Genomics & Informatics

Korea Genome Organization (한국유전체학회)
권호 표지
DOI QR코드

DOI QR Code

The Hairless Gene: A Putative Navigator of Hair Follicle Development

  • Kim, Jeong-Ki (Department of Medical Lifescience, The Catholic University of Korea) ;
  • Kim, Bong-Kyu (Department of Medical Lifescience, The Catholic University of Korea) ;
  • Park, Jong-Keun (Department of Medical Lifescience, The Catholic University of Korea) ;
  • Choi, Jee-Hyun (Department of Medical Lifescience, The Catholic University of Korea) ;
  • KimYoon, Sung-Joo (Department of Medical Lifescience, The Catholic University of Korea)
  • Accepted : 2011.09.01
  • Published : 2011.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

The Hairless (HR ) gene regulates the expression of several target genes as a transcriptional corepressor of nuclear receptors. The hair follicle (HF), a small independent organ of the skin, resides in the epidermis and undergoes regenerative cycling for normal hair formation. HF development requires many genes and signaling pathways to function properly in time and space, one of them being the HR gene. Various mutations of the HR gene have been reported to cause the hair loss pheno-type in rodents and humans. In recent studies, it has been suggested that the HR gene is a critical player in the regulation of the hair cycle and, thus, HF development. Furthermore, the HR gene is associated with the Wnt signaling pathway, which regulates proliferation and differentiation of cells and plays an essential role in hair and skin development. In this review, we summarize the mutations responsible for human hair disorders and discuss the roles of the HR gene in HF development.

Keywords

References

  1. Ahmad, W., Faiyaz ul Haque, M., Brancolini, V., Tsou, H.C., ul Haque, S., Lam, H., Aita, V.M., Owen, J., deBlaquiere, M., Frank, J., Cserhalmi-Friedman, P.B., Leask, A., McGrath, J.A., Peacocke, M., Ahmad, M., Ott, J., and Christiano, A.M. (1998a). Alopecia universalis associated with a mutation in the human Hairless gene. Science 279, 720-724. https://doi.org/10.1126/science.279.5351.720
  2. Ahmad, W., Irvine, A.D., Lam, H., Buckley, C., Bingham, E.A., Panteleyev, A.A., Ahmad, M., McGrath, J.A., and Christiano, A.M. (1998b). A missense mutation in the zinc-finger domain of the human Hairless gene underlies congenital atrichia in a family of Irish travellers. Am. J. Hum. Genet. 63, 984-991. https://doi.org/10.1086/302069
  3. Ahmad, W., Panteleyev, A.A., Sundberg, J.P., and Christiano, A.M. (1998c). Molecular basis for the rhino (hrrh-8J) phenotype: a nonsense mutation in the mouse Hairless gene. Genomics 53, 383-386. https://doi.org/10.1006/geno.1998.5495
  4. Aita, V.M., Ahmad, W., Panteleyev, A.A., Kozlowska, U., Kozlowska, A., Gilliam, T.C., Jablonska, S., and Christiano, A.M. (2000). A novel missense mutation (C622G) in the zinc-finger domain of the human Hairless gene associated with congenital atrichia with papular lesions. Exp. Dermatol. 9, 157-162. https://doi.org/10.1034/j.1600-0625.2000.009002157.x
  5. Alonso, L.C., and Rosenfield, R.L. (2003). Molecular genetic and endocrine mechanisms of hair growth. Horm. Res. 60, 1-13.
  6. Argenziano, G., Sammarco, E., Rossi, A., Delfino, M., and Calvieri, S. (1999). Marie Unna hereditary hypotrichosis. Eur. J. Dermatol. 9, 278-280.
