Cell and Tissue Research

, Volume 351, Issue 2, pp 281–288 | Cite as

Harlequin ichthyosis: ABCA12 mutations underlie defective lipid transport, reduced protease regulation and skin-barrier dysfunction

  • Claire A. Scott
  • Shefali Rajpopat
  • Wei-Li DiEmail author


Harlequin ichthyosis (HI) is a devastating autosomal recessive congenital skin disease. It has been vital to elucidate the biological importance of the protein ABCA12 in skin-barrier permeability, following the discovery that ABCA12 gene mutations can result in this rare disease. ATP-binding cassette transporter A12 (ABCA12) is a member of the subfamily of ATP-binding cassette transporters and functions to transport lipid glucosylceramides (GlcCer) to the extracellular space through lamellar granules (LGs). GlcCer are hydrolysed into hydroxyceramides extracellularly and constitute a portion of the extracellular lamellar membrane, lipid envelope and lamellar granules. In HI skin, loss of function of ABCA12 due to null mutations results in impaired lipid lamellar membrane formation in the cornified layer, leading to defective permeability of the skin barrier. In addition, abnormal lamellar granule formation (distorted shape, reduced in number or absent) could further cause aberrant production of LG-associated desquamation enzymes, which are likely to contribute to the impaired skin barrier in HI. This article reviews current opinions on the patho-mechanisms of ABCA12 action in HI and potential therapeutic interventions based on targeted molecular therapy and gene therapy strategies.


Harlequin ichthyosis ABCA12 Proteases Glucosylceramides Skin barrier 



Dr Claire A Scott is supported by Barts and the London Charity and Dr Shefali Rajpopat is a Clinical Research Fellow supported by the British Skin Foundation.


  1. Akiyama M (2006) Pathomechanisms of harlequin ichthyosis and ABCA transporters in human diseases. Arch Dermatol 142:914–918PubMedCrossRefGoogle Scholar
  2. Akiyama M (2011) The roles of ABCA12 in keratinocyte differentiation and lipid barrier formation in the epidermis. Dermatoendocrinol 3:107–112PubMedCrossRefGoogle Scholar
  3. Akiyama M, Shimizu H, Yoneda K, Nishikawa T (1997) Collodion baby: ultrastructure and distribution of cornified cell envelope proteins and keratins. Dermatology 195:164–168PubMedCrossRefGoogle Scholar
  4. Akiyama M, Sugiyama-Nakagiri Y, Sakai K, McMillan JR, Goto M, Arita K, Tsuji-Abe Y, Tabata N, Matsuoka K, Sasaki R, Sawamura D, Shimizu H (2005) Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer. J Clin Invest 115:1777–1784PubMedCrossRefGoogle Scholar
  5. Akiyama M, Sakai K, Sugiyama-Nakagiri Y, Yamanaka Y, McMillan JR, Sawamura D, Niizeki H, Miyagawa S, Shimizu H (2006) Compound heterozygous mutations including a de novo missense mutation in ABCA12 led to a case of harlequin ichthyosis with moderate clinical severity. J Invest Dermatol 126:1518–1523PubMedCrossRefGoogle Scholar
  6. Akiyama M, Titeux M, Sakai K, McMillan JR, Tonasso L, Calvas P, Jossic F, Hovnanian A, Shimizu H (2007) DNA-based prenatal diagnosis of harlequin ichthyosis and characterization of ABCA12 mutation consequences. J Invest Dermatol 127:568–573PubMedCrossRefGoogle Scholar
  7. Andressoo JO, Jans J, de Wit J, Coin F, Hoogstraten D, van de Ven M, Toussaint W, Huijmans J, Thio HB, van Leeuwen WJ, de Boer J, Egly JM, Hoeijmakers JH, van der Horst GT, Mitchell JR (2006) Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles. PLoS Biol 4:e322PubMedCrossRefGoogle Scholar
