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

Abstract

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.

A case report of neonatal incontinentia pigmenti complicated by severe cerebrovascular lesions in one of the male monozygotic twins

“…In addition to the difficulty of detecting mutations beyond the classic 11.7 kb deletion, somatic mosaicism can result in the failure to detect a pathogenic mutation in peripheral blood, in which case molecular genetic testing of a tissue sample (e.g., skin from an affected site, sperm) may be needed ( 18 ). For these reasons, the rate of positive genetic testing in men with IP is low, with one review of the male IP literature finding that 58% of men tested negative for genes ( 19 ).…”

A Case of Mucopolysaccharidosis II Caused by a Novel Variant with Skin Linear Hyperpigmented Streaks along Blaschko’s Lines

“…Skin lesions change over the years from stage I to IV in the clinical course of IP [ 15 ]; however, his hyperpigmentation started just after his birth as “confetti” splashes and grew into streaks (like stage III lesions in IP)—and continued over eight years, which is not a typical clinical course for IP. Since IP is a disorder of X-linked dominance, a male with a pathogenic variant in the IKBKG gene is embryonically lethal, except for a few cases of male patients with mosaicism of the wild type and a pathogenic IKBKG gene or with Klinefelter syndrome (47, XXY) [ 17 , 18 , 19 , 20 , 21 ]. In this case, the proband’s karyotype was normal by G-banding, and mosaicism was not detected with clinical exome sequencing using peripheral blood.…”

Critical Roles of NF-κB Signaling Molecules in Bone Metabolism Revealed by Genetic Mutations in Osteopetrosis

“…The ZF region of NEMO contains genetic mutations associated not only with osteopetrosis but also with other diseases. This finding suggests that the observed phenotypic variations are not determined simply by the strength of the NF-κB signal [ 42 , 43 , 48 , 49 , 50 , 51 , 52 , 53 ]. In recent years, a sequence recognized as an intron splice donor site between the fourth and fifth exons of the IKBKG gene in patients with EDA-ID has emerged to generate pseudoexons.…”

“…However, patients with EDA-ID are always male and hemizygous for IKBKG mutations that maintain persistently reduced NF-κB activation. EDA-ID is associated with susceptibility to life-threatening infection and ectodermal dysplasia, which is characterized by rare conical teeth, sparse scalp hair, frontal ridges, and a lack of sweat glands [ 42 , 43 , 47 , 48 , 49 ].…”