The Genetics of Ichthyosis: A Primer for Epidemiologists.

Bale, Sherri J.; Doyle, Sharon Z.

doi:10.1111/1523-1747.ep12388591

Cited by 39 publications

(27 citation statements)

References 21 publications

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“…This historical event may account for the high frequency of this gene in the population, with the incidence of LI and CIE in Norway being reported at 1/91,000 over the last 10 years (Pigg et al 1998). This is more than twice the frequency estimated in the US population (1:200,000-300,000; Bale and Doyle 1994).…”

Section: Discussionmentioning

confidence: 63%

Splice-site mutation in TGM1 in congenital recessive ichthyosis in American families: molecular, genetic, genealogic, and clinical studies

et al. 2000

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Lamellar ichthyosis (LI, OMIM no. 242300) is a severe autosomal recessive genodermatosis with an estimated prevalence of 1:200,000. LI represents one end of the spectrum of congenital recessive ichthyosis (CRI). Mutations in the gene for transglutaminase-1 (TGM1) are responsible for many cases of LI and occur throughout the coding sequence of the gene. Our analyses of patients with CRI revealed a common TGM1 mutation involving loss of the intron 5 splice acceptor site leading to alternative splicing of the message. We found families in which the splice acceptor site mutation was homozygous, and families where the patients were compound heterozygotes for the splice acceptor site mutation and another TGM1 mutation. A mutation at this same site occurs in the majority of Norwegian patients as a founder effect. In our ethnically diverse patient population, none of whom have known Norwegian ancestry, haplotype analysis of the TGM1 chromosomal region also suggested the existence of a founder effect. Comparison of the common haplotype in our data with the Norwegian data showed that 2/7 of our splice acceptor site mutation chromosomes had the full reported Norwegian haplotype, and the remaining five chromosomes exhibited recombination at the most distal marker studied. History, family origins, and haplotype analysis suggested that the mutation originally arose on a German background and was introduced into Norway around 800-1000 AD. We also found a limited correlation between genotype and phenotype in our study, with the four homozygous patients having less severe disease than many of the heterozygotes, and no patient with a splice acceptor site mutation having erythroderma or a congenital ichthyosiform erythroderma phenotype.

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Section: Discussionmentioning

confidence: 63%

Splice-site mutation in TGM1 in congenital recessive ichthyosis in American families: molecular, genetic, genealogic, and clinical studies

et al. 2000

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“…The most frequently quoted prevalence is 1 case of LI in 200,000 to 300,000 newborns. [3][4][5] In Spain, official reference centers for the disease have not been defined. Patients are treated by many dermatologists, but concentrate in centers with pediatric dermatology clinics that act as reference centers.…”

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confidence: 99%

Prevalence of autosomal recessive congenital ichthyosis: A population-based study using the capture-recapture method in Spain

Hernández‐Martín

García‐Doval

Aranegui

et al. 2012

Journal of the American Academy of Dermatology

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“…Among these are epidermolysis bullosa (EB) (1) and severe autosomal recessive ichthyoses such as lamellar ichthyosis (LI) (2,3). EB comprises a group of blistering skin disorders caused by mutations in a variety of genes responsible for epithelial-mesenchymal and intraepidermal cohesion.…”

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confidence: 99%

In vivo restoration of laminin 5 β3 expression and function in junctional epidermolysis bullosa

Robbins

Lin

Goodnough

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

117

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The blistering disorder, lethal junctional epidermolysis bullosa (JEB), can result from mutations in the LAMB3 gene, which encodes laminin 5 ␤3 (␤3). Appropriate expression of LAM␤3 in JEB skin tissue could potentially ameliorate the symptoms of the underlying disease. To explore the utility of this therapeutic approach, primary keratinocytes from six unrelated JEB patients were transduced with a retroviral vector encoding ␤3 and used to regenerate human skin on severe combined immunodeficient (SCID) mice. Tissue regenerated from ␤3-transduced JEB keratinocytes produced phenotypically normal skin characterized by sustained ␤3 expression and the formation of hemidesmosomes. Additionally, ␤3 gene transfer corrected the distribution of a number of important basement membrane zone proteins including BPAG2, integrins ␤4͞␤1, and laminins ␣3͞␥2. Skin produced from ␤3-negative (␤3[؊]) JEB cells mimicked the hallmarks of the disease state and did not exhibit any of the aforementioned traits. Therefore, by effecting therapeutic gene transfer to ␤3-deficient primary keratinocytes, it is possible to produce healthy, normal skin tissue in vivo. These data support the utility of gene therapy for JEB and highlight the potential for gene delivery in the treatment of human genetic skin disease.gene therapy ͉ skin ͉ retrovirus A number of devastating inherited skin disorders have been characterized at the molecular level. Among these are epidermolysis bullosa (EB) (1) and severe autosomal recessive ichthyoses such as lamellar ichthyosis (LI) (2, 3). EB comprises a group of blistering skin disorders caused by mutations in a variety of genes responsible for epithelial-mesenchymal and intraepidermal cohesion. These genes include keratins 5 and 14 as well as plectin in the superficial simplex EB subtypes, BPAG2 (type XVII collagen͞BP180), laminin 5 chains, ␣6 and ␤4 integrins in junctional EB, and type VII collagen in deeper, dystrophic EB (4-6). In more severe subtypes of junctional EB (Herlitz JEB) (7), caused by mutations in any of the ␣3, ␤3, and ␥2 chains of laminin 5, affected children may die in infancy and early childhood (6). Currently, no corrective therapies are available for these disorders.In epidermis, basal keratinocytes adherent to an underlying basement membrane zone (BMZ) give rise to progeny that migrate outwards, lose contact with the BMZ, and undergo terminal differentiation to form the stratum corneum. Genetic lesions responsible for junctional epidermolysis bullosa (JEB) affect proteins important in adhesion of basal layer cells to the dermis, including laminin 5, BPAG2, and ␣6͞␤4 integrin. Laminin 5 is an important adhesion molecule of epithelial origin (8) that, along with ␣6͞␤4 integrin, BPAG2, and plectin, contributes to hemidesmosome attachment structures. Loss of any of these components reduces normal epidermal-dermal cohesion and leads to clinical blister formation, as seen in JEB (9-14) and in targeted gene disruption of homologous genes in mice (15-17). Therefore, localization of key proteins at the BM...

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The Genetics of Ichthyosis: A Primer for Epidemiologists.

Cited by 39 publications

References 21 publications

Splice-site mutation in TGM1 in congenital recessive ichthyosis in American families: molecular, genetic, genealogic, and clinical studies

Splice-site mutation in TGM1 in congenital recessive ichthyosis in American families: molecular, genetic, genealogic, and clinical studies

Prevalence of autosomal recessive congenital ichthyosis: A population-based study using the capture-recapture method in Spain

In vivo restoration of laminin 5 β3 expression and function in junctional epidermolysis bullosa

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