Mutations in Cause Autosomal Recessive Congenital Ichthyosis in Humans

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Autosomal recessive congenital ichthyosis (ARCI) is a rare genetic disorder of the skin characterized by abnormal desquamation over the whole body. In this study we report four patients from three consanguineous Tunisian families with skin, eye, heart, and skeletal anomalies, who harbor a homozygous contiguous gene deletion syndrome on chromosome 15q26.3. Genome-wide SNP-genotyping revealed a homozygous region in all affected individuals, including the same microdeletion that partially affects two coding genes (ADAMTS17, CERS3) and abolishes a sequence for a long non-coding RNA (FLJ42289). Whereas mutations in ADAMTS17 have recently been identified in autosomal recessive Weill-Marchesani-like syndrome in humans and dogs presenting with ophthalmologic, cardiac, and skeletal abnormalities, no disease associations have been described for CERS3 (ceramide synthase 3) and FLJ42289 so far. However, analysis of additional patients with non-syndromic ARCI revealed a splice site mutation in CERS3 indicating that a defect in ceramide synthesis is causative for the present skin phenotype of our patients. Functional analysis of patient skin and in vitro differentiated keratinocytes demonstrated that mutations in CERS3 lead to a disturbed sphingolipid profile with reduced levels of epidermis-specific very long-chain ceramides that interferes with epidermal differentiation. Taken together, these data present a novel pathway involved in ARCI development and, moreover, provide the first evidence that CERS3 plays an essential role in human sphingolipid metabolism for the maintenance of epidermal lipid homeostasis.

Vyšlo v časopise: Mutations in Cause Autosomal Recessive Congenital Ichthyosis in Humans. PLoS Genet 9(6): e32767. doi:10.1371/journal.pgen.1003536
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003536

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1. LefévreC, AudebertS, JobardF, BouadjarB, LakhdarH, et al. (2003) Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2. Hum Mol Genet 12: 2369–2378.

2. JobardF, LefèvreC, KaradumanA, Blanchet-BardonC, EmreS, et al. (2002) Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1. Hum Mol Genet 11: 107–113.

3. LefèvreC, BouadjarB, FerrandV, TadiniG, MégarbanéA, et al. (2006) Mutations in a new cytochrome P450 gene in lamellar ichthyosis type 3. Hum Mol Genet 15: 767–776.

4. LefèvreC, BouadjarB, KaradumanA, JobardF, SakerS, et al. (2004) Mutations in ichthyin a new gene on chromosome 5q33 in a new form of autosomal recessive congenital ichthyosis. Hum Mol Genet 13: 2473–2482.

5. GrallA, GuaguèreE, PlanchaisS, GrondS, BourratE, et al. (2012) PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans. Nat Genet 44: 140–147 doi:10.1038/ng.1056

6. HuberM, RettlerI, BernasconiK, FrenkE, LavrijsenSP, et al. (1995) Mutations of keratinocyte transglutaminase in lamellar ichthyosis. Science 267: 525–528.

7. FischerJ (2009) Autosomal recessive congenital ichthyosis. J Invest Dermatol 129: 1319–1321 doi:10.1038/jid.2009.57

8. MoralesJ, Al-SharifL, KhalilDS, Shinwari JMa, BaviP, et al. (2009) Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Am J Hum Genet 85: 558–568 doi:10.1016/j.ajhg.2009.09.011

9. FariasFHG, JohnsonGS, TaylorJF, GiulianoE, KatzML, et al. (2010) An ADAMTS17 splice donor site mutation in dogs with primary lens luxation. Invest Ophthalmol Vis Sci 51: 4716–4721.

10. SchwarzJM, RödelspergerC, SchuelkeM, SeelowD (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7: 575–576 doi:10.1038/nmeth0810-575

11. MizutaniY, KiharaA, IgarashiY (2006) LASS3 (longevity assurance homologue 3) is a mainly testis-specific (dihydro)ceramide synthase with relatively broad substrate specificity. Biochem J 398: 531–538.

12. JennemannR, RabionetM, GorgasK, EpsteinS, DalpkeA, et al. (2012) Loss of ceramide synthase 3 causes lethal skin barrier disruption. Hum Mol Genet 21: 586–608 doi:10.1093/hmg/ddr494

13. VielhaberG, PfeifferS, BradeL, LindnerB, GoldmannT, et al. (2001) Localization of ceramide and glucosylceramide in human epidermis by immunogold electron microscopy. J Invest Dermatol 117: 1126–1136 doi:10.1046/j.0022-202x.2001.01527.x

14. NagyE, MaquatLE (1998) A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem Sci 23: 198–199.

15. GillinghamAK, MunroS (2003) Long coiled-coil proteins and membrane traffic. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1641: 71–85 doi:10.1016/S0167-4889(03)00088-0

16. MasonJM, ArndtKM (2004) Coiled coil domains: stability, specificity, and biological implications. Chembiochem 5: 170–176 doi:10.1002/cbic.200300781

17. HarburyPH, KimPS, AlberT (1994) Crystal structure of an isoleucine-zipper trimer. Nature 371: 80–83.

18. MahrenholzCC, AbfalterIG, BodenhoferU, VolkmerR, HochreiterS (2011) Complex networks govern coiled-coil oligomerization–predicting and profiling by means of a machine learning approach. Mol Cell Proteomics 10: M110.004994 doi:10.1074/mcp.M110.004994

19. VenkataramanK, RiebelingC, BodennecJ, RiezmanH, AllegoodJC, et al. (2002) Upstream of growth and differentiation factor 1 (uog1), a mammalian homolog of the yeast longevity assurance gene 1 (LAG1), regulates N-stearoyl-sphinganine (C18-(dihydro)ceramide) synthesis in a fumonisin B1-independent manner in mammalian cells. J Biol Chem 277: 35642–35649.

