milstone, a member of the FIRST network of researchers and a dermatologist who provides care for HI patients, they have derived immortalized keratinocyte cells lines from the mice lacking ABCA12. Preliminary results indicate that these cells will also serve as a useful model to study the biochemical mechanism of ABCA12 function and should allow the study the feasibility of re-expressing ABCA12 in these cells to correct their lipid transport defect. It hoped that this work will provide methods and information that one day may lead to new therapies to treat patients with ichthyoses caused by the loss of ABCA12 activity.

Endogenous β-glucocerebrosidase activity in Abca12−/−epidermis elevates ceramide levels after topical lipid application but does not restore barrier function

Journal of Lipid Research March (2014) 55(3): 493–503.

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