Selection Against Mutant Alleles in Blood Leukocytes is a Consistent Feature in Incontinentia Pigmenti Type 2
Reads0
Chats0
TLDR
Fibroblast subclones from a biopsy at the boundary of a skin lesion in a newborn IP2 patient were isolated, and clones with either one or the other X active were identified, demonstrating that cells with the active disease-bearing X chromosome are still present in stage I skin lesions.Abstract:
Incontinentia Pigmenti 2 (IP2) is an X-linked dominantdisorder with male lethality. Affected females display acharacteristic skin eruption that evolves through fourclassic stages, frequently accompanied by dental andretinal abnormalities. Non-random (skewed)X-inactivation in peripheral blood leukocytes and infibroblasts has been observed in females with IP2;however, sample sizes have been small and methods ofanalysis varied. We have examined X-inactivation in alarge group of multigenerational IP2 families, in smallerfamilies, and in isolated cases. Ninety-eight percent ofaffected females in multigenerational IP2 pedigreesshow completely skewed patterns of X-inactivation,while only ∼10% of a normal control population isskewed. Results both in small families and in newmutation cases with subsequent segregation consistentwith Xq28 linkage are similar. Isolated cases show alower percentage (85%) of skewed affected individuals;this difference may be due to inaccurate clinicalascertainment. The parent of origin of new mutationscould be determined in 15 families; paternal newmutations were twice as common as maternal. Fibro-blast subclones from a biopsy at the boundary of a skinlesion in a newborn IP2 patient were isolated, andclones with either one or the other X active wereidentified, demonstrating that cells with the activedisease-bearing X chromosome are still present instage I skin lesions.INTRODUCTIONFamilial Incontinentia Pigmenti (IP2) is a neurocutaneousgenodermatosis which segregates as an X-linked dominant traitwith prenatal male lethality (for review, see ref. 1). In affectedfemales, its most prominent phenotypic features involve the skinand its derivatives, the eye and the central nervous system. Thisdisorder is diagnosed in affected females at or soon after birth bythe presence of a progressive erythematous and vesicular rash. Thisrash becomes sequentially verrucous, pigmented, then atrophic, andmay leave adolescents and adults with areas of linear and reticularhypopigmentation. Other manifestations include cicatricial al opecia,hypodontia or anodontia, eosinophilia (in the early stages),peripheral vascular abnormalities and cicatrization of the retina,and other secondary ocular findings. The penetrance of the diseaseapproaches 100%, but its expressivity is highly variable, evenwithin families.Linkage of IP2 to Xq28 markers was demonstrated in 1989 ( 2);subsequently, IP2 was localized more precisely to the regionsurrounding and most likely telomeric to DXS52 (3). Morerecently, the region of interest has been narrowed to Xq28 distalto Factor VIII; the highest LOD scores are found with DXS1108(θ = 0.00) (4).Non-random X inactivation in patients with IP2 has beenreported by several groups. Migeon et al. (5), using G6PDvariants and an RFLP at the HPRT locus which detects adifferentially methylated HpaII site, observed that thechromosome bearing the normal allele at the IP locus is the activeX in the majority of skin fibroblasts in affected females in threefamilies. Variable skewing in peripheral blood leukocytes wasalso observed in these families, which was unexpected since thistissue had not previously been thought to be involved in thisdisease. Analysis of G6PD isozymes showed a more randomdistribution in red blood cells, suggesting that red cell progenitorsare less likely to be affected negatively by the IP mutation thanare white cell progenitors. Other investigators (6) used somaticcell hybrid analysis to compare skin biopsies taken from normaland hyperpigmented (stage III) areas of the skin; the same Xchromosome was found to be active in every clone, regardless ofwhether it was derived from normal or hyperpigmented skin.These authors concluded that invasion of affected skin by normalcells most likely takes place at the transition from theinflammatory (I) to the verrucous (II) stage, and that their resultssupport the model that normal cells have a proliferativeadvantage. A third study ( 7), again with RFLP analysis, producedcontradictory results. Extreme skewing was found in a minorityof cases, and in most of these cases it was not possible todetermine parental origin of the inactive X chromosome; in theone fully informative family with extreme skewing, the Xread more
Citations
More filters
Journal ArticleDOI
Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium.
A. Smahi,Gilles Courtois,Pierre Vabres,Shoji Yamaoka,S. Heuertz,Arnold Munnich,Alain Israël,Nina S. Heiss,Sabine M. Klauck,Petra Kioschis,Stefan Wiemann,Annemarie Poustka,Teresa Esposito,T. Bardaro,Fernando Gianfrancesco,Alfredo Ciccodicola,Michele D'Urso,Hayley Woffendin,T. Jakins,D. Donnai,H. Stewart,Susan Kenwrick,Swaroop Aradhya,Takanori Yamagata,Michael J. Levy,Richard A. Lewis,David L. Nelson +26 more
TL;DR: Most cases of familial incontinentia pigmenti are due to mutations of this locus and that a new genomic rearrangement accounts for 80% of new mutations, which means that NF-κB activation is defective in IP cells.
Journal ArticleDOI
Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots.
Mimi Wan,Stephen Sung Jae Lee,Xianyu Zhang,Isa Houwink-Manville,Hae Ri Song,Ruthie E. Amir,Sarojini S. Budden,Sakku Bai Naidu,Jose Luiz Pinto Pereira,Ivan F M Lo,Huda Y. Zoghbi,N. Carolyn Schanen,Uta Francke +12 more
TL;DR: Some males with RTT-causing MECP2 mutations may survive to birth, and female heterozygotes with favorably skewed X-inactivation patterns may have little or no involvement.