  7. Ashoor, G.G., Greenstein, R.M., Lam, H., Martinez-Mir, A., Zlotogorski, A., and Christiano, A.M. (2005). Novel compound heterozygous nonsense mutations in the Hairless gene causing atrichia with papular lesions. J. Dermatol. Sci. 40, 29-33. https://doi.org/10.1016/j.jdermsci.2005.04.004
  8. Baek, I.C., Kim, J.K., Cho, K.H., Cha, D.S., Cho, J.W., Park, J.K., Song, C.W., and Yoon, S.K. (2009). A novel mutation in Hr causes abnormal hair follicle morphogenesis in hairpoor mouse, an animal model for Marie Unna Hereditary Hypotrichosis. Mamm. Genome. 20, 350-358. https://doi.org/10.1007/s00335-009-9191-8
  9. Balighi, K., Lajevardi, V., Moeineddin, F., Jelani, M., Tamizifar, B., Nikoo, A., Javed, Q., Ahmad, W., and Parvaneh, N. (2009). A novel deletion mutation in the human Hairless (HR) gene in an Iranian family with atrichia and papular lesions. Clin. Exp. Dermatol. 34, e498-500. https://doi.org/10.1111/j.1365-2230.2009.03578.x
  10. Beaudoin, G.M., 3rd, Sisk, J.M., Coulombe, P.A., and Thompson, C.C. (2005). Hairless triggers reactivation of hair growth by promoting Wnt signaling. Proc. Natl. Acad. Sci. U.S.A. 102, 14653-14658. https://doi.org/10.1073/pnas.0507609102
  11. Betz, R.C., Indelman, M., Pforr, J., Schreiner, F., Bauer, R., Bergman, R., Lentze, M.J., Nothen, M.M., Cichon, S., and Sprecher, E. (2007). Identification of mutations in the human Hairless gene in two new families with congenital atrichia. Arch. Dermatol. Res. 299, 157-161. https://doi.org/10.1007/s00403-007-0747-8
  12. Blanpain, C., and Fuchs, E. (2006). Epidermal stem cells of the skin. Annu. Rev. Cell. Dev. Biol. 22, 339-373. https://doi.org/10.1146/annurev.cellbio.22.010305.104357
  13. Burke, L.J., and Baniahmad, A. (2000). Co-repressors 2000. FASEB J. 14, 1876-1888. https://doi.org/10.1096/fj.99-0943rev
  14. Cachon-Gonzalez, M.B., Fenner, S., Coffin, J.M., Moran, C., Best, S., and Stoye, J.P. (1994). Structure and expression of the Hairless gene of mice. Proc. Natl. Acad. Sci. U.S.A. 91, 7717-7721. https://doi.org/10.1073/pnas.91.16.7717
  15. Cachon-Gonzalez, M.B., San-Jose, I., Cano, A., Vega, J.A., Garcia, N., Freeman, T., Schimmang, T., and Stoye, J.P. (1999). The Hairless gene of the mouse: relationship of phenotypic effects with expression profile and genotype. Dev. Dyn. 216, 113-126. https://doi.org/10.1002/(SICI)1097-0177(199910)216:2<113::AID-DVDY3>3.0.CO;2-M
  16. Chen, J.D., and Evans, R.M. (1995). A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377, 454-457. https://doi.org/10.1038/377454a0
  17. Cichon, S., Anker, M., Vogt, I.R., Rohleder, H., Putzstuck, M., Hillmer, A., Farooq, S.A., Al-Dhafri, K.S., Ahmad, M., Haque, S., Rietschel, M., Propping, P., Kruse, R., and Nothen, M.M. (1998). Cloning, genomic organization, alternative transcripts and mutational analysis of the gene responsible for autosomal recessive universal congenital alopecia. Hum. Mol. Genet. 7, 1671-1679. https://doi.org/10.1093/hmg/7.11.1671
  18. Cichon, S., Kruse, R., Hillmer, A.M., Kukuk, G., Anker, M., Altland, K., Knapp, M., Propping, P., and Nothen, M.M. (2000). A distinct gene close to the Hairless locus on chromosome 8p underlies hereditary Marie Unna type hypotrichosis in a German family. Br. J. Dermatol. 143, 811-814. https://doi.org/10.1046/j.1365-2133.2000.03781.x
  19. Coulombe, P.A., and Omary, M.B. (2002). 'Hard' and 'soft' principles defining the structure, function and regulation of keratin intermediate filaments. Curr. Opin. Cell Biol. 14, 110-122. https://doi.org/10.1016/S0955-0674(01)00301-5
