Genes and Phenotypes involved in Autosomal Recessive Ichthyosis: A clinical and Genetical review


Autosomal Recessive

How to Cite

Ali, wajid A., Rahim, M. C., Faiz, S., Samad, A., & Gull, M. (2020). Genes and Phenotypes involved in Autosomal Recessive Ichthyosis: A clinical and Genetical review. Pak-Euro Journal of Medical and Life Sciences, 3(3), 142-155.


Ichthyosis is a large heterogeneous group of genetic anomalies of skin which are distinguished by either distribution or quality of scaling and hyperkeratosis, also may contain other extra cutaneous and dermatologic involvement. These anomalies are due to gene sequence variants often linked in skin barrier formation. Inherited ichthyoses can be of either two forms; non syndromic and syndromic forms. Non syndromic ichthyoses only have phenotypic expression causing effect to skin. Non syndromic ichthyoses consists of autosomal recessive congenital ichthyoses, X-linked ichthyoses, ichthyoses vulgaris. Keratinopathic ichthyoses and other forms. This review emphasis on updates of all types of non-syndromic ichthyoses.  This review figures out the molecular pathways and phenotype/ genotype associations. Autosomal recessive congenital ichthyoses can be of either three major phenotypes (lamellar ichthyoses, congenital ichthyosiform erythroderma and harlequin ichthyoses) more over, and be three of the minor subtypes (acral self-healing collodion baby, self-healing collodion baby and bathing suit ichthyoses). Keratinopithic ichthyoses are caused due to keratin genes sequence variant so are termed Keratinopithic ichthyoses. For diagnoses and discovery of ichthyoses genetic causes, the next generation sequencing is considered the influential tool. This paper reviews the recent pathomechanisms for the non-syndromic ichthyoses and explains the future perspectives


