Disruption of the X-linked gene encoding NF-κB essential modulator (NEMO) produces male embryonic lethality, completely blocks NF-κB activation by proinflammatory cytokines, and interferes with the ...generation and/or persistence of lymphocytes. Heterozygous female mice develop patchy skin lesions with massive granulocyte infiltration and hyperproliferation and increased apoptosis of keratinocytes. Diseased animals present severe growth retardation and early mortality. Surviving mice recover almost completely, presumably through clearing the skin of NEMO-deficient keratinocytes. Male lethality and strikingly similar skin lesions in heterozygous females are hallmarks of the human genetic disorder incontinentia pigmenti (IP). Together with the recent discovery that mutations in the human
NEMO gene cause IP, our results indicate that we have created a mouse model for that disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Incontinentia pigmenti is an uncommon X-linked dominant disorder, lethal in the majority of affected males in utero and variably expressed in females. Cutaneous manifestations are classically ...subdivided into 4 stages: vesicular, verrucous, hyperpigmented, and atrophic. Various hair and nail abnormalities, dental anomalies, and ophthalmologic and neurologic deficits are associated with the disorder. The gene for incontinentia pigmenti has been mapped to Xq28. Recently, mutations in the NEMO/IKKγ gene located at Xq28 have been found to cause expression of the disease. Knockout mice heterozygous for NEMO/IKKγ gene deficiency develop a clinical phenotype very similar to that of incontinentia pigmenti. NEMO/IKKγ is an essential component of the newly discovered nuclear factor κB (NF-κB) signaling pathway. When activated, NF-κB controls the expression of multiple genes, including cytokines and chemokines, and protects cells against apoptosis. The mechanism by which NEMO/IKKγ deficiency causes, via the NF-κB pathway, the phenotypical expression of the disease has recently been elucidated. In addition, the newest research findings on eosinophil recruitment through eotaxin release by activated keratinocytes are described in the review. Finally, anhidrotic ectodermal dysplasia with immunodeficiency, a disorder allelic to incontinentia pigmenti, is discussed together with implications on the current understanding of NF-κB function. (J Am Acad Dermatol 2002;47:169-87.) Learning objective: At the completion of this learning activity, participants will have a comprehensive and current understanding of incontinentia pigmenti, including its typical and uncommon clinical and histopathologic characteristics, diagnostic assessment, and current management strategies. Additionally, participants will gain the most current knowledge of the genetic and molecular basis of cutaneous pathomechanism.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Gene therapy critically relies on vectors that combine high transduction efficiency with a high degree of target specificity and that can be administered through a safe intravenous route. The lack of ...suitable vectors, especially for gene therapy of brain disorders, represents a major obstacle. Therefore, we applied an in vivo screening system of random ligand libraries displayed on adeno‐associated viral capsids to select brain‐targeted vectors for the treatment of neurovascular diseases. We identified a capsid variant showing an unprecedented degree of specificity and long‐lasting transduction efficiency for brain microvasculature endothelial cells as the primary target of selection. A therapeutic vector based on this selected viral capsid was used to markedly attenuate the severe cerebrovascular pathology of mice with incontinentia pigmenti after a single intravenous injection. Furthermore, the versatility of this selection system will make it possible to select ligands for additional in vivo targets without requiring previous identification of potential target‐specific receptors.
Synopsis
A capsid AAV2 mutant, AAV‐BR1, with tropism for the neurovascular endothelium, generated by selecting an AAV2 display peptide library in vivo, holds promise as a gene therapy vector for neurovascular and potentially other central nervous system diseases.
Capsid mutants with a specific redirected tropism can be selected from AAV display peptide libraries in vivo.
One mutant, AAV‐BR1, effectively transduces neurovascular (blood–brain barrier‐associated) endothelial cells in vivo and in vitro.
AAV‐BR1 can be used to ameliorate the severe neurological impairments in a mouse model of incontinentia pigmenti.