  20. DasGupta, R., and Fuchs, E. (1999). Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 126, 4557-4568.
  21. Djabali, K., Aita, V.M., and Christiano, A.M. (2001). Hairless is translocated to the nucleus via a novel bipartite nuclear localization signal and is associated with the nuclear matrix. J. Cell. Sci. 114, 367-376.
  22. Downes, M., Ordentlich, P., Kao, H.Y., Alvarez, J.G., and Evans, R.M. (2000). Identification of a nuclear domain with deacetylase activity. Proc. Natl. Acad. Sci. U.S.A. 97, 10330-10335. https://doi.org/10.1073/pnas.97.19.10330
  23. Giguere, V. (1999). Orphan nuclear receptors: from gene to function. Endocr. Rev. 20, 689-725. https://doi.org/10.1210/er.20.5.689
  24. Glass, C.K., and Rosenfeld, M.G. (2000). The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 14, 121-141.
  25. He, P.P., Zhang, X.J., Yang, Q., Li, M., Liang, Y.H., Yang, S., Yan, K.L., Cui, Y., Shen, Y.Y., Wang, H.Y., Sun, L.D., Du, W.H., Shen, Y.J., Xu, S.J., and Huang, W. (2004). Refinement of a locus for Marie Unna hereditary hypotrichosis to a 1.1-cM interval at 8p21.3. Br. J. Dermatol. 150, 837-842. https://doi.org/10.1111/j.1365-2133.2004.05913.x
  26. Henn, W., Zlotogorski, A., Lam, H., Martinez-Mir, A., Zaun, H., and Christiano, A.M. (2002). Atrichia with papular lesions resulting from compound heterozygous mutations in the Hairless gene: A lesson for differential diagnosis of alopecia universalis. J. Am. Acad. Dermatol. 47, 519-523. https://doi.org/10.1067/mjd.2002.124609
  27. Hirst, M.A., Hochman, H.I., and Feldman, D. (1985). Vitamin D resistance and alopecia: a kindred with normal 1,25-dihydroxyvitamin D binding, but decreased receptor affinity for deoxyribonucleic acid. J. Clin. Endocrinol. Metab. 60, 490-495. https://doi.org/10.1210/jcem-60-3-490
  28. Horlein, A.J., Naar, A.M., Heinzel, T., Torchia, J., Gloss, B., Kurokawa, R., Ryan, A., Kamei, Y., Soderstrom, M., Glass, C.K., and Rosenfeld, M.G. (1995). Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377, 397-404. https://doi.org/10.1038/377397a0
  29. Hsieh, J.C., Sisk, J.M., Jurutka, P.W., Haussler, C.A., Slater, S.A., Haussler, M.R., and Thompson, C.C. (2003). Physical and functional interaction between the vitamin D receptor and Hairless corepressor, two proteins required for hair cycling. J. Biol. Chem. 278, 38665-38674. https://doi.org/10.1074/jbc.M304886200
  30. Huelsken, J., and Birchmeier, W. (2001). New aspects of Wnt signaling pathways in higher vertebrates. Curr. Opin. Genet. Dev. 11, 547-553. https://doi.org/10.1016/S0959-437X(00)00231-8
  31. Huelsken, J., Vogel, R., Erdmann, B., Cotsarelis, G., and Birchmeier, W. (2001). beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105, 533-545. https://doi.org/10.1016/S0092-8674(01)00336-1
  32. Hughes, M.R., Malloy, P.J., Kieback, D.G., Kesterson, R.A., Pike, J.W., Feldman, D., and O'Malley, B.W. (1988). Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science 242, 1702-1705. https://doi.org/10.1126/science.2849209
  33. Indelman, M., Bergman, R., Lestringant, G.G., Peer, G., and Sprecher, E. (2003). Compound heterozygosity for mutations in the Hairless gene causes atrichia with papular lesions. Br. J. Dermatol. 148, 553-557. https://doi.org/10.1046/j.1365-2133.2003.05177.x
  34. Jepsen, K., and Rosenfeld, M.G. (2002). Biological roles and mechanistic actions of co-repressor complexes. J. Cell. Sci. 115, 689-698.
