Milestones in Genetics of Structural Skin Disorders

Abstract

Heritable skin diseases consist of a group of conditions in which the cutaneous findings can be relatively minor at one end of the spectrum, whereas at the other end the cutaneous manifestations—often part of multisystem pathology—can cause significant morbidity and untimely demise of the affected individuals (Uitto et al., 2012). Tremendous progress has been made in the past two decades in molecular genetics of heritable skin diseases, and candidate genes and pathogenic mutations have been identified in as many as 500 different genes in a manner that the genetic lesions explain the cutaneous manifestations (Feramisco et al., 2009). Examination of the mutation databases in different diseases has revealed both obvious candidate genes and a number of surprises, but nevertheless the identification of the mutant genes has been very helpful in providing increased understanding of the pathogenetic mechanisms of these conditions. Many of these diseases could be characterized as metabolic disorders with cellular perturbations, or characterized as multisystem diseases with structural defects. Identification of the mutated genes and specific underlying mutations has been instructive not only in providing information of the molecular basis of the disease but also providing critical understanding of the pathophysiologic role of structural components and specific proteins in normal skin. Particularly instructive have been those diseases affecting the structural components of the skin. This series of milestones articles deals with genetic disorders with cutaneous manifestations affecting primarily the structural components of the skin. These include identification of defects in the cutaneous basement membrane zone in epidermolysis bullosa (Milestone 1), and the role of collagen and elastic fibers in providing physiologic properties to the dermis, as exemplified by the Ehlers–Danlos syndrome, cutis laxa, and pseudoxanthoma elasticum (Milestones 2–4). Heritable filaggrin disorders, with atopic dermatitis as the paradigm, have provided critical information on the role of epidermal barrier function under physiologic conditions (Milestone 5), and dissecting the genetics of structural hair disorders has been highly instructive in understanding the growth and maintenance of normal hair (Milestone 6). In a broader sense, development of the next-generation diagnostics (Milestone 7) and molecular therapeutics (Milestone 8) for these disorders is the next step to build improved diagnosis and treatment of these, currently often intractable, disorders.