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 IP locus 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 IP locus. 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 IP locus 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. .



Aradhya S, Bardaro T, Galgoczy P et al. (2001a) Multiple pathogenic and benign genomic rearrangements occur at a 35 kb duplication involving the NEMO and LAGE2 genes. Human Molecular Genetics 10: 2557–2567.

Aradhya S, Courtois G, Rajkovic A et al. (2001b) Atypical forms of incontinentia pigmenti in male individuals result from mutations of a cytosine tract in exon 10 of NEMO (IKK‐gamma). American Journal of Human Genetics 68: 765–771.

Aradhya S, Woffendin H, Bonnen P et al. (2002) Physical and genetic characterization reveals a pseudogene, an evolutionary junction, and unstable loci in distal Xq28. Genomics 79: 31–40.

Aradhya S, Woffendin H, Jakins T et al. (2001c) A recurrent deletion in the ubiquitously expressed NEMO (IKK‐gamma) gene accounts for the vast majority of incontinentia pigmenti mutations. Human Molecular Genetics 10: 2171–2179.

Argueso JL, Westmoreland J, Mieczkowski PA et al. (2008) Double‐strand breaks associated with repetitive DNA can reshape the genome. Proceedings of the National Academy of Sciences of the USA 105: 11845–11850.

Bardaro T, Falco G, Sparago A et al. (2003) Two cases of misinterpretation of molecular results in incontinentia pigmenti, and a PCR‐based method to discriminate NEMO/IKKgamma gene deletion. Human Mutation 21: 8–11.

Beckmann JS, Estivill X and Antonarakis SE (2007) Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability. Nature Reviews Genetics 8: 639–646.

Bischof JM, Chiang AP, Scheetz TE et al. (2006) Genome‐wide identification of pseudogenes capable of disease‐causing gene conversion. Human Mutation 27: 545–552.

Cappellini MD and Fiorelli G (2008) Glucose‐6‐phosphate dehydrogenase deficiency. Lancet 371: 64–74.

Chen JM, Cooper DN, Chuzhanova N, Ferec C and Patrinos GP (2007) Gene conversion: mechanisms, evolution and human disease. Nature Reviews Genetics 8: 762–775.

Doffinger R, Smahi A, Bessia C et al. (2001) X‐linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF‐kappaB signaling. Nature Genetics 27: 277–285.

Filosa S, Giacometti N, Wangwei C et al. (1996) Somatic‐cell selection is a major determinant of the blood‐cell phenotype in heterozygotes for glucose‐6‐phosphate dehydrogenase mutations causing severe enzyme deficiency. American Journal of Human Genetics 59: 887–895.

Franze A, Ferrante MI, Fusco F et al. (1998) Molecular anatomy of the human glucose 6‐phosphate dehydrogenase core promoter. Federation of European Biochemical Societies Letters 437: 313–318.

Fusco F, Bardaro T, Fimiani G et al. (2004) Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF‐kappaB activation. Human Molecular Genetics 13: 1763–1773.

Fusco F, Mercadante V, Miano MG and Ursini MV (2006) Multiple regulatory regions and tissue‐specific transcription initiation mediate the expression of NEMO/IKKgamma gene. Gene 383: 99–107.

Fusco F, Paciolla M, Napolitano F et al. (2012) Genomic architecture at the Incontinentia Pigmenti locus favours de novo pathological alleles through different mechanisms. Human Molecular Genetics 21: 1260–1271.

Fusco F, Paciolla M, Pescatore A et al. (2009) Microdeletion/duplication at the Xq28 IP locus causes a de novo IKBKG/NEMO/IKKgamma exon4_10 deletion in families with Incontinentia Pigmenti. Human Mutation 30: 1284–1291.

Fusco F, Pescatore A, Bal E et al. (2008) Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations. Human Mutation 29: 595–604.

Galgoczy P, Rosenthal A and Platzer M (2001) Human‐mouse comparative sequence analysis of the NEMO gene reveals an alternative promoter within the neighboring G6PD gene. Gene 271: 93–98.

Gautheron J, Pescatore A, Fusco F et al. (2010) Identification of a new NEMO/TRAF6 interface affected in incontinentia pigmenti pathology. Human Molecular Genetics 19: 3138–3149.

Hayden MS and Ghosh S (2004) Signaling to NF‐kappaB. Genes and Development 18: 2195–2224.

Inoue K and Lupski JR (2002) Molecular mechanisms for genomic disorders. Annual Review of Genomics and Human Genetics 3: 199–242.

Kenwrick S, Woffendin H, Jakins T et al. (2001) Survival of male patients with incontinentia pigmenti carrying a lethal mutation can be explained by somatic mosaicism or Klinefelter syndrome. American Journal of Human Genetics 69: 1210–1217.

Landy SJ and Donnai D (1993) Incontinentia pigmenti (Bloch–Sulzberger syndrome). Journal of Medical Genetics 30: 53–59.

Leduc F, Maquennehan V, Nkoma GB and Boissonneault G (2008) DNA damage response during chromatin remodeling in elongating spermatids of mice. Biology of Reproduction 78: 324–332.

Lee JA, Carvalho CM and Lupski JR (2007) A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131: 1235–1247.

Lee JA, Inoue K, Cheung SW et al. (2006) Role of genomic architecture in PLP1 duplication causing Pelizaeus‐Merzbacher disease. Human Molecular Genetics 15: 2250–2265.

Lobachev KS, Rattray A and Narayanan V (2007) Hairpin‐ and cruciform‐mediated chromosome breakage: causes and consequences in eukaryotic cells. Frontiers in Bioscience 12: 4208–4220.

Lovett ST (2004) Encoded errors: mutations and rearrangements mediated by misalignment at repetitive DNA sequences. Molecular Microbiology 52: 1243–1253.