  35. John, P., Aslam, M., Rafiq, M.A., Amin-ud-din, M., Haque, S., and Ahmad, W. (2005). Atrichia with papular lesions in two Pakistani consanguineous families resulting from mutations in the human Hairless gene. Arch. Dermatol. Res. 297, 226-230. https://doi.org/10.1007/s00403-005-0593-5
  36. Kawano, Y., and Kypta, R. (2003). Secreted antagonists of the Wnt signalling pathway. J. Cell. Sci. 116, 2627-2634. https://doi.org/10.1242/jcs.00623
  37. Kim, H., Wajid, M., Kraemer, L., Shimomura, Y., and Christiano, A.M. (2007). Nonsense mutations in the Hairless gene underlie APL in five families of Pakistani origin. J. Dermatol. Sci. 48, 207-211. https://doi.org/10.1016/j.jdermsci.2007.07.007
  38. Kim, J.K., Kim, E., Baek, I.C., Kim, B.K., Cho, A.R., Kim, T.Y., Song, C.W., Seong, J.K., Yoon, J.B., Stenn, K.S., Parimoo, S., and Yoon, S.K. (2010). Overexpression of Hr links excessive induction of Wnt signaling to Marie Unna hereditary hypotrichosis. Hum. Mol. Genet. 19, 445-453. https://doi.org/10.1093/hmg/ddp509
  39. Klein, I., Bergman, R., Indelman, M., and Sprecher, E. (2002). A novel missense mutation affecting the human Hairless thyroid receptor interacting domain 2 causes congenital atrichia. J. Invest. Dermatol. 119, 920-922. https://doi.org/10.1046/j.1523-1747.2002.00268.x
  40. Kruse, R., Cichon, S., Anker, M., Hillmer, A.M., Barros-Nunez, P., Cantu, J.M., Leal, E., Weinlich, G., Schmuth, M., Fritsch, P., Ruzicka, T., Propping, P., and Nothen, M.M. (1999). Novel Hairless mutations in two kindreds with autosomal recessive papular atrichia. J. Invest. Dermatol. 113, 954-959. https://doi.org/10.1046/j.1523-1747.1999.00790.x
  41. Langbein, L., Rogers, M.A., Praetzel, S., Winter, H., and Schweizer, J. (2003). K6irs1, K6irs2, K6irs3, and K6irs4 represent the inner-root-sheath-specific type II epithelial keratins of the human hair follicle. J. Invest. Dermatol. 120, 512-522. https://doi.org/10.1046/j.1523-1747.2003.12087.x
  42. Langbein, L., Rogers, M.A., Winter, H., Praetzel, S., and Schweizer, J. (2001). The catalog of human hair keratins. II. Expression of the six type II members in the hair follicle and the combined catalog of human type I and II keratins. J. Biol. Chem. 276, 35123-35132. https://doi.org/10.1074/jbc.M103305200
  43. Langbein, L., and Schweizer, J. (2005). Keratins of the human hair follicle. Int. Rev. Cytol. 243, 1-78. https://doi.org/10.1016/S0074-7696(05)43001-6
  44. Lefevre, P., Rochat, A., Bodemer, C., Vabres, P., Barrandon, Y., de Prost, Y., Garner, C., and Hovnanian, A. (2000). Linkage of Marie-Unna hypotrichosis locus to chromosome 8p21 and exclusion of 10 genes including the Hairless gene by mutation analysis. Eur. J. Hum. Genet. 8, 273-279. https://doi.org/10.1038/sj.ejhg.5200417
  45. Li, M., Indra, A.K., Warot, X., Brocard, J., Messaddeq, N., Kato, S., Metzger, D., and Chambon, P. (2000). Skin abnormalities generated by temporally controlled RXRalpha mutations in mouse epidermis. Nature 407, 633-636. https://doi.org/10.1038/35036595
  46. Li, Y.C., Pirro, A.E., Amling, M., Delling, G., Baron, R., Bronson, R., and Demay, M.B. (1997). Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc. Natl. Acad. Sci. U.S.A. 94, 9831-9835. https://doi.org/10.1073/pnas.94.18.9831
