Compound Heterozygous <i>ABCA12</i> Mutations Including a Novel Nonsense Mutation Underlie Harlequin Ichthyosis

Abstract

Recently, it has been reported that several harlequin ichthyosis (HI) patients survive the neonatal period and their condition subsequently improves. Here we describe a 2-year-old Japanese boy who exhibited typical clinical features of HI at birth. He survived beyond the neonatal period after oral retinoid treatment and, at the age of 2 years, showed moderately thick, lamellar scales and erythroderma over his whole body. The patient is a compound heterozygote for 2 ABCA12 mutations, a paternal deletion mutation c.2021_2022del (p.Lys674ArgfsX63) and a novel maternal nonsense mutation c.7444C → T (p.Arg2482X). Electron microscopic observation of a skin biopsy specimen from the perinatal period revealed epidermal ultrastructural features consistent with HI. Immunofluorescence labeling using antiserum against a C-terminal ABCA12 epitope showed loss of expression in the patient’s epidermis. The present patient demonstrates that rapid diagnosis of HI by ABCA12 expression analysis and mutation detection, and early commencement of systemic retinoid therapy are crucial to significantly improving an HI patient’s prognosis.

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…7,8 HI exhibits abnormal LB, 203 with a marked deficiency of intercellular lamellae in the SC. 16,204 Disruption of the keratin cytoskeleton, with detachment from the desmosomal plaques and often perinuclear shell formation is observed in the KPI. 50,51,53,54,62,65,176 Abnormal intranuclear granules seen in the SG and SC are observed in loricrin keratoderma, which is ultrastructurally further characterized by a reduced thickness of the cornified cell envelope.…”

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

“…Out of further 10 different ABCA12 mutations, each mutation has been identified in two unrelated families from certain geographic regions. 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.…”

An update on molecular aspects of the non‐syndromic ichthyoses

“…However, most mutations in HI are truncation or deletion mutations which lead to more severe changes, such as loss of function of ABCA12 peptide affecting important nucleotide-binding fold domains and ⁄ or transmembrane domains. In HI, thus far at least one mutation on each allele must be a truncation or deletion mutation within a conserved region that seriously affects ABCA12 function (8,9,(40)(41)(42)(43)(44)(45). Only a couple of cases showing a NBCIE phenotype were reported to have ABCA12 mutations as the causative genetic defect (29).…”