Marie Unna hereditary hypotrichosis (MUHH; OMIM 146550) is a rare autosomal dominant hair loss genetic disorder. Recently, it was discovered that defects in an inhibitory upstream open reading frame (ORF) of the human hairless gene (HR), named U2HR, is responsible for this disease. We have detected a novel heterozygous missense mutation for Marie Unna hereditary hypotrichosis in a Jewish Ashkenazi family, thereby extending the mutation spectrum of U2HR mutations. The mutation, c.74C>T, results in the amino acid change p.P25L in the U2HR region of the HR gene. Functional assays clearly show that the novel mutation c.74C>T causes increased translation of the main ORF, which leads to an apparent change in hair phenotype. Mutations in upstream ORFs are an emerging new mechanism for human genetic diseases. The spectrum of mutations found so far in MUHH suggests that the U2HR codes a functional inhibitory peptide, and loss-of-function mutations lead to increased translation of the main ORF. The fact that MUHH is caused by alteration in HR translation underlines the importance of this protein, and it is possible that alterations in the HR protein may underlie other genotrichoses.