Makris C, Godfrey VL, Krahn‐Senftleben G et al. (2000) Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X‐linked disorder incontinentia pigmenti. Molecular Cell 5: 969–979.

Martini G and Ursini MV (1996) A new lease of life for an old enzyme. Bioessays 18: 631–637.

Nelson DL (2006) NEMO, NFkappaB signaling and incontinentia pigmenti. Current Opinion in Genetics and Development 16: 282–288.

Pearson CE, Nichol Edamura K and Cleary JD (2005) Repeat instability: mechanisms of dynamic mutations. Nature Reviews Genetics 6: 729–742.

Piotrowski A, Bruder CE, Andersson R et al. (2008) Somatic mosaicism for copy number variation in differentiated human tissues. Human Mutation 29: 1118–1124.

Potocki L, Bi W, Treadwell‐Deering D et al. (2007) Characterization of Potocki‐Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage‐sensitive critical interval that can convey an autism phenotype. American Journal of Human Genetics 80: 633–649.

Scheuerle A and Ursini MV (2010) Incontinentia pigmenti. In: Pagon RA, Bird TD, Dolan CR and Stephens K (eds) Gene Reviews, pp 1993–1999. Seattle, WA: University of Washington.

Schmidt LS, Nickerson ML, Warren MB et al. (2005) Germline BHD‐mutation spectrum and phenotype analysis of a large cohort of families with Birt‐Hogg‐Dube syndrome. American Journal of Human Genetics 76: 1023–1033.

Schmidt‐Supprian M, Bloch W, Courtois G et al. (2000) NEMO/IKK gamma‐deficient mice model incontinentia pigmenti. Molecular Cell 5: 981–992.

Shaw CJ and Lupski JR (2004) Implications of human genome architecture for rearrangement‐based disorders: the genomic basis of disease. Human Molecular Genetics 13(Spec No 1): R57–R64.

Smahi A, Courtois G, Vabres P et al. (2000) Genomic rearrangement in NEMO impairs NF‐kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature 405: 466–472.

Srivastava N and Raman MJ (2007) Homologous recombination‐mediated double‐strand break repair in mouse testicular extracts and comparison with different germ cell stages. Cell Biochemistry and Function 25: 75–86.

Stankiewicz P and Lupski JR (2002) Genome architecture, rearrangements and genomic disorders. Trends in Genetics 18: 74–82.

Streffer C (2009) Strong association between cancer and genomic instability. Radiation and Environmental Biophysics 49: 125–131.

Vissers LE, Bhatt SS, Janssen IM et al. (2009) Rare pathogenic microdeletions and tandem duplications are microhomology‐mediated and stimulated by local genomic architecture. Human Molecular Genetics 18: 3579–3593.

Vissers LE, Veltman JA, van Kessel AG and Brunner HG (2005) Identification of disease genes by whole genome CGH arrays. Human Molecular Genetics 14(Spec No. 2): R215–R223.

Voineagu I, Narayanan V, Lobachev KS and Mirkin SM (2008) Replication stalling at unstable inverted repeats: interplay between DNA hairpins and fork stabilizing proteins. Proceedings of the National Academy of Sciences of the USA 105: 9936–9941.

Vulliamy T, Beutler E and Luzzatto L (1993) Variants of glucose‐6‐phosphate dehydrogenase are due to missense mutations spread throughout the coding region of the gene. Human Mutation 2: 159–167.

Wells RD (2007) Non‐B DNA conformations, mutagenesis and disease. Trends in Biochemical Sciences 32: 271–278.

Wiese C, Pierce AJ, Gauny SS, Jasin M and Kronenberg A (2002) Gene conversion is strongly induced in human cells by double‐strand breaks and is modulated by the expression of BCL‐x(L). Cancer Research 62: 1279–1283.

Woodward KJ, Cundall M, Sperle K et al. (2005) Heterogeneous duplications in patients with Pelizaeus‐Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination. American Journal of Human Genetics 77: 966–987.

Yamaoka S, Courtois G, Bessia C et al. (1998) Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF‐kappaB activation. Cell 93: 1231–1240.

Yoshida N, Abe H, Ohkuri T et al. (2006) Expression of the MAGE‐A4 and NY‐ESO‐1 cancer‐testis antigens and T cell infiltration in non‐small cell lung carcinoma and their prognostic significance. International Journal of Oncology 28: 1089–1098.

Zhang F, Seeman P, Liu P et al. (2010) Mechanisms for nonrecurrent genomic rearrangements associated with CMT1A or HNPP: rare CNVs as a cause for missing heritability. American Journal of Human Genetics 86: 892–903.

Zonana J, Elder ME, Schneider LC et al. (2000) A novel X‐linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK‐gamma (NEMO). American Journal of Human Genetics 67: 1555–1562.

Further Reading

Courtois G and Israël A (2000) NF‐kappa B defects in humans: the NEMO/incontinentia pigmenti connection. Science Signal Transduction Knowledge Environment 58: pe1

Hastings PJ, Lupski JR, Rosenberg SM and Ira G (2009) Mechanisms of change in gene copy number. Nature Reviews Genetics 10: 551–564.

Lupski JR (1998) Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends in Genetics 14: 417–422.

Simmons AD, Carvalho CM and Lupski JR (2012) What have studies of genomic disorders taught us about our genome? Methods in Molecular Biology 838: 1–27.

Smahi A, Courtois G, Rabia SH et al. (2002) The NF‐kappaB signalling pathway in human diseases: from incontinentia pigmenti to ectodermal dysplasias and immune‐deficiency syndromes. Human Molecular Genetics 11: 2371–2375.

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.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
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]