Mutations in ABCA12 Underlie the Severe Congenital Skin Disease Harlequin Ichthyosis

University of Milan, Milano, Lombardy, Italy
The American Journal of Human Genetics (Impact Factor: 10.93). 06/2005; 76(5):794-803. DOI: 10.1086/429844
Source: PubMed


Harlequin ichthyosis (HI) is the most severe and frequently lethal form of recessive congenital ichthyosis. Although defects in lipid transport, protein phosphatase activity, and differentiation have been described, the genetic basis underlying the clinical and cellular phenotypes of HI has yet to be determined. By use of single-nucleotide-polymorphism chip technology and homozygosity mapping, a common region of homozygosity was observed in five patients with HI in the chromosomal region 2q35. Sequencing of the ABCA12 gene, which maps within the minimal region defined by homozygosity mapping, revealed disease-associated mutations, including large intragenic deletions and frameshift deletions in 11 of the 12 screened individuals with HI. Since HI epidermis displays abnormal lamellar granule formation, ABCA12 may play a critical role in the formation of lamellar granules and the discharge of lipids into the intercellular spaces, which would explain the epidermal barrier defect seen in this disorder. This finding paves the way for early prenatal diagnosis. In addition, functional studies of ABCA12 will lead to a better understanding of epidermal differentiation and barrier formation.

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    • "HI appears with severe thickened and scaly skin on the entire body. In addition, ectropion, lack of development of the external parts of the nose and ears, eclabium and open mouth, hypoplastic fingers, anonychia and mobility limitation of the joints are some other clinical features of the HI.[245] Patients with HI are at high risk for hypo/hyperthermia, dehydration, respiratory distress, hypoventilation, malnutrition, hypernatremia, seizure, and skin infection.[26] HI is associated with preterm birth and often leads to death due to neonatal complications such as fluid loss and septicemia.[3] "
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    ABSTRACT: Harlequin fetus is a rare and the most severe form of the congenital ichthyosis with an autosomal recessive inheritance. Incidence of the disease is nearly 1 in 3,00,000 live births. The disease might be lethal at birth and the affected babies are often premature. Harlequin ichthyosis (HI) is marked by severe keratinized and alligator-like horned skin. The present study reports a new case with HI and adds to the collective knowledge of this rare skin disorder. HI has been linked to mutation in the ABCA12 gene; therefore, genetic counseling and mutation screening of this gene should be considered.
    Full-text · Article · Nov 2013 · Journal of research in medical sciences
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    • "Over the last decade at least six different genes have been implicated in the etiology of ARCI, all of which encode proteins essential for the formation of the skin barrier: TGM1 [3, 4], ABCA12 [5, 6], two lipoxygenase genes (ALOXE3 and ALOX12B) [7, 8], ichthyin (NIPAL4) [9] and CYP4F2 homolog (FLJ39501) [10]. "
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    ABSTRACT: Lamellar ichthyosis (LI, MIM# 242300) is a severe autosomal recessive genodermatosis present at birth in the form of collodion membrane covering the neonate. Mutations in the TGM1 gene encoding transglutaminase-1 are a major cause of LI. In this study molecular analysis of two LI Tunisian patients revealed a common nonsense c.788G>A mutation in TGM1 gene. The identification of a cluster of LI pedigrees carrying the c.788G>A mutation in a specific area raises the question of the origin of this mutation from a common ancestor. We carried out a haplotype-based analysis by way of genotyping 4 microsatellite markers and 8 SNPs flanking and within the TGM1 gene spanning a region of 6 Mb. Haplotype reconstruction from genotypes of all members of the affected pedigrees indicated that all carriers for the mutation c.788G>A harbored the same haplotype, indicating common ancestor. The finding of a founder effect in a rare disease is essential for the genetic diagnosis and the genetic counselling of affected LI pedigrees in Tunisia.
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    • "The main pathophysiological feature of this disease is a failure of skin barrier permeability, leading to a spectrum of conditions ranging from the most mild, such as the common ichthyosis vulgaris, to the most severe, such as Harlequin type ichthyosis, which is rare but fatal in newborns. Recently, mutations in ABCA12, a keratinocyte lipid transporter, were shown to underlie the latter phenotype [120, 121]. Under normal conditions, ABCA12 facilitates the uptake of lipids into specialized secretory granules, called lamellar bodies, within keratinocytes. "
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