  47. Lo Celso, C., Prowse, D.M., and Watt, F.M. (2004). Transient activation of beta-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours. Development 131, 1787-1799. https://doi.org/10.1242/dev.01052
  48. Ludwig, E. (1953). Hypotrichosis congenital hereditaria type M. Unna. Arch. Dermatol. Syph. 196, 261-278. https://doi.org/10.1007/BF00362052
  49. Ma, L., Liu, J., Wu, T., Plikus, M., Jiang, T.X., Bi, Q., Liu, Y.H., Muller-Rover, S., Peters, H., Sundberg, J.P., Maxson, R., Maas, R.L., and Chuong, C.M. (2003). 'Cyclic alopecia' in Msx2 mutants: defects in hair cycling and hair shaft differentiation. Development 130, 379-389. https://doi.org/10.1242/dev.00201
  50. Malloy, P.J., Pike, J.W., and Feldman, D. (1999). The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets. Endocr. Rev. 20, 156-188. https://doi.org/10.1210/er.20.2.156
  51. Mangelsdorf, D.J., and Evans, R.M. (1995). The RXR heterodimers and orphan receptors. Cell 83, 841-850. https://doi.org/10.1016/0092-8674(95)90200-7
  52. Merrill, B.J., Gat, U., DasGupta, R., and Fuchs, E. (2001). Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin. Genes Dev. 15, 1688-1705. https://doi.org/10.1101/gad.891401
  53. Michailidis, E., Theos, A., Zlotogorski, A., Martinez-Mir, A., and Christiano, A.M. (2007). Atrichia with papular lesions resulting from novel compound heterozygous mutations in the human Hairless gene. Pediatr. Dermatol. 24, E79-82. https://doi.org/10.1111/j.1525-1470.2007.00448.x
  54. Millar, S.E. (2002). Molecular mechanisms regulating hair follicle development. J. Invest. Dermatol. 118, 216-225. https://doi.org/10.1046/j.0022-202x.2001.01670.x
  55. Miller, J., Djabali, K., Chen, T., Liu, Y., Ioffreda, M., Lyle, S., Christiano, A.M., Holick, M., and Cotsarelis, G. (2001). Atrichia caused by mutations in the vitamin D receptor gene is a phenocopy of generalized atrichia caused by mutations in the Hairless gene. J. Invest. Dermatol. 117, 612-617. https://doi.org/10.1046/j.0022-202x.2001.01438.x
  56. Moll, R., Divo, M., and Langbein, L. (2008). The human keratins: biology and pathology. Histochem. Cell Biol. 129, 705-733. https://doi.org/10.1007/s00418-008-0435-6
  57. Moraitis, A.N., and Giguere, V. (2003). The co-repressor Hairless protects RORalpha orphan nuclear receptor from proteasome-mediated degradation. J. Biol. Chem. 278, 52511-52518. https://doi.org/10.1074/jbc.M308152200
  58. Moraitis, A.N., Giguere, V., and Thompson, C.C. (2002). Novel mechanism of nuclear receptor corepressor interaction dictated by activation function 2 helix determinants. Mol. Cell. Biol. 22, 6831-6841. https://doi.org/10.1128/MCB.22.19.6831-6841.2002
  59. Nam, Y., Kim, J.K., Cha, D.S., Cho, J.W., Cho, K.H., Yoon, S., Yoon, J.B., Oh, Y.S., Suh, J.G., Han, S.S., Song, C.W., and Yoon, S.K. (2006). A novel missense mutation in the mouse Hairless gene causes irreversible hair loss: genetic and molecular analyses of Hr m1Enu. Genomics 87, 520-526. https://doi.org/10.1016/j.ygeno.2005.12.005
  60. Panteleyev, A.A., Ahmad, W., Malashenko, A.M., Ignatieva, E.L., Paus, R., Sundberg, J.P., and Christiano, A.M. (1998). Molecular basis for the rhino Yurlovo (hr(rhY)) phenotype: severe skin abnormalities and female reproductive defects associated with an insertion in the Hairless gene. Exp. Dermatol. 7, 281-288.
