Michael Fitzgerald, PhD
Harvard Medical School, Boston, MA
|Dr. Mason Freeman|
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.
« Back to Previous Page