Journal ArticleDOI
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)
Jonathan Zonana,Melissa E. Elder,Lynda C. Schneider,Seth J. Orlow,Celia Moss,Mahin Golabi,Stuart K. Shapira,Peter Farndon,Diane W. Wara,Stephanie A. Emmal,Betsy Ferguson +10 more
TL;DR: A new X-linked recessive immunodeficiency syndrome is defined, distinct from other types of HED and immunODeficiency syndromes, and the data provide further evidence that the development of ectodermal appendages is mediated through a tumor necrosis factor/tumor necrosis factors receptor-like signaling pathway, with the IKK signalsome complex playing a significant role.
Journal ArticleDOI
NEMO/IKKγ-Deficient Mice Model Incontinentia Pigmenti
Marc Schmidt-Supprian,Wilhelm Bloch,Gilles Courtois,Klaus Addicks,Alain Israël,Klaus Rajewsky,Manolis Pasparakis +6 more
TL;DR: The results indicate that the mouse model for the human genetic disorder incontinentia pigmenti, together with the recent discovery that mutations in the human NEMO gene cause IP, is created.
Journal ArticleDOI
Mechanisms and consequences of somatic mosaicism in humans
TL;DR: The role of selection in the phenotypic manifestations of mosaicism is emphasized, as well as the molecular genetic mechanisms by which they arise, in this review of somatic mosaicism.
References
More filters
Journal Article
Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation.
TL;DR: The human androgen-receptor gene (HUMARA) contains a highly polymorphic trinucleotide repeat in the first exon that correlates with X inactivation, and the development of a PCR assay that distinguishes between the maternal and paternal alleles and identifies their methylation status is developed.
Journal ArticleDOI
Incontinentia pigmenti (Bloch-Sulzberger syndrome).
S J Landy,Dian Donnai +1 more
TL;DR: The name incontinentia pigmenti describes the characteristic, albeit non-specific, histological feature where there is incontinence of melanin from the melanocytes in the basal layer of the epidermis into the superficial dermis.
Journal ArticleDOI
Exclusive paternal origin of new mutations in Apert syndrome
Dominique M. Moloney,Sarah R Slaney,Michael Oldridge,Steven A. Wall,Pelle Sahlin,Göran Stenman,Göran Stenman,Andrew O.M. Wilkie +7 more
TL;DR: Using a novel application of the amplification refractory mutation system (ARMS), the parental origin of the new mutation in 57 Apert families is determined: in every case, the mutation arose from the father.
Journal Article
Heritability of X chromosome--inactivation phenotype in a large family
Anna K. Naumova,R. M. Plenge,Lynne M. Bird,M. Leppert,K. Morgan,Huntington F. Willard,Carmen Sapienza +6 more
TL;DR: This work has attempted to uncover evidence for genetic control of X-chromosome inactivation in the human by examining X chromosome-inactivation patterns in 255 females from 36 three-generation pedigrees, to determine whether this quantitative character exhibits evidence of heritability.
Journal ArticleDOI
Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells
Judith Pratt Rosslter,Michele Young,Michele Young,Michelle L. Kimberland,Pierre Hutter,Pierre Hutter,Rhett P. Ketterling,Jane Gitschier,Jane Gitschier,Jürgen Horst,Jürgen Horst,Michael A. Morris,Michael A. Morris,Daniel J. Schaid,Phillppe de Moerloose,Phillppe de Moerloose,Steve S. Sommer,Steve S. Sommer,Haig H. Kazazian,Styllanos E. Antonarakis,Styllanos E. Antonarakis +20 more
TL;DR: DNA polymorphism analysis determined that factor VIII gene inversions leading to severe hemophilia A occur almost exclusively in male germ cells, indicating that pairing of Xq with its homolog inhibits the inversion process.
Related Papers (5)
Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium.
A. Smahi,Gilles Courtois,Pierre Vabres,Shoji Yamaoka,S. Heuertz,Arnold Munnich,Alain Israël,Nina S. Heiss,Sabine M. Klauck,Petra Kioschis,Stefan Wiemann,Annemarie Poustka,Teresa Esposito,T. Bardaro,Fernando Gianfrancesco,Alfredo Ciccodicola,Michele D'Urso,Hayley Woffendin,T. Jakins,D. Donnai,H. Stewart,Susan Kenwrick,Swaroop Aradhya,Takanori Yamagata,Michael J. Levy,Richard A. Lewis,David L. Nelson +26 more
IKK-γ is an essential regulatory subunit of the IκB kinase complex
X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling.
Rainer Doffinger,Asma Smahi,Christine Bessia,Frederic Geissmann,Jacqueline Feinberg,Anne Durandy,Christine Bodemer,Sue Kenwrick,Sophie Dupuis-Girod,Stéphane Blanche,Philip A. Wood,Smail Hadj Rabia,Denis J. Headon,Paul A. Overbeek,Françoise Le Deist,Steven M. Holland,Kiran Belani,Dinakantha S. Kumararatne,Alain Fischer,Ralph S. Shapiro,Mary Ellen Conley,Eric Reimund,Hermann Kalhoff,Mario Abinun,Arnold Munnich,Alain Israël,Gilles Courtois,Jean-Laurent Casanova +27 more