Genetic Exploration of the Ichthyoses

A DERMATOLOGY FOUNDATION PUBLICATION SPONSORED BY ORTHO DERMATOLOGICS A Division of Valeant Pharmaceuticals North America LLC VOL.DERMATOLOGYDERMATOLOGY 36 NO. 3 FALL 2017 ™ FOCUSFOCUS Also In This Issue DF Welcomes New Annenberg Circle and AC Sustaining Members Genetic Exploration Dr. John E. Harris Leads Medical & Scientific Committee of the Ichthyoses: JAAD Highlights Research Reaping a Multitude of Benefits From DF-Supported Investigators odern next-generation sequencing (NGS) keratinization (DOK), which encompass at M technologies—also known as high- least 28 ichthyoses and other scaly skin disor- Focus on Research throughput DNA sequencing—burst onto the ders that disrupt the skin barrier and thus sig- CAAR-T Cells— scene roughly a decade ago, powering a nificantly impair cutaneous water retention A Revolution in Therapy for revolution in genetics research. It completely (see boxes on pages 8 and 10). These diseases outstripped Moore’s law—normally the have been a career-long passion in both Autoimmune Disease Begins benchmark for measuring technologic the clinic and lab for Keith A. Choate, MD, With Pemphigus Vulgaris advance—which observes that computing PhD, professor of dermatology, genetics, capacity doubles nearly every two years, with and pathology at Yale and director of research Aimee S. Payne, MD, PhD dramatic progress enabling the transforma- in dermatology there. When this game- Albert M. Kligman Associate Professor of Dermatology, Department of Dermatology, Perelman School of tional power of iPhones, personal computers, changing revolution in molecular diagnostics Medicine, University of Pennsylvania and social media. Although advances in DNA emer ged, he was ready to dive in—and has sequencing technology were in line with been a prime mover in this progress from the r. Payne and her research team have Moore’s law until about 2007, the advent very beginning. D developed a breakthrough treatment of NGS sequencing power initiated an expo- designed to change the health and lives of nential increase every year since. Massively Transformational Potential patients with pemphi- parallel DNA sequencing generates vast In addition to enabling the discovery of gus vulgaris (PV). This amounts of data and provides results in hours new phenotypes, NGS has enabled the dis- rare and life-threatening to days instead of months to years, and at a covery of DOK-causing mutations in over a autoimmune disease fraction of what earlier approaches cost. dozen new genes identified—often with sub- impairs the suprabasal Vital new questions about disease biology stantial effort—by Choate and others in the portion of the epider- can be framed. And the potential impact on field. Every gene found thus far to cause DOK mis, with blisters typi- the capacity to identify, understand—and affects one of the many molecular players in cally affecting mucous eventually to treat—rare genetic skin diseases the highly complex sequence of keratinocyte membranes, followed is profound. differentiation (see illustration at left and by skin. It is caused by One group of disorders for which NGS box on page 8). Thus each newly identified autoantibodies (see box on page 12) to the has fueled new discoveries is disorders of genetic cause reveals a specific molecular keratinocyte adhesion protein desmoglein 3 pathway—either poorly (Dsg3), one of the primary cell–cell adhesion Extrusion of Stratum corneum understood or not previ- molecules found in desmosomes. The disease contents of LB to form lipid ously known—that par- typically affects people between the ages of barrier Stratum granulosum Suprabasal ticipates in creating and 50–60. PV had been uniformly fatal until the layers Formation of maintaining the epider- advent of corticosteroids, followed by other lamellar bodies Stratum spinosum Epidermis (LB) mis and/or the lipid com- immunosuppressive treatment strategies that ponents that constitute emerged several decades ago. But the death the barrier to water loss. rate remains significant even with these treat- Stratum basale Studying the pathobiol- ments. Some patients are not responsive Basement ogy of these newly found or become refractory. And the broadly im- membrane mutations helps to un- munosuppressive nature of such treatments as derstand the specific oral prednisone and rituximab carry a high— Epidermal structure. Epidermal barrier function is maintained by a complex disease and suggest a and potentially fatal—risk for severe infection and tightly regulated pattern of epidermal differentiation and generation of lipid components. (Reprinted with permission from F1000Res. See Suggested Readings.) (Continued on page 