Relationship Between Hypomorphic Alleles and Mosaicism of Lethal Mutations

Abstract

Some genes may harbor different mutant alleles resulting in either a very severe or a rather mild disorder. For example, male embryos hemizygous for incontinentia pigmenti are dying in utero. Remarkably, however, other mutations within the same gene are hypomorphic alleles giving rise to ectodermal dysplasia of Zonana, a disease that is so mild that hemizygous males can survive. Female carriers only show a systematized linear pattern of pigmentary disturbance that should not be confused with incontinentia pigmenti, whereas affected males suffer from a rather severe immunodeficiency. In another X-linked male-lethal trait, Conradi-Hünermann-Happle syndrome, the presence of a hypomorphic allele accounts for survival of men who suffer from “MEND syndrome”, representing a quite different phenotype. A similar dichotomy of severity has been documented in CHILD syndrome versus CK syndrome, and in autosomal dominant acanthosis nigricans versus FGFR3 epidermal nevus syndrome.