  8. Annilo T, Shulenin S, Chen ZQ, Arnould I, Prades C, Lemoine C, Maintoux-Larois C, Devaud C, Dean M, Denefle P, Rosier M (2002) Identification and characterization of a novel ABCA subfamily member, ABCA12, located in the lamellar ichthyosis region on 2q34. Cytogenet Genome Res 98:169–176PubMedCrossRefGoogle Scholar
  9. Braff MH, Zaiou M, Fierer J, Nizet V, Gallo RL (2005) Keratinocyte production of cathelicidin provides direct activity against bacterial skin pathogens. Infect Immun 73:6771–6781PubMedCrossRefGoogle Scholar
  10. Brecher AR, Orlow SJ (2003) Oral retinoid therapy for dermatologic conditions in children and adolescents. J Am Acad Dermatol 49:171–182PubMedCrossRefGoogle Scholar
  11. Buxman MM, Goodkin PE, Fahrenbach WH, Dimond RL (1979) Harlequin ichthyosis with epidermal lipid abnormality. Arch Dermatol 115:189–193PubMedCrossRefGoogle Scholar
  12. Candi E, Schmidt R, Melino G (2005) The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol 6:328–340PubMedCrossRefGoogle Scholar
  13. Castiglia D, Castori M, Pisaneschi E, Sommi M, Covaciu C, Zambruno G, Fischer J, Magnani C (2009) Trisomic rescue causing reduction to homozygosity for a novel ABCA12 mutation in harlequin ichthyosis. Clin Genet 76:392–397PubMedCrossRefGoogle Scholar
  14. Caubet C, Jonca N, Brattsand M, Guerrin M, Bernard D, Schmidt R, Egelrud T, Simon M, Serre G (2004) Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7. J Invest Dermatol 122:1235–1244PubMedCrossRefGoogle Scholar
  15. Dale BA, Holbrook KA, Fleckman P, Kimball JR, Brumbaugh S, Sybert VP (1990) Heterogeneity in harlequin ichthyosis, an inborn error of epidermal keratinization: variable morphology and structural protein expression and a defect in lamellar granules. J Invest Dermatol 94:6–18PubMedCrossRefGoogle Scholar
  16. Di WL, Larcher F, Semenova E, Talbot GE, Harper JI, Del RM, Thrasher AJ, Qasim W (2011) Ex-vivo gene therapy restores LEKTI activity and corrects the architecture of Netherton syndrome-derived skin grafts. Mol Ther 19:408–416PubMedCrossRefGoogle Scholar
  17. Egberts F, Heinrich M, Jensen JM, Winoto-Morbach S, Pfeiffer S, Wickel M, Schunck M, Steude J, Saftig P, Proksch E, Schutze S (2004) Cathepsin D is involved in the regulation of transglutaminase 1 and epidermal differentiation. J Cell Sci 117:2295–2307PubMedCrossRefGoogle Scholar
  18. Ekholm IE, Brattsand M, Egelrud T (2000) Stratum corneum tryptic enzyme in normal epidermis: a missing link in the desquamation process? J Invest Dermatol 114:56–63PubMedCrossRefGoogle Scholar
  19. Elias PM (2005) Stratum corneum defensive functions: an integrated view. J Invest Dermatol 125:183–200PubMedGoogle Scholar
  20. Elias PM, Menon GK (1991) Structural and lipid biochemical correlates of the epidermal permeability barrier. Adv Lipid Res 24:1–26PubMedGoogle Scholar
  21. Elias PM, Fartasch M, Crumrine D, Behne M, Uchida Y, Holleran WM (2000) Origin of the corneocyte lipid envelope (CLE): observations in harlequin ichthyosis and cultured human keratinocytes. J Invest Dermatol 115:765–769PubMedCrossRefGoogle Scholar
  22. Elias PM, Williams ML, Holleran WM, Jiang YJ, Schmuth M (2008) Pathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism. J Lipid Res 49:697–714PubMedCrossRefGoogle Scholar
  23. Elias PM, Williams ML, Feingold KR (2012) Abnormal barrier function in the pathogenesis of ichthyosis: therapeutic implications for lipid metabolic disorders. Clin Dermatol 30:311–322PubMedCrossRefGoogle Scholar
