Abstract
A spontaneous mouse hair mutation was identified in a C3H/HeN colony. The mode of inheritance of the mutation was semidominant, with incomplete penetrance when heterozygous. The trait is controlled by a single locus hague (Hag), which was mapped to the telomeric region of chromosome 15. This mutation was shown to be unstable, since its transmission could be switched from semidominant to recessive. To identify the causative gene and the nature of the mutation, hague was introduced into a high-resolution and high-density molecular genetic map. Over 2000 meioses were analyzed and the mutation was mapped to the keratin 2 complex genes. A YAC and BAC physical map of the critical region was then constructed and the gene involved was located in a 600- to 800-kb-long segment. Fourteen genes were mapped to this region; of these, 11 were expressed in the skin (5 epidermic cytokeratin and 6 hard keratin genes), but none were mutated in hague mice.
Full Text
The Full Text of this article is available as a PDF (384.4 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Argeson A. C., Nelson K. K., Siracusa L. D. Molecular basis of the pleiotropic phenotype of mice carrying the hypervariable yellow (Ahvy) mutation at the agouti locus. Genetics. 1996 Feb;142(2):557–567. doi: 10.1093/genetics/142.2.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cachon-Gonzalez M. B., Fenner S., Coffin J. M., Moran C., Best S., Stoye J. P. Structure and expression of the hairless gene of mice. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7717–7721. doi: 10.1073/pnas.91.16.7717. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Carle G. F., Olson M. V. Orthogonal-field-alternation gel electrophoresis. Methods Enzymol. 1987;155:468–482. doi: 10.1016/0076-6879(87)55031-5. [DOI] [PubMed] [Google Scholar]
- Cotsarelis G., Sun T. T., Lavker R. M. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell. 1990 Jun 29;61(7):1329–1337. doi: 10.1016/0092-8674(90)90696-c. [DOI] [PubMed] [Google Scholar]
- Dietrich W. F., Miller J., Steen R., Merchant M. A., Damron-Boles D., Husain Z., Dredge R., Daly M. J., Ingalls K. A., O'Connor T. J. A comprehensive genetic map of the mouse genome. Nature. 1996 Mar 14;380(6570):149–152. doi: 10.1038/380149a0. [DOI] [PubMed] [Google Scholar]
- Duhl D. M., Vrieling H., Miller K. A., Wolff G. L., Barsh G. S. Neomorphic agouti mutations in obese yellow mice. Nat Genet. 1994 Sep;8(1):59–65. doi: 10.1038/ng0994-59. [DOI] [PubMed] [Google Scholar]
- Fuchs E. Keratins and the skin. Annu Rev Cell Dev Biol. 1995;11:123–153. doi: 10.1146/annurev.cb.11.110195.001011. [DOI] [PubMed] [Google Scholar]
- Haldi M. L., Strickland C., Lim P., VanBerkel V., Chen X., Noya D., Korenberg J. R., Husain Z., Miller J., Lander E. S. A comprehensive large-insert yeast artificial chromosome library for physical mapping of the mouse genome. Mamm Genome. 1996 Oct;7(10):767–769. doi: 10.1007/s003359900228. [DOI] [PubMed] [Google Scholar]
- Hardy M. H. The secret life of the hair follicle. Trends Genet. 1992 Feb;8(2):55–61. doi: 10.1016/0168-9525(92)90350-d. [DOI] [PubMed] [Google Scholar]
- Herring C. D., Chevillard C., Johnston S. L., Wettstein P. J., Riblet R. Vector-hexamer PCR isolation of all insert ends from a YAC contig of the mouse Igh locus. Genome Res. 1998 Jun;8(6):673–681. doi: 10.1101/gr.8.6.673. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hunter K. W., Ontiveros S. D., Watson M. L., Stanton V. P., Jr, Gutierrez P., Bhat D., Rochelle J., Graw S., Ton C., Schalling M. Rapid and efficient construction of yeast artificial chromosome contigs in the mouse genome with interspersed repetitive sequence PCR (IRS-PCR): generation of a 5-cM, > 5 megabase contig on mouse chromosome 1. Mamm Genome. 1994 Oct;5(10):597–607. doi: 10.1007/BF00411453. [DOI] [PubMed] [Google Scholar]
