Caso Clinico

HMG Advance Access published July 15, 2003

Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2

Caroline Lefèvre , Stéphanie Audebert , Florence Jobard , Bakar Bouadjar2, Hakima Lakhdar3, Omar Boughdene-Stambouli4, Claudine Blanchet-Bardon5, Roland Heilig6, Mario Foglio , Jean Weissenbach , Mark Lathrop , Jean-François Prud'homme and Judith
1 Fischer * 1 6 1 71

1

1

Downloaded from http://hmg.oxfordjournals.org/ by guest on April 30, 2012

1

Centre National de Génotypage, Evry, France, Department of Dermatology, CHU Bab-El-Oued,
3 5

2

Algiers, Algeria, Department of Dermatology, CHU Ibn Rochd, Casablanca, Morocco,
4

Department of Dermatology, CHU T Djamerni, Tlemcen, Algeria, Department of Dermatology,
6

CHU Saint-Louis,Paris, France, Centre National de Séquençage, Genoscope, Evry, France and
7

Généthon, Evry, France

* To whom correspondence should be addressed. Tel.: +33 1 60 87 83 57; Fax: +33 1 60 87 83 83; Email: fischer@cng.fr

Copyright (c) 2003 Oxford University Press

ABSTRACT Lamellar ichthyosis type 2 (LI2) is a rare autosomal recessive skin disorder for which a gene has been previouslylocalized on chromosome 2q33-35. We report the identification of five missense mutations in the ABCA12 gene in 9 families from Africa affected by LI2. The mutations were homozygous in eight consanguineous families and heterozygous in one nonconsanguineous family. Four of these mutations are localized in the first ATP-binding domain (nucleotide-binding fold), which is highly conserved in all ABCproteins. The ABCA12 protein belongs to a superfamily of membrane proteins that translocate a variety of substrates across extra- and intra-cellular membranes. ABCA transporters have been implicated in several autosomal recessive disorders, notably of lipid metabolism. By analogy with ABCA3, a lamellar body membrane protein in lung alveolar type II cells, ABCA12 could function in
Downloaded fromhttp://hmg.oxfordjournals.org/ by guest on April 30, 2012

cellular lipid trafficking in keratinocytes.

INTRODUCTION Autosomal recessive congenital ichthyoses (ARCI) comprise a clinically and genetically heterogeneous group of disorders of keratinisation characterized by skin desquamation over the whole body, often associated with erythema (1,2). Two non-syndromic forms have been clinicallydefined: lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE). Both forms have an estimated incidence of between one in 300,000 to 500,000 live-born babies. Clinically, LI can be distinguished from NCIE by the characteristics of the scales, which are large, adherent, dark and pigmented, and by the absence of erythema. In NCIE, scales are fine, white and on anerythematous background, with the exception of the extension sites on the limbs, where the scales are larger and grayish (3). However, overlapping phenotypes exist and a clear differentiation between the groups is often not evident. Histologic characteristics of LI are orthohyperkeratosis and
Downloaded from http://hmg.oxfordjournals.org/ by guest on April 30, 2012

mild focal parakeratosis; the stratumcorneum is at least twice as thick as in NCIE patients (3,4), and there is a normal or increased granular layer. Biochemically, the terminal differentiation of the epidermis is disturbed in LI, with a reduced barrier function, defects in the stratum corneum lipid composition (4,5), a rise in ceramides (sphingolipids) and in free sterols in severe cases of LI (1). LI has been considered to be aretention ichthyosis, in contrast to NCIE or psoriasis, which are hyperproliferative diseases (5,6). Besides clinical heterogeneity, both LI and NCIE have been demonstrated to be genetically heterogeneous. For LI, four genes have been localized to date: LI1 (MIM 242300) on chromosome 14q11, LI2 (MIM 601277) on chromosome 2q33-35, LI3 (MIM 604777) on chromosome 19p12q12, and LI5 (MIM 606545), also...