ABCA12 Is the Major Harlequin Ichthyosis Gene

Abstract

Harlequin ichthyosis (HI) is the most severe form of autosomal-recessive, congenital ichthyosis. Affected infants have markedly impaired barrier function and are more susceptible to infection. Abnormalities in the localization of epidermal lipids as well as abnormal lamellar granule formation are features of HI skin. Previously, we and others have shown that mutations in the ABCA12 gene encoding an adenosine triphosphate-binding cassette (ABC) transporter underlie the skin disease HI. In this study, we have sequenced the ABCA12 gene in an additional 14 patients and show that all contain mutations, with the majority being either nonsense substitution or frameshift mutations. Eleven HI patients had bi-allelic ABCA12 mutations, whereas in the remaining three HI patients in this study, ABCA12 mutations were detected on only one allele by sequencing. In addition, the one patient from the previous study where no sequence mutations were detected was screened for heterozygous deletions. A combination of oligonucleotide arrays, multiplex PCR analysis and single-nucleotide polymorphism genotyping revealed a heterozygous intragenic deletion in exon 8. These mutation data establish ABCA12 as the major HI gene.

ABCA12 mutations and autosomal recessive congenital ichthyosis: A review of genotype/phenotype correlations and of pathogenetic conceptsa

“…Among these 10 mutations, 5 ABCA12 mutations, c.2021_2022del2, c.3295À2A4G, p.Thr1387del, p.Arg1950Ter, and p.Arg2482Ter, were found in two independent patients from Japan [Akiyama et al, , 2007aSakai et al, 2009]. As for the other five mutations, p.Trp1294Ter, p.Gly1651Ser, p.Tyr1090Ter, c.2025delG, and p.Trp1744Ter were found in two independent families with Pakistani [Rajpar et al, 2006;Thomas et al, 2006], Algeria [Lefèvre et al, 2003], Albanian/ Bosnian [Thomas et al, 2008], Anglo-Saxon [Thomas et al, 2006], and native American [Kelsell et al, 2005] origins, respectively. These data suggest the presence of founder mutations in patients in Pakistani/Indian, African, European, and Japanese origins.…”

“…The most common reported mutation in ABCA12 is c.7322delC (p.Val2442SerfsTer28) in exon 49, which has been reported in seven HI families with Pakistani background [Kelsell et al, 2005;Thomas et al, 2006Thomas et al, , 2008. This mutation has been identified only in the Pakistani population.…”

“…Kelsell et al [2005] reported one HI patient in whom ABCA12 mutation was not detected by direct sequencing analysis. However, multiplex PCR and oligonucleotide array analysis subsequently revealed deletion of exon 8 in this patient [Thomas et al, 2006]. In this context, HI is thought to be genetically homogeneous for causal ABCA12 mutations.…”

“…Thus far, in HI patients, at least one mutation on each allele must be a truncation or deletion mutation within a conserved region to cause serious loss of ABCA12 function [Akiyama et al, ,b, 2007aCastiglia et al, 2009;Kelsell et al, 2005;Rajpar et al, 2006;Thomas et al, 2006Thomas et al, , 2008. Complete loss of ABCA12 function due to homozygous or compound heterozygous truncation mutations always results in the HI patient phenotype (Table 1).…”

Highly effective SNP-based association mapping and management of recessive defects in livestock

“…Missense mutations in the first ATP-binding domain of human ABCA12 cause lamellar ichthyosis type 2 (ref. 19), whereas nonsense, frameshift and in rare cases missense mutations have been shown to cause the more severe harlequin ichthyosis (OMIM 242500) [20][21][22][23][24] , which markedly resembles IF. We therefore sequenced ABCA12 in the affected cases and controls and identified a missense mutation in exon 39 (A5804G) resulting in an H1935R substitution in the fourth extracellular loop.…”