3) (Continued on page 11) January 24–28, 2018 2018 The Ritz-Carlton, Naples, Florida “Truly the best derm meeting I have ever been to.” Limited Space Available—Register Now! Visit www.dermatologyfoundation.org/symposia EXPERT FACULTY PRACTICE-RELEVANT David E. Cohen, MD, MPH Jack S. Resneck, Jr., MD MINI-SYMPOSIA New York University University of California, Infectious Disease San Francisco Beth A. Drolet, MD Inflammatory Disease Updates Medical College of Wisconsin Bethanee J. Schlosser, MD, PhD Northwestern University Dermatologic Surgery and Kristina Callis Duffin, MD Minor Procedures University of Utah Kanade Shinkai, MD, PhD Emerging Evidence and University of California, Emerging Diseases Jonathan A. Dyer, MD San Francisco University of Missouri CPC Steven M. Sperry, MD Karen E. Edison, MD University of Iowa Cutaneous Oncology University of Missouri Marta J. Van Beek, MD, MPH Comorbidities and Associations of Skin Diseases Kenneth A. Katz, MD University of Iowa Kaiser Permanente Health Policy Karolyn A. Wanat, MD Suzanne M. Olbricht, MD University of Iowa Patient Interactions, Technologies, Harvard Medical School and Practice Satisfaction This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) of The Yale School of Medicine. The Yale School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. The Yale School of Medicine designates this live activity for a maximum of 17.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. 2 Fall 2017 Dermatology Foundation treatment target. The hope is for effective ther- retroviral vectors. Choate fondly recalls the apeutics for these often challenging diseases. regular drives he and Khavari made to the DERMATOLOGY And there is more. This work as a whole UCSF ichthyosis clinic of Mary A. Williams, MD, enhances our understanding of normal skin (now clinical professor of dermatology and FOCUS biology, especially when novel pathways are pediatrics there) to collect patient tissue sam- A PUBLICATION OF THE discovered. ples for growing cell cultures to work with in DERMATOLOGY FOUNDATION In pursuit of new genes, Choate and his the lab. “The exposures I had with Paul and Sponsored by colleagues regularly search nationally and Mary and patients with ichthyosis were form- Ortho Dermatologics internationally to recruit patients with skin ative,” he says. “I realized that dermatology is A Division of Valeant Pharmaceuticals North America LLC disorders that deviate from the known spec- a serious business. And I was struck by how Editors-in-Chief trum. “Then we harness these new genetic profoundly these disorders affect patients.” analysis tools to systematically dissect the Choate’s very first patient meeting at the clinic Lindy Fox, MD Associate Professor of Dermatology genetic basis of these disor- had lasting impact. Her dis- University of California, San Francisco ders—and in doing this, we ease had appeared fairly mild reveal completely new path- to him until she began remov- Mary M. Tomayko, MD, PhD Assistant Professor of Dermatology ways,” Choate explains. “And ing layers of makeup—“and Yale School of Medicine, New Haven, CT this points to what is began to cry as she did so,” exciting to me, and what I see he remembers. “It was so clear Heidi A. Waldorf, MD Director, Laser and Cosmetic Dermatology as the most important thing to me that her skin disease The Mount Sinai Medical Center, New York, NY about what we do,” he empha- was severely affecting her life sizes. “It’s not making incre- in a fundamental way.” This Executive Director mental progress. It’s blowing experience solidified Choate’s Sandra Rahn Benz open completely new fields by decision to seek MD/PhD Deputy Executive Director discovering genetic causes of training, which he completed Christine M. Boris disease in genes not previ- in 2004 (and he is now associ- Please address correspondence to: ously known to be relevant to ate director of Yale’s Medical skin biology. Scientist Training Program). Editors-in-Chief Keith A. Choate, MD, PhD Dermatology Focus “Because genetics has the His experiences in medical c/o The Dermatology Foundation power to identify a priori unexpected genetic school and doctoral training consolidated his 1560 Sherman Avenue causes of disease, and we are performing ge- early sense of dermatology’s value as a clini- Evanston, Illinois 60201 netic investigations to identify fundamental cian and a scientist. And he continues to find Tel: 847-328-2256 Fax: 847-328-0509 pathways for differentiation and development caring for ichthyosis patients in the clinic and e-mail: [email protected] in the skin, this essentially enables us to use directing translational research

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