  61. Panteleyev, A.A., Botchkareva, N.V., Sundberg, J.P., Christiano, A.M., and Paus, R. (1999). The role of the Hairless (hr) gene in the regulation of hair follicle catagen transformation. Am. J. Pathol. 155, 159-171. https://doi.org/10.1016/S0002-9440(10)65110-3
  62. Paradisi, M., Chuang, G.S., Angelo, C., Pedicelli, C., Martinez-Mir, A., and Christiano, A.M. (2003). Atrichia with papular lesions resulting from a novel homozygous missense mutation in the Hairless gene. Clin. Exp. Dermatol. 28, 535-538. https://doi.org/10.1046/j.1365-2230.2003.01333.x
  63. Paus, R., and Foitzik, K. (2004). In search of the "hair cycle clock": a guided tour. Differentiation 72, 489-511. https://doi.org/10.1111/j.1432-0436.2004.07209004.x
  64. Pazin, M.J., and Kadonaga, J.T. (1997). What's up and down with histone deacetylation and transcription? Cell 89, 325-328. https://doi.org/10.1016/S0092-8674(00)80211-1
  65. Potter, G.B., Beaudoin, G.M., 3rd, DeRenzo, C.L., Zarach, J.M., Chen, S.H., and Thompson, C.C. (2001). The Hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor. Genes Dev. 15, 2687-2701. https://doi.org/10.1101/gad.916701
  66. Potter, G.B., Zarach, J.M., Sisk, J.M., and Thompson, C.C. (2002). The thyroid hormone-regulated corepressor Hairless associates with histone deacetylases in neonatal rat brain. Mol. Endocrinol. 16, 2547-2560. https://doi.org/10.1210/me.2002-0115
  67. Privalsky, M.L. (2004). The role of corepressors in transcriptional regulation by nuclear hormone receptors. Annu. Rev. Physiol. 66, 315-360. https://doi.org/10.1146/annurev.physiol.66.032802.155556
  68. Runkel, F., Klaften, M., Koch, K., Bohnert, V., Bussow, H., Fuchs, H., Franz, T., and Hrabe de Angelis, M. (2006). Morphologic and molecular characterization of two novel Krt71 (Krt2-6g) mutations: Krt71rco12 and Krt71rco13. Mamm. Genome 17, 1172-1182. https://doi.org/10.1007/s00335-006-0084-9
  69. Rut, A.R., Hewison, M., Kristjansson, K., Luisi, B., Hughes, M.R., and O'Riordan, J.L. (1994). Two mutations causing vitamin D resistant rickets: modelling on the basis of steroid hormone receptor DNA-binding domain crystal structures. Clin. Endocrinol. (Oxf). 41, 581-590. https://doi.org/10.1111/j.1365-2265.1994.tb01822.x
  70. Sande, S., and Privalsky, M.L. (1996). Identification of TRACs (T3 receptor-associating cofactors), a family of cofactors that associate with, and modulate the activity of, nuclear hormone receptors. Mol. Endocrinol. 10, 813-825. https://doi.org/10.1210/me.10.7.813
  71. Schlake, T., Schorpp, M., Maul-Pavicic, A., Malashenko, A.M., and Boehm, T. (2000). Forkhead/winged-helix transcription factor Whn regulates hair keratin gene expression: molecular analysis of the nude skin phenotype. Dev. Dyn. 217, 368-376. https://doi.org/10.1002/(SICI)1097-0177(200004)217:4<368::AID-DVDY4>3.0.CO;2-Z
