Molecular Genetics of Incontinentia Pigmenti


Incontinentia Pigmenti (IP) is a rare X‐linked dominant neuroectodermal disorder caused by mutations in the nuclear factor kappaB essential modulator (NEMO)/Inhibitor of Kappa light polypeptide gene enhancer in B‐cells Kinase Gamma (IKBKG) gene. The NEMO locus maps in a region with a unique genomic organisation: in the centromeric direction, NEMO partially overlaps the glucose‐6‐phosphate dehydrogenase gene; in the telomeric direction, NEMO is part of a 35.7 kb segmental duplication containing its nonfunctional truncated copy pseudoNEMO. Moreover, a high frequency of micro‐/macro‐homologies, tandem repeats and repeat/repetitive sequences characterise the local architecture of the locus increasing its vulnerability to the production of de novo genomic rearrangements through different mechanisms. Indeed, instances of nonallelic homologous recombination (NAHR) causing both benign and pathological alleles, nonhomologous end joining (NHEJ) and AluAlu‐mediated recombination events producing either recurrent or nonrecurrent deletions have been reported. These events, occurring during both meiosis and mitosis, reveal that the region is prone to generate complex human genomic rearrangements.

Key Concepts:

  • Genomic rearrangements in the NEMO gene can be generated during meiosis or mitosis.

  • Low copy repeats or segmental duplication regions can act as substrates for aberrant recombination and for gene conversion events.

  • The complex architecture of the locus enhances its vulnerability to the production of de novo genomic rearrangements through different mechanisms.

  • The mutational mechanisms that can give rise to genomic rearrangements in the IP locus are: NAHR, NHEJ, Alu–Alu mediated recombination and gene conversion.

  • NAHR, mediated through sequences that exhibit a considerable homology called MER67B, is one of the major mechanisms for the generation of de novo rearrangements in the IP locus.

Keywords: incontinentia pigmenti; NEMO/IKBKG locus; pseudogene; G6PD; NAHR; NHEJ; Alu–Alu recombination; genomic rearrangement; deletion; duplication

Figure 1.

(a) A schematic representation of the IPlocus in Xq28 (chrX:153, 740–153, 900 kb, UCSC Genome Browser on Human February 2009, GRCh37/hg19). The square arrows represent LCRs. The G6PD exons, NEMO exons and ΨNEMO exons are shown. The transcriptional direction for each gene is indicated by arrows. (b) Rearrangements in the IPlocus. A schematic representation of the recurrent pathogenical NEMOdel deletion and the benign CNVs, MER67Bdup and ΨNEMOdel, produced by NAHR. The frequency of each rearrangement is shown.

Figure 2.

(a) IP‐516 family: the unaffected mother (I:1) carried the ΨNEMOdel (Δ) in the pseudogene. The IP child (II:1) carried the pathogenical NEMOdel (Δ) on the rearranged maternal chromosome. (b) NAHR mechanism model: the pathogenical deletion NEMOdel (Δ) is produced by a mis‐alignment between the two inverted LCRs and the formation of an intra‐chromosomal loop. (c) IP‐688 family: the affected IP patient (II:1) carried NEMOdel (Δ) in the gene on the paternal chromosome. The IP‐688 father (I:2) carried MER67Bdup in the gene. (d) NAHR mechanism model: the pathogenical deletion NEMOdel (Δ) is produced by a mis‐alignment between the two direct MER67Bs and the formation of an intra‐chromosomal loop. (e) IP‐CV family: the affected IP patient (II:1) is a mosaic male for the NEMOdel and MER67Bdup in the gene. The IP‐CV mother (I:1) carried only MER67Bdup in the gene on the inherited chromosome.

Figure 3.

A gene conversion event in the IP‐603 and IP‐583 families. (a) IP‐603 family: the IP patient (II:1) carried a point mutation (mtz, c.1167delC) in the NEMO gene and in ΨNEMO pseudogene both on the paternal chromosome. The father of IP patient (I:2) carried a point mutation (mtz, c.1167delC, chrX:delG_153 868 348–153 868 349) in the ΨNEMO pseudogene. (b) IP‐583 family: the IP patient (II:1) carried the deletion NEMOdel(Δ) in the gene and the ΨNEMOdel (Δ) in the pseudogene both on the paternal chromosome. The father of IP patient (I:2) carried the deletion NEMOdel(Δ) in the pseudogene.

Figure 4.

An IPlocus comprehensive map of the genomic rearrangements. A schematic view of the deleted regions in the IP patients. The dotted lines show the localisation and size of the rearrangements associated with IP. Modified from Fusco et al. . Copyright by Oxford University Press.

Figure 5.

The distribution of NEMO mutations in different exons of the gene. The Cn ‘runs’ distribution is also shown. Cn ‘runs’ are only present in exons 9 and 10. Modified from Fusco et al. .



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Further Reading

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Stankiewicz P and Lupski JR (2010) Structural variation in the human genome and its role in disease. Annual Review of Medicine 61: 437–455.

Zhang F, Carvalho CM and Lupski JR (2009) Complex human chromosomal and genomic rearrangements. Trends in Genetics 25: 298–307.

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Ursini, Matilde Valeria, Conte, Matilde Immacolata, Pescatore, Alessandra, Miano, Maria Giuseppina, and Fusco, Francesca(Oct 2012) Molecular Genetics of Incontinentia Pigmenti. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024332]