20. GuillasI, JiangJC, VionnetC, RoubatyC, UldryD, et al. (2003) Human homologues of LAG1 reconstitute Acyl-CoA-dependent ceramide synthesis in yeast. J Biol Chem 278: 37083–37091.

21. RiebelingC, AllegoodJC, WangE, MerrillAH, FutermanAH (2003) Two mammalian longevity assurance gene (LAG1) family members, trh1 and trh4, regulate dihydroceramide synthesis using different fatty acyl-CoA donors. J Biol Chem 278: 43452–43459.

22. LevyM, FutermanAH (2010) Mammalian ceramide synthases. IUBMB Life 62: 347–356 doi:10.1002/iub.319

23. StibanJ, TidharR, FutermanAH (2010) Ceramide synthases: roles in cell physiology and signaling. Adv Exp Med Biol 688: 60–71.

24. MizutaniY, KiharaA, IgarashiY (2005) Mammalian Lass6 and its related family members regulate synthesis of specific ceramides. Biochem J 390: 263–271.

25. LaviadEL, AlbeeL, Pankova-KholmyanskyI, EpsteinS, ParkH, et al. (2008) Characterization of ceramide synthase 2: tissue distribution, substrate specificity, and inhibition by sphingosine 1-phosphate. J Biol Chem 283: 5677–5684.

26. LahiriS, FutermanAH (2005) LASS5 is a bona fide dihydroceramide synthase that selectively utilizes palmitoyl-CoA as acyl donor. J Biol Chem 280: 33735–33738.

27. RabionetM, Van der SpoelAC, ChuangC-C, Von Tümpling-RadostaB, LitjensM, et al. (2008) Male germ cells require polyenoic sphingolipids with complex glycosylation for completion of meiosis: a link to ceramide synthase-3. J Biol Chem 283: 13357–13369.

28. MizutaniY, KiharaA, ChibaH, TojoH, IgarashiY (2008) 2-Hydroxy-ceramide synthesis by ceramide synthase family: enzymatic basis for the preference of FA chain length. J Lipid Res 49: 2356–2364 doi:10.1194/jlr.M800158-JLR200

29. MizutaniY, MitsutakeS, TsujiK, KiharaA, IgarashiY (2009) Ceramide biosynthesis in keratinocyte and its role in skin function. Biochimie 91: 784–790 doi:10.1016/j.biochi.2009.04.001

30. FeingoldKR (2007) Thematic review series: skin lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis. J Lipid Res 48: 2531–2546.

31. UchidaY, HolleranWM (2008) Omega-O-acylceramide, a lipid essential for mammalian survival. J Dermatol Sci 51: 77–87 doi:10.1016/j.jdermsci.2008.01.002

32. AldahmeshMA, MohamedJY, AlkurayaHS, VermaIC, PuriRD, et al. (2011) Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia. Am J Hum Genet 89: 745–750.

33. VasireddyV, UchidaY, SalemN, KimSY, MandalMNA, et al. (2007) Loss of functional ELOVL4 depletes very long-chain fatty acids (> or = C28) and the unique omega-O-acylceramides in skin leading to neonatal death. Hum Mol Genet 16: 471–482.

34. McMahonA, Butovich Ia, MataNL, KleinM, RitterR, et al. (2007) Retinal pathology and skin barrier defect in mice carrying a Stargardt disease-3 mutation in elongase of very long chain fatty acids-4. Mol Vis 13: 258–272.

35. UchidaY, ChoY, MoradianS, KimJ, NakajimaK, et al. (2010) Neutral lipid storage leads to acylceramide deficiency, likely contributing to the pathogenesis of Dorfman-Chanarin syndrome. J Invest Dermatol 130: 2497–2499 doi:10.1038/jid.2010.145

36. RadnerFPW, StreithIE, SchoiswohlG, SchweigerM, KumariM, et al. (2010) Growth retardation, impaired triacylglycerol catabolism, hepatic steatosis, and lethal skin barrier defect in mice lacking comparative gene identification-58 (CGI-58). J Biol Chem 285: 7300–7311 doi:10.1074/jbc.M109.081877

37. JennemannR, KadenS, SandhoffR, NordströmV, WangS, et al. (2012) Glycosphingolipids are essential for intestinal endocytic function. J Biol Chem 287: 32598–32616.

38. FuruseM, HataM, FuruseK, YoshidaY, HaratakeA, et al. (2002) Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice. J Cell Biol 156: 1099–1111 doi:10.1083/jcb.200110122

39. SchemppW, MeerB (1983) Cytologic evidence for three human X-chromosomal segments escaping inactivation. Hum Genet 63: 171–174.

40. SchemppW, BinkeleA, ArnemannJ, GläserB, MaK, et al. (1995) Comparative mapping of YRRM- and TSPY-related cosmids in man and hominoid apes. Chromosome Res 3: 227–234.

41. RiedT, BaldiniA, RandTC, WardDC (1992) Simultaneous visualization of seven different DNA probes by in situ hybridization using combinatorial fluorescence and digital imaging microscopy. Proc Natl Acad Sci U S A 89: 1388–1392.

42. BreidenB, GallalaH, DoeringT, SandhoffK (2007) Optimization of submerged keratinocyte cultures for the synthesis of barrier ceramides. Eur J Cell Biol 86: 657–673 doi:10.1016/j.ejcb.2007.02.006

43. WertzPW, MiethkeMC, LongSA, StraussJS, DowningDT (1985) The composition of the ceramides from human stratum corneum and from comedones. J Invest Dermatol 84: 410–412.