  72. Shimomura, Y., and Christiano, A.M. (2010). Biology and genetics of hair. Annu. Rev. Genomics Hum. Genet. 11, 109-132. https://doi.org/10.1146/annurev-genom-021610-131501
  73. Smith, C.L., and O'Malley, B.W. (2004). Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr. Rev. 25, 45-71. https://doi.org/10.1210/er.2003-0023
  74. Sprecher, E., Bergman, R., Szargel, R., Friedman-Birnbaum, R., and Cohen, N. (1999). Identification of a genetic defect in the Hairless gene in atrichia with papular lesions: evidence for phenotypic heterogeneity among inherited atrichias. Am. J. Hum. Genet. 64, 1323-1329. https://doi.org/10.1086/302368
  75. Sreekumar, G.P., Roberts, J.L., Wong, C.Q., Stenn, K.S., and Parimoo, S. (2000). Marie Unna hereditary hypotrichosis gene maps to human chromosome 8p21 near Hairless. J. Invest. Dermatol. 114, 595-597. https://doi.org/10.1046/j.1523-1747.2000.02001.x
  76. Stenn, K.S., and Paus, R. (2001). Controls of hair follicle cycling. Physiol. Rev. 81, 449-494.
  77. Stoye, J.P., Fenner, S., Greenoak, G.E., Moran, C., and Coffin, J.M. (1988). Role of endogenous retroviruses as mutagens: the Hairless mutation of mice. Cell 54, 383-391. https://doi.org/10.1016/0092-8674(88)90201-2
  78. Sundberg, J.P. (1994). Handbook of mouse mutations with skin and hair abnormalities: animal models and biomedical tools (Boca Raton: CRC Press).
  79. Tanaka, S., Miura, I., Yoshiki, A., Kato, Y., Yokoyama, H., Shinogi, A., Masuya, H., Wakana, S., Tamura, M., and Shiroishi, T. (2007). Mutations in the helix termination motif of mouse type I IRS keratin genes impair the assembly of keratin intermediate filament. Genomics 90, 703-711. https://doi.org/10.1016/j.ygeno.2007.07.013
  80. Thompson, C.C. (1996). Thyroid hormone-responsive genes in developing cerebellum include a novel synaptotagmin and a Hairless homolog. J. Neurosci. 16, 7832-7840.
  81. Thompson, C.C. (2009). Hairless is a nuclear receptor corepressor essential for skin function. Nucl. Recept. Signal. 7, 1-11.
  82. Thompson, C.C., and Bottcher, M.C. (1997). The product of a thyroid hormone-responsive gene interacts with thyroid hormone receptors. Proc. Natl. Acad. Sci. U.S.A. 94, 8527-8532. https://doi.org/10.1073/pnas.94.16.8527
  83. Thompson, C.C., Sisk, J.M., and Beaudoin, G.M., 3rd.(2006). Hairless and Wnt signaling: allies in epithelial stem cell differentiation. Cell Cycle 5, 1913-1917. https://doi.org/10.4161/cc.5.17.3189
  84. Tkatchenko, A.V., Visconti, R.P., Shang, L., Papenbrock, T., Pruett, N.D., Ito, T., Ogawa, M., and Awgulewitsch, A. (2001). Overexpression of Hoxc13 in differentiating keratinocytes results in downregulation of a novel hair keratin gene cluster and alopecia. Development 128, 1547-1558.