  24. Fartasch M, Williams ML, Elias PM (1999) Altered lamellar body secretion and stratum corneum membrane structure in Netherton syndrome: differentiation from other infantile erythrodermas and pathogenic implications. Arch Dermatol 135:823–832PubMedCrossRefGoogle Scholar
  25. Fortugno P, Bresciani A, Paolini C, Pazzagli C, El HM, D’Alessio M, Zambruno G (2011) Proteolytic activation cascade of the Netherton syndrome-defective protein, LEKTI, in the epidermis: implications for skin homeostasis. J Invest Dermatol 131:2223–2232PubMedCrossRefGoogle Scholar
  26. Haftek M, Cambazard F, Dhouailly D, Reano A, Simon M, Lachaux A, Serre G, Claudy A, Schmitt D (1996) A longitudinal study of a harlequin infant presenting clinically as non-bullous congenital ichthyosiform erythroderma. Br J Dermatol 135:448–453PubMedCrossRefGoogle Scholar
  27. Hanley K, Jiang Y, Holleran WM, Elias PM, Williams ML, Feingold KR (1997) Glucosylceramide metabolism is regulated during normal and hormonally stimulated epidermal barrier development in the rat. J Lipid Res 38:576–584PubMedGoogle Scholar
  28. Hsu WY, Chen JY, Lin WL, Tsay CH (1989) Harlequin fetus—a case report. Zhonghua Yi Xue Za Zhi (Taipei) 43:63–66Google Scholar
  29. Ishida-Yamamoto A, Kishibe M (2011) Involvement of corneodesmosome degradation and lamellar granule transportation in the desquamation process. Med Mol Morphol 44:1–6PubMedCrossRefGoogle Scholar
  30. Ishida-Yamamoto A, Simon M, Kishibe M, Miyauchi Y, Takahashi H, Yoshida S, O’brien TJ, Serre G, Iizuka H (2004) Epidermal lamellar granules transport different cargoes as distinct aggregates. J Invest Dermatol 122:1137–1144PubMedCrossRefGoogle Scholar
  31. Ishida-Yamamoto A, Deraison C, Bonnart C, Bitoun E, Robinson R, O’brien TJ, Wakamatsu K, Ohtsubo S, Takahashi H, Hashimoto Y, Dopping-Hepenstal PJ, McGrath JA, Iizuka H, Richard G, Hovnanian A (2005) LEKTI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum. J Invest Dermatol 124:360–366PubMedCrossRefGoogle Scholar
  32. Kelsell DP, Norgett EE, Unsworth H, Teh MT, Cullup T, Mein CA, Dopping-Hepenstal PJ, Dale BA, Tadini G, Fleckman P, Stephens KG, Sybert VP, Mallory SB, North BV, Witt DR, Sprecher E, Taylor AE, Ilchyshyn A, Kennedy CT, Goodyear H, Moss C, Paige D, Harper JI, Young BD, Leigh IM, Eady RA, O’Toole EA (2005) Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. Am J Hum Genet 76:794–803PubMedCrossRefGoogle Scholar
  33. Lefevre C, Audebert S, Jobard F, Bouadjar B, Lakhdar H, Boughdene-Stambouli O, Blanchet-Bardon C, Heilig R, Foglio M, Weissenbach J, Lathrop M, Prud’homme JF, Fischer J (2003) Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2. Hum Mol Genet 12:2369–2378PubMedCrossRefGoogle Scholar
  34. Li Q, Frank M, Akiyama M, Shimizu H, Ho SY, Thisse C, Thisse B, Sprecher E, Uitto J (2011) Abca12-mediated lipid transport and Snap29-dependent trafficking of lamellar granules are crucial for epidermal morphogenesis in a zebrafish model of ichthyosis. Dis Model Mech 4:777–785PubMedCrossRefGoogle Scholar
  35. Mavilio F, Pellegrini G, Ferrari S, Di Nunzio F, Di Iorio E, Recchia A, Maruggi G, Ferrari G, Provasi E, Bonini C, Capurro S, Conti A, Magnoni C, Giannetti A, De Luca M (2006) Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. Nat Med 12:1397–1402PubMedCrossRefGoogle Scholar
  36. Milner ME, O’Guin WM, Holbrook KA, Dale BA (1992) Abnormal lamellar granules in harlequin ichthyosis. J Invest Dermatol 99:824–829PubMedCrossRefGoogle Scholar
