Overlapping Xq13.3 duplications define an X-linked hypotrichosis simplex and implicate TAB3 dosage sensitivity.

Abstract

Hereditary hypotrichosis comprises a group of nonsyndromic hair growth disorders for which molecularly characterized forms have been predominantly attributed to autosomal inheritance. Here, we identified three unrelated families with X-linked hypotrichosis simplex (XLHS), characterized by normal hair at birth followed by progressive scalp hair sparsity that emerges in childhood or adolescence. Affected males showed more severe and diffuse involvement, whereas affected females exhibited milder, patchy thinning, consistent with X-linked inheritance. Genomic analyses revealed partially overlapping duplications at Xq13.3 in all affected individuals, defining a shared critical interval encompassing TAB3, FTHL17, and part of DMD. Among these genes, FTHL17 is mainly expressed in the testicular system, and DMD is classically associated with muscular dystrophy, whereas neither FTHL17 nor DMD showed detectable differences in protein abundance between affected individuals and healthy control subjects in scalp tissue. In contrast, TAB3 showed increased accumulation in scalp tissue from affected individuals compared with healthy control subjects, supporting TAB3 as the most likely dosage-sensitive candidate gene. Functionally, both an inducible keratinocyte-specific Tab3-overexpressing mouse model and TAB3-overexpressing HaCaT keratinocyte models demonstrated impaired TAK1-dependent canonical NF-κB signaling. In mice, Tab3 overexpression recapitulated the human hypotrichosis phenotype and induced early pathological changes on postnatal day 31, including hyperkeratosis, thickening of the stratum corneum, and inflammatory cell infiltration. Anti-inflammatory treatment improved hair density in mice, and clinical observations in affected individuals suggested potential benefit. Together, these findings define a previously unrecognized XLHS, implicate an increase in TAB3 dosage as its genetic driver, and identify dysregulated TAK1-NF-κB signaling as a candidate pathogenic mechanism.