Generalized vitiligo is an acquired disorder in which white patches of skin and hair result from autoimmune loss of melanocytes (Hahn and Nordlund, 2000), often associated with other autoimmune disorders (Alkhateeb et al, 2003). Most cases occur in a sporadic family pattern suggesting polygenic, multifactorial inheritance. However, we previously described a striking family in which a somewhat unusual vitiligo phenotype, characterized by progressively coalescent diffuse depigmentation and relatively early disease onset, segregated as an apparent autosomal dominant with incomplete penetrance (Alkhateeb et al, 2002). By genetic linkage analysis of this family, we mapped a vitiligo susceptibility locus, AIS1, to a 7.4-Mb interval of chromosome 1p31 (Alkhateeb et al, 2002).

The AIS1 interval contains only $27 genes, including an obvious biological candidate, FOXD3, which encodes a forkhead transcription factor that is a primary regulator of melanoblast differentiation in the embryonic neural crest (Sutton et al, 1996; Hromas et al, 1999; Dottori et al, 2001; Kos et al, 2001), and perhaps also for some endodermal lineages (Guo et al, 2002). FOXD3 is expressed in all embryonic neural crest lineages except late-emigrating melanoblasts (Sutton et al, 1996; Hromas et al, 1999; Dottori et al, 2001; Kos et al, 2001). Inhibition of FOXD3 expression expands the melanoblast lineage and persistent FOXD3 overexpression results in developmental failure of melanoblasts (Dottori et al, 2001). FOXD3 mutations that result in transcriptional upregulation thus might interfere with melanoblast differentiation, thereby predisposing to vitiligo.