  37. Mitsutake S, Suzuki C, Akiyama M, Tsuji K, Yanagi T, Shimizu H, Igarashi Y (2010) ABCA12 dysfunction causes a disorder in glucosylceramide accumulation during keratinocyte differentiation. J Dermatol Sci 60:128–129PubMedCrossRefGoogle Scholar
  38. Moreau S, Salame E, de Goullet RM, Delmas P (1999) Harlequin fetus: a case report. Surg Radiol Anat 21:215–216PubMedCrossRefGoogle Scholar
  39. Natsuga K, Akiyama M, Kato N, Sakai K, Sugiyama-Nakagiri Y, Nishimura M, Hata H, Abe M, Arita K, Tsuji-Abe Y, Onozuka T, Aoyagi S, Kodama K, Ujiie H, Tomita Y, Shimizu H (2007) Novel ABCA12 mutations identified in two cases of non-bullous congenital ichthyosiform erythroderma associated with multiple skin malignant neoplasia. J Invest Dermatol 127:2669–2673PubMedCrossRefGoogle Scholar
  40. Oren A, Ganz T, Liu L, Meerloo T (2003) In human epidermis, beta-defensin 2 is packaged in lamellar bodies. Exp Mol Pathol 74:180–182PubMedCrossRefGoogle Scholar
  41. O’Shaughnessy RF, Choudhary I, Harper JI (2010) Interleukin-1 alpha blockade prevents hyperkeratosis in an in vitro model of lamellar ichthyosis. Hum Mol Genet 19:2594–2605PubMedCrossRefGoogle Scholar
  42. Paller AS, van Steensel MA, Rodriguez-Martin M, Sorrell J, Heath C, Crumrine D, van Geel M, Cabrera AN, Elias PM (2011) Pathogenesis-based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism. J Invest Dermatol 131:2242–2248PubMedCrossRefGoogle Scholar
  43. Peelman F, Labeur C, Vanloo B, Roosbeek S, Devaud C, Duverger N, Denefle P, Rosier M, Vandekerckhove J, Rosseneu M (2003) Characterization of the ABCA transporter subfamily: identification of prokaryotic and eukaryotic members, phylogeny and topology. J Mol Biol 325:259–274PubMedCrossRefGoogle Scholar
  44. Quazi F, Molday RS (2011) Lipid transport by mammalian ABC proteins. In: Sharom FJ (ed) ABC transporters. Portland Press Limited, London, pp 265–286Google Scholar
  45. Rajpar SF, Cullup T, Kelsell DP, Moss C (2006) A novel ABCA12 mutation underlying a case of Harlequin ichthyosis. Br J Dermatol 155:204–206PubMedCrossRefGoogle Scholar
  46. Rajpopat S, Moss C, Mellerio J, Vahlquist A, Ganemo A, Hellstrom-Pigg M, Ilchyshyn A, Burrows N, Lestringant G, Taylor A, Kennedy C, Paige D, Harper J, Glover M, Fleckman P, Everman D, Fouani M, Kayserili H, Purvis D, Hobson E, Chu C, Mein C, Kelsell D, O’Toole E (2011) Harlequin ichthyosis: a review of clinical and molecular findings in 45 cases. Arch Dermatol 147:681–686PubMedCrossRefGoogle Scholar
  47. Sakai K, Akiyama M, Sugiyama-Nakagiri Y, McMillan JR, Sawamura D, Shimizu H (2007) Localization of ABCA12 from Golgi apparatus to lamellar granules in human upper epidermal keratinocytes. Exp Dermatol 16:920–926PubMedCrossRefGoogle Scholar
  48. Sakai K, Akiyama M, Yanagi T, McMillan JR, Suzuki T, Tsukamoto K, Sugiyama H, Hatano Y, Hayashitani M, Takamori K, Nakashima K, Shimizu H (2009) ABCA12 is a major causative gene for non-bullous congenital ichthyosiform erythroderma. J Invest Dermatol 129:2306–2309PubMedCrossRefGoogle Scholar
  49. Sarkar R, Sharma RC, Sethi S, Basu S, Das R, Mendiratta V, Sardana K, Kakar N (2000) Three unusual siblings with Harlequin icthyosis in an Indian family. J Dermatol 27:609–611PubMedGoogle Scholar
  50. Schurer NY, Elias PM (1991) The biochemistry and function of stratum corneum lipids. Adv Lipid Res 24:27–56PubMedGoogle Scholar
  51. Smyth I, Hacking DF, Hilton AA, Mukhamedova N, Meikle PJ, Ellis S, Satterley K, Collinge JE, de Graaf CA, Bahlo M, Sviridov D, Kile BT, Hilton DJ (2008) A mouse model of harlequin ichthyosis delineates a key role for Abca12 in lipid homeostasis. PLoS Genet 4:e1000192PubMedCrossRefGoogle Scholar