A capsid AAV2 mutant, AAV‐BR1, with tropism for the neurovascular endothelium, generated by selecting an AAV2 display peptide library in vivo, holds promise as a gene therapy vector for neurovascular and potentially other central nervous system diseases.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Incontinentia pigmenti (IP) is a rare syndrome with skin lesions, ocular abnormalities in the retina and elsewhere, central nervous system abnormalities, and teeth defects. The authors present an ...updated review of the literature, highlighting diagnosis, epidemiology, pathophysiology, clinical features, and management of IP. IP is an X-linked dominant syndrome with an incidence of 0.0025%; most patients are female. IP is caused by a mutation in the IKBKG gene, causing a loss of function of NF-κß, leaving cells susceptible to apoptosis from intrinsic factors. The cardinal feature of IP is four stages of skin distinctive lesions. Of those with IP, 36.5% have detectable eye pathology and 60% to 90% of those have retinal issues. Peripheral avascularity and macular occlusive disease commonly occur. The authors performed a comprehensive review of Medline from 1947 to 2014. All papers mentioning IP in ophthalmologic journals were reviewed as well as applicable publications from other medical specialties.
Ophthalmic Surg Lasers Imaging Retina
. 2015;46:650–657.
Objective
Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic ...variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits.
Methods
In a mouse model of IP, we administered a single intravenous dose of the adeno‐associated virus (AAV) vector, AAV‐BR1‐CAG‐NEMO, delivering the Nemo gene to the brain endothelium. Spontaneous epileptic seizures and the integrity of the blood–brain barrier (BBB) were monitored.
Results
The endothelium‐targeted gene therapy improved the integrity of the BBB. In parallel, it reduced the incidence of seizures and delayed their occurrence. Neonate mice intravenously injected with the AAV‐BR1‐CAG‐NEMO vector developed no hepatocellular carcinoma or other major adverse effects 11 months after vector injection, demonstrating that the vector has a favorable safety profile.
Interpretation
The data show that the BBB is a target of antiepileptic treatment and, more specifically, provide evidence for the therapeutic benefit of a brain endothelial‐targeted gene therapy in IP. Ann Neurol 2017;82:93–104
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
47.
Retinal imaging in incontinentia pigmenti Narang, Subina; Sindhu, Meenakshi; Jain, Suksham ...
Indian journal of ophthalmology,
06/2019, Volume:
67, Issue:
6
Journal Article
Peer reviewed
Open access
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Incontinentia pigmenti (IP) is a rare X‐linked skin disease caused by mutations in the IKBKG gene, which is required for activation of the nuclear factor‐kappa B signalling pathway. Multiple systems ...can be affected with highly variable phenotypic expressivity. We aimed to clarify the clinical characteristics observed in molecularly confirmed Korean IP patients. The medical records of 25 females confirmed as IP by molecular genetic analysis were retrospectively reviewed. The phenotypic score of extracutaneous manifestations was calculated to assess the disease severity. The IKBKG gene partial deletion or intragenic mutations were investigated using long‐range PCR, multiplex ligation‐dependent probe amplification and direct sequencing methods. Among the 25 individuals, 18 (72%) were sporadic cases. All patients showed typical skin manifestations at birth or during the neonatal period. Extracutaneous findings were noted in 17 (68%) patients; ocular manifestations (28%), neurological abnormalities (28%), hair abnormalities (20%), dental anomalies (12%), nail dystrophy (8%). The common exon 4–10 IKBKG deletion was observed in 20 (80%) patients. In addition, five intragenic sequence variants were identified, including three novel variants. The phenotype scores were highly variable, ranging from abnormal skin pigmentation only to one or more extracutaneous features, although no significant difference was observed for each clinical characteristic between the group with sequence variants and that with common large deletion. Our cohort with IP showed heterogeneity of extracutaneous manifestations and high incidence of sporadic cases. Long‐term monitoring with multidisciplinary management is essential for evaluating the clinical status, providing adequate genetic counselling and understanding the genotype‐phenotype correlation in IP.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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