1. Marukian NV, Choate KA. Recent advances in understanding ichthyosis pathogenesis. F1000Research. 2016;5.
2. Schmuth M, Martinz V, Janecke AR, Fauth C, Schossig A, Zschocke J, Gruber R. Inherited ichthyoses/generalized Mendelian disorders of cornification. European Journal of Human Genetics. 2013 Feb;21(2):123-33.
3. Oji V, Tadini G, Akiyama M, Bardon CB, Bodemer C, Bourrat E, Coudiere P, DiGiovanna JJ, Elias P, Fischer J, Fleckman P. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Soreze 2009. Journal of the American Academy of Dermatology. 2010 Oct 1;63(4):607-41.
4.Takeichi T, Akiyama M. Inherited ichthyosis: non‐syndromic forms. The Journal of dermatology. 2016 Mar;43(3):242-51.
5. Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, Liao H, Evans AT, Goudie DR, Lewis-Jones S, Arseculeratne G. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nature genetics. 2006 Mar;38(3):337-42.
6. Lykkesfeldt GE, Nielsen MD, Lykkesfeldt AE. Placental steroid sulfatase deficiency: biochemical diagnosis and clinical review. Obstetrics and gynecology. 1984 Jul;64(1):49-54.
7. Alperin ES, Shapiro LJ. Characterization of Point Mutations in Patients with X-linked Ichthyosis EFFECTS ON THE STRUCTURE AND FUNCTION OF THE STEROID SULFATASE PROTEIN. Journal of Biological Chemistry. 1997 Aug 15;272(33):20756-63.
8. Richard G, Smith LE, Bailey RA, Itin P, Hohl D, Epstein EH, DiGiovanna JJ, Compton JG, Bale SJ. Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis. Nature genetics. 1998 Dec;20(4):366-9.
9. Shigehara Y, Okuda S, Nemer G, Chedraoui A, Hayashi R, Bitar F, Nakai H, Abbas O, Daou L, Abe R, Sleiman MB. Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis. Human molecular genetics. 2016;25(20):4484-93.;
10. Bastaki F, Mohamed M, Nair P, Saif F, Mustafa EM, Bizzari S, Al‐Ali MT, Hamzeh AR. Summary of mutations underlying autosomal recessive congenital ichthyoses (ARCI) in Arabs with four novel mutations in ARCI‐related genes from the United Arab Emirates. International Journal of Dermatology. 2017;56(5):514-23.
11. Akiyama M. Severe congenital ichthyosis of the neonate. International journal of dermatology. 1998 Oct;37(10):722-8.
12. Wakil SM, Binamer Y, Al‐Dossari H, Al‐Humaidy R, Thuraya RA, Khalifa O, Finsterer J, Meyer BF, Al Owain M. Novel mutations in TGM 1 and ABCA 12 cause autosomal recessive congenital ichthyosis in five Saudi families. International Journal of Dermatology. 2016 Jun;55(6):673-9.
13. Farasat S, Wei MH, Herman M, Liewehr DJ, Steinberg SM, Bale SJ, Fleckman P, Toro JR. Novel transglutaminase-1 mutations and genotype–phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA. Journal of medical genetics. 2009 Feb 1;46(2):103-11.
14. Williams ML, Elias PM. Heterogeneity in autosomal recessive ichthyosis: clinical and biochemical differentiation of lamellar ichthyosis and nonbullous congenital ichthyosiform erythroderma. Archives of dermatology. 1985;121(4):477-88.
15. Dale BA, Kam E. Harlequin ichthyosis: variability in expression and hypothesis for disease mechanism. Archives of dermatology. 1993;129(11):1471-7.
16. Akiyama M, Sugiyama-Nakagiri Y, Sakai K, McMillan JR, Goto M, Arita K, Tsuji-Abe Y, Tabata N, Matsuoka K, Sasaki R, Sawamura D. Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer. The Journal of clinical investigation. 2005;115(7):1777-84.
17. Takeichi T, Sugiura K, Hsu CK, Nomura T, Takama H, Simpson MA, Shimizu H, McGrath JA, Akiyama M. Erythrokeratoderma variabilis caused by p. Gly45Glu in connexin 31: importance of the first extracellular loop glycine residue for gap junction function. Acta dermato-venereologica. 2016 1;96(4):557-9.
18. Shah K, Ansar M, Khan FS, Ahmad W, Ferrara TM, Spritz RA. Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix. Journal of Medical Genetics. 2017;54(3):186-9.
19. Van Steensel MA, Oranje AP, Van der Schroeff JG, Wagner A, Van Geel M. The missense mutation G12D in connexin30. 3 can cause both erythrokeratodermia variabilis of Mendes da Costa and progressive symmetric erythrokeratodermia of Gottron. American Journal of Medical Genetics Part A. 2009;149(4):657-61.
20. Ishida-Yamamoto A, McGrath JA, Lam H, Iizuka H, Friedman RA, Christiano AM. The molecular pathology of progressive symmetric erythrokeratoderma: a frameshift mutation in the loricrin gene and perturbations in the cornified cell envelope. The American Journal of Human Genetics. 1997;61(3):581-9.
21. Eckl KM, De Juanes S, Kurtenbach J, Nätebus M, Lugassy J, Oji V, Traupe H, Preil ML, Martínez F, Smolle J, Harel A. Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B. Journal of Investigative Dermatology. 2009;129(6):1421-8.
22. Eckl KM, Krieg P, Küster W, Traupe H, André F, Wittstruck N, Fürstenberger G, Hennies HC. Mutation spectrum and functional analysis of epidermis‐type lipoxygenases in patients with autosomal recessive congenital ichthyosis. Human mutation. 2005;26(4):351-61.
23.Santos-Cortez RL, Khan V, Khan FS, Chakchouk I, Lee K, Rasheed M, Hamza R, Acharya A, Ullah E, Saqib MA, Abbe I. Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability. Human genetics. 2018;137(9):735-52.
24. Liao H, Waters AJ, Goudie DR, Aitken DA, Graham G, Smith FJ, Lewis-Jones S, McLean WI. Filaggrin mutations are genetic modifying factors exacerbating X-linked ichthyosis. Journal of investigative dermatology. 2007;127(12):2795-8.