  52. Thomas AC, Cullup T, Norgett EE, Hill T, Barton S, Dale BA, Sprecher E, Sheridan E, Taylor AE, Wilroy RS, DeLozier C, Burrows N, Goodyear H, Fleckman P, Stephens KG, Mehta L, Watson RM, Graham R, Wolf R, Slavotinek A, Martin M, Bourn D, Mein CA, O’Toole EA, Kelsell DP (2006) ABCA12 is the major harlequin ichthyosis gene. J Invest Dermatol 126:2408–2413PubMedCrossRefGoogle Scholar
  53. Thomas AC, Sinclair C, Mahmud N, Cullup T, Mellerio JE, Harper J, Dale BA, Turc-Carel C, Hohl D, McGrath JA, Vahlquist A, Hellstrom-Pigg M, Ganemo A, Metcalfe K, Mein CA, O’Toole EA, Kelsell DP (2008) Novel and recurring ABCA12 mutations associated with harlequin ichthyosis: implications for prenatal diagnosis. Br J Dermatol 158:611–613PubMedCrossRefGoogle Scholar
  54. Thomas AC, Tattersall D, Norgett EE, O’Toole EA, Kelsell DP (2009) Premature terminal differentiation and a reduction in specific proteases associated with loss of ABCA12 in Harlequin ichthyosis. Am J Pathol 174:970–978PubMedCrossRefGoogle Scholar
  55. Titeux M, Pendaries V, Zanta-Boussif MA, Decha A, Pironon N, Tonasso L, Mejia JE, Brice A, Danos O, Hovnanian A (2010) SIN retroviral vectors expressing COL7A1 under human promoters for ex vivo gene therapy of recessive dystrophic epidermolysis bullosa. Mol Ther 18:1509–1518PubMedCrossRefGoogle Scholar
  56. Tolar J, Le BK, Keating A, Blazar BR (2010) Concise review: hitting the right spot with mesenchymal stromal cells. Stem Cells 28:1446–1455PubMedCrossRefGoogle Scholar
  57. Wagner JE, Ishida-Yamamoto A, McGrath JA, Hordinsky M, Keene DR, Woodley DT, Chen M, Riddle MJ, Osborn MJ, Lund T, Dolan M, Blazar BR, Tolar J (2010) Bone marrow transplantation for recessive dystrophic epidermolysis bullosa. N Engl J Med 363:629–639PubMedCrossRefGoogle Scholar
  58. Waring JI (1932) Early mention of a Harlequin fetus in America. Arch Pediatr Adolesc 43:442CrossRefGoogle Scholar
  59. Watkinson A (1999) Stratum corneum thiol protease (SCTP): a novel cysteine protease of late epidermal differentiation. Arch Dermatol Res 291:260–268PubMedCrossRefGoogle Scholar
  60. Wong T, Gammon L, Liu L, Mellerio JE, Dopping-Hepenstal PJ, Pacy J, Elia G, Jeffery R, Leigh IM, Navsaria H, McGrath JA (2008) Potential of fibroblast cell therapy for recessive dystrophic epidermolysis bullosa. J Invest Dermatol 128:2179–2189PubMedCrossRefGoogle Scholar
  61. Yanagi T, Akiyama M, Nishihara H, Ishikawa J, Sakai K, Miyamura Y, Naoe A, Kitahara T, Tanaka S, Shimizu H (2010) Self-improvement of keratinocyte differentiation defects during skin maturation in ABCA12-deficient harlequin ichthyosis model mice. Am J Pathol 177:106–118PubMedCrossRefGoogle Scholar
  62. Yanagi T, Akiyama M, Nishihara H, Miyamura Y, Sakai K, Tanaka S, Shimizu H (2011) AKT has an anti-apoptotic role in ABCA12-deficient keratinocytes. J Invest Dermatol 131:1942–1945PubMedCrossRefGoogle Scholar
  63. Zuo Y, Zhuang DZ, Han R, Isaac G, Tobin JJ, McKee M, Welti R, Brissette JL, Fitzgerald ML, Freeman MW (2008) ABCA12 maintains the epidermal lipid permeability barrier by facilitating formation of ceramide linoleic esters. J Biol Chem 283:36624–36635PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Centre for Cutaneous Research, Blizard Institute, Barts & The London School of Medicine and Dentistry, Queen MaryUniversity of LondonLondonUK
  2. 2.ImmunobiologyUCL Institute of Child HealthLondonUK

Personalised recommendations