  85. Unna, M. (1925). Ueber Hypotrichosis congenita hereditaria. Dermatol. Wochenschr. 81, 1167-1178.
  86. van Steensel, M., Smith, F.J., Steijlen, P.M., Kluijt, I., Stevens, H.P., Messenger, A., Kremer, H., Dunnill, M.G., Kennedy, C., Munro, C.S., Doherty, V.R., McGrath, J.A., Covello, S.P., Coleman, C.M., Uitto, J., and McLean, W.H. (1999). The gene for hypotrichosis of Marie Unna maps between D8S258 and D8S298: exclusion of the hr gene by cDNA and genomic sequencing. Am. J. Hum. Genet. 65, 413-419. https://doi.org/10.1086/302506
  87. Wali, A., Ansar, M., Khan, M.N., and Ahmad, W. (2006). Atrichia with papular lesions resulting from a novel insertion mutation in the human Hairless gene. Clin. Exp. Dermatol. 31, 695-698. https://doi.org/10.1111/j.1365-2230.2006.02165.x
  88. Wen, Y., Liu, Y., Xu, Y., Zhao, Y., Hua, R., Wang, K., Sun, M., Li, Y., Yang, S., Zhang, X.J., Kruse, R., Cichon, S., Betz, R.C., Nothen, M.M., van Steensel, M.A., van Geel, M., Steijlen, P.M., Hohl, D., Huber, M., Dunnill, G.S., Kennedy, C., Messenger, A., Munro, C.S., Terrinoni, A., Hovnanian, A., Bodemer, C., de Prost, Y., Paller, A.S., Irvine, A.D., Sinclair, R., Green, J., Shang, D., Liu, Q., Luo, Y., Jiang, L., Chen, H.D., Lo, W.H., McLean, W.H., He, C.D., and Zhang, X. (2009). Loss-of-function mutations of an inhibitory upstream ORF in the human Hairless transcript cause Marie Unna hereditary hypotrichosis. Nat. Genet. 41, 228-233. https://doi.org/10.1038/ng.276
  89. Xie, Z., Chang, S., Oda, Y., and Bikle, D.D. (2006). Hairless suppresses vitamin D receptor transactivation in human keratinocytes. Endocrinology 147, 314-323. https://doi.org/10.1016/j.ygcen.2006.02.001
  90. Yan, K.L., He, P.P., Yang, S., Li, M., Yang, Q., Ren, Y.Q., Cui, Y., Gao, M., Xiao, F.L., Huang, W., and Zhang, X.J. (2004). Marie Unna hereditary hypotrichosis: report of a Chinese family and evidence for genetic heterogeneity. Clin. Exp. Dermatol. 29, 460-463. https://doi.org/10.1111/j.1365-2230.2004.01570.x
  91. Yoshizawa, T., Handa, Y., Uematsu, Y., Takeda, S., Sekine, K., Yoshihara, Y., Kawakami, T., Arioka, K., Sato, H., Uchiyama, Y., Masushige, S., Fukamizu, A., Matsumoto, T., and Kato, S. (1997). Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat. Genet. 16, 391-396. https://doi.org/10.1038/ng0897-391
  92. Zarach, J.M., Beaudoin, G.M., 3rd, Coulombe, P.A., and Thompson, C.C. (2004). The co-repressor Hairless has a role in epithelial cell differentiation in the skin. Development 131, 4189-4200. https://doi.org/10.1242/dev.01303
  93. Zlotogorski, A., Martinez-Mir, A., Green, J., Lamdagger, H., Panteleyevdagger, A.A., Sinclair, R., and Christiano, A.M. (2002a). Evidence for pseudodominant inheritance of atrichia with papular lesions. J. Invest. Dermatol. 118, 881-886. https://doi.org/10.1046/j.1523-1747.2002.01740.x
  94. Zlotogorski, A., Panteleyev, A.A., Aita, V.M., and Christiano, A.M. (2002b). Clinical and molecular diagnostic criteria of congenital atrichia with papular lesions. J. Invest. Dermatol. 118, 887-890. https://doi.org/10.1046/j.1523-1747.2001.01767.x