25. Kelsell PD, Norgett EE, Unsworth H, Teh MT, Cullup T, Mein CA, Dopping-Hepenstal JP, Dale AB, Tadini G, Fleckman P, Stephens GK. Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. Am J Hum Genet. 2005;76:794-803.
26. Wajid M, Kurban M, Shimomura Y, Christiano AM. NIPAL4/ichthyin is expressed in the granular layer of human epidermis and mutated in two Pakistani families with autosomal recessive ichthyosis. Dermatology. 2010;220(1):8-14.
27. Dahlqvist J, Westermark GT, Vahlquist A, Dahl N. Ichthyin/NIPAL4 localizes to keratins and desmosomes in epidermis and Ichthyin mutations affect epidermal lipid metabolism. Archives of dermatological research. 2012;304(5):377-86.
28. Fachal L, Rodríguez-Pazos L, Ginarte M, Carracedo A, Toribio J. Identification of a novel PNPLA1 mutation in a Spanish family with autosomal recessive congenital ichthyosis. British journal of dermatology. 2014;170(4):980-2.
29. Ahmad F, Ansar M, Mehmood S, Izoduwa A, Lee K, Nasir A, Abrar M, Mehmood S, Ullah A, Aziz A, University of Washington Center for Mendelian Genomics, Smith JD, Shendure J, Bamshad MJ, Nicekrson DA, Santos-Cortez RL, Leal SM, Ahmad W. A novel missense variant in the PNPLA1 gene underlies congenital ichthyosis in three consanguineous families. J Eur Acad Dermato. 2016;30:210-213.
30. Grall A, Guaguère E, Planchais S, Grond S, Bourrat E, Hausser I, Hitte C, Le Gallo M, Derbois C, Kim GJ, Lagoutte L. PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans. Nature genetics. 2012;44(2):140-7.
31. Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN (2017). The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665-677.
32. sraeli S, Khamaysi Z, Fuchs-Telem D, Nousbeck J, Bergman R, Sarig O, Sprecher E. A mutation in LIPN, encoding epidermal lipase N, causes a late-onset form of autosomal-recessive congenital ichthyosis. The American Journal of Human Genetics. 2011;8;88(4):482-7.
33. Radner FP, Marrakchi S, Kirchmeier P, Kim GJ, Ribierre F, Kamoun B, Abid L, Leipoldt M, Turki H, Schempp W, Heilig R. Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans. PLoS Genet. 2013;9(6):e1003536.
34. Kitts C, Eckles D, Romano LM. Emerging science: new hope in harlequin ichthyosis. Journal of Obstetric, Gynecologic & Neonatal Nursing. 2010;39:S132-3.
35. Yamanishi K, Inazawa J, Liew FM, Nonomura K, Ariyama T, Yasuno H, Abe T, Doi H, Hirano J, Fukushima S. Structure of the gene for human transglutaminase 1. J BiolChem. 1992;267:17858-17863.
36. Kim CM, Koike K, Saito I, Miyamura T, Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature. 1991;351(6324):317-20.
37. Greenberg CS, Birckbichler PJ, Rice RH. Transglutaminases: multifunctional cross‐linking enzymes that stabilize tissues. The FASEB Journal. 1991;5(15):3071-7.
38. Raghunath M, Hennies HC, Ahvazi B, Vogel M, Reis A, Steinert PM, Traupe H. Self-healing collodion baby: a dynamic phenotype explained by a particular transglutaminase-1 mutation. Journal of investigative dermatology. 2003;120(2):224-8.
39. Farasat S, Wei MH, Herman M, Liewehr DJ, Steinberg SM, Bale SJ, Fleckman P, Toro JR. Novel transglutaminase-1 mutations and genotype–phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA. Journal of medical genetics. 2009;46(2):103-11.
40. Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nature reviews Molecular cell biology. 2005;6(4):328-40.
41. Dale RM, McClure BA, Houchins JP. A rapid single-stranded cloning strategy for producing a sequential series of overlapping clones for use in DNAsequencing: application to sequencing the corn mitochondrial 18S rDNA. Plasmid. 1985;13:31-40.
42. Listwan P, Rothnagel JA . Keratin bundling proteins. Methods Cell Biol. 2004;78:817-827.
43. Joh GY, Traupe H, Metze D, Nashan D, Huber M, Hohl D, Longley MA, Rothnagel JA, Roop DR. A novel dinucleotide mutation in keratin 10 in the annular epidermolytic ichthyosis variant of bullous congenital ichthyosiform erythroderma. Journal of investigative dermatology. 1997;108(3):357-61.
44. Chipev CC, Korge BP, Markova N, Bale SJ, DiGiovanna JJ, Compton JG, Steinert PM. A leucine→ proline mutation in the H1 subdomain of keratin 1 causes epidermolytic hyperkeratosis. Cell. 1992;70(5):821-8.
45. Hotz A, Bourrat E, Küsel J, Oji V, Alter S, Hake L, Korbi M, Ott H, Hausser I, Zimmer AD, Fischer J. Mutation update for CYP4F22 variants associated with autosomal recessive congenital ichthyosis. Human mutation. 2018;39(10):1305-13.
46. Naeem M, Wajid M, Lee K, Leal SM, Ahmad W. A mutation in the hair matrix and cuticle keratin KRTHB5 gene causes ectodermal dysplasia of hair and nail type. Journal of medical genetics. 2006;43(3):274-9.
47. Chen W, Song MS, Napoli JL. SDR-O: an orphan short-chain dehydrogenase/reductase localized at mouse chromosome 10/human chromosome 12. Gene. 2002;294(1-2):141-6.
48. Her C, Wood TC, Eichler EE, Mohrenweiser HW, Ramagli LS, Siciliano MJ, Weinshilboum RM. Human hydroxysteroid sulfotransferase SULT2B1: two enzymes encoded by a single chromosome 19 gene. Genomics. 1998;53(3):284-95.
Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.