Journal Article

Human Genetic Diseases Linked to the Absence of NEMO: An Obligatory Somatic Mosaic Disorder in Male

Casale, Carmela, Fusco, Francesca, Ursini, Matilde Valeria, Spinosa, Ezia, Pescatore, Alessandra, Lioi, Maria Brigida

2022

Overview

De novo somatic mutations are well documented in diseases such as neoplasia but are rarely reported in rare diseases. Hovewer, severe genetic diseases that are not compatible with embryonic development are caused exclusively by deleterious mutations that could only be found as mosaic and not as inherited mutations. We will review here the paradigmatic case of Incontinentia Pigmenti, a rare X-linked dominant disease caused by deficiency of the NEMO (also called IKKgamma) protein, which plays a pivotal role in tissue homeostasis. The loss-of-function mutations of NEMO are embryonically lethal in males while females survive because of unbalanced X-inactivation due to NEMO wild type (WT) expressing cells survival despite of NEMO mutant expressing cells. The few surviving IP males are obligatory mosaic mutants with the typical clinical presentation of IP in female. Indeed, the IP pathogenesis in the female and most likely also in the male somatic mosaics is based on the cellular effects of an impaired NEMO activity, but in the context of the interaction of genetically different cells in the affected tissue, which might underline the inflammatory status.

• Publisher: MDPI AG,MDPI
• Subject: Atrophy / Cell death / Disease / Females / Genetic disorders / Genotype & phenotype / Humans / I-kappa B Kinase - deficiency / I-kappa B Kinase - genetics / Immune system / Incontinentia Pigmenti - etiology / Incontinentia Pigmenti - metabolism / Incontinentia Pigmenti - pathology / Kinases / Loss of Function Mutation / Male / Males / Microcephaly / Mosaicism / Mutation / Nervous system / Proteins / Rare diseases / Review / Teeth / X chromosomes