- Huppi K., Siwarski D., Letts V. Encyclopedia of the mouse genome VII. Mouse chromosome 15. Mamm Genome. 1998;8(Spec No):S292–S306. doi: 10.1007/s003359900660. [DOI] [PubMed] [Google Scholar]
- Hébert J. M., Rosenquist T., Götz J., Martin G. R. FGF5 as a regulator of the hair growth cycle: evidence from targeted and spontaneous mutations. Cell. 1994 Sep 23;78(6):1017–1025. doi: 10.1016/0092-8674(94)90276-3. [DOI] [PubMed] [Google Scholar]
- Larin Z., Monaco A. P., Lehrach H. Yeast artificial chromosome libraries containing large inserts from mouse and human DNA. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4123–4127. doi: 10.1073/pnas.88.10.4123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Luetteke N. C., Phillips H. K., Qiu T. H., Copeland N. G., Earp H. S., Jenkins N. A., Lee D. C. The mouse waved-2 phenotype results from a point mutation in the EGF receptor tyrosine kinase. Genes Dev. 1994 Feb 15;8(4):399–413. doi: 10.1101/gad.8.4.399. [DOI] [PubMed] [Google Scholar]
- Luetteke N. C., Qiu T. H., Peiffer R. L., Oliver P., Smithies O., Lee D. C. TGF alpha deficiency results in hair follicle and eye abnormalities in targeted and waved-1 mice. Cell. 1993 Apr 23;73(2):263–278. doi: 10.1016/0092-8674(93)90228-i. [DOI] [PubMed] [Google Scholar]
- Manly K. F. A Macintosh program for storage and analysis of experimental genetic mapping data. Mamm Genome. 1993;4(6):303–313. doi: 10.1007/BF00357089. [DOI] [PubMed] [Google Scholar]
- Mann G. B., Fowler K. J., Gabriel A., Nice E. C., Williams R. L., Dunn A. R. Mice with a null mutation of the TGF alpha gene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation. Cell. 1993 Apr 23;73(2):249–261. doi: 10.1016/0092-8674(93)90227-h. [DOI] [PubMed] [Google Scholar]
- McLean W. H., Lane E. B. Intermediate filaments in disease. Curr Opin Cell Biol. 1995 Feb;7(1):118–125. doi: 10.1016/0955-0674(95)80053-0. [DOI] [PubMed] [Google Scholar]
- Michaud E. J., Bultman S. J., Klebig M. L., van Vugt M. J., Stubbs L. J., Russell L. B., Woychik R. P. A molecular model for the genetic and phenotypic characteristics of the mouse lethal yellow (Ay) mutation. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2562–2566. doi: 10.1073/pnas.91.7.2562. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Michaud E. J., van Vugt M. J., Bultman S. J., Sweet H. O., Davisson M. T., Woychik R. P. Differential expression of a new dominant agouti allele (Aiapy) is correlated with methylation state and is influenced by parental lineage. Genes Dev. 1994 Jun 15;8(12):1463–1472. doi: 10.1101/gad.8.12.1463. [DOI] [PubMed] [Google Scholar]
- Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nehls M., Pfeifer D., Schorpp M., Hedrich H., Boehm T. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature. 1994 Nov 3;372(6501):103–107. doi: 10.1038/372103a0. [DOI] [PubMed] [Google Scholar]
- Ness S. L., Edelmann W., Jenkins T. D., Liedtke W., Rustgi A. K., Kucherlapati R. Mouse keratin 4 is necessary for internal epithelial integrity. J Biol Chem. 1998 Sep 11;273(37):23904–23911. doi: 10.1074/jbc.273.37.23904. [DOI] [PubMed] [Google Scholar]
- Powell B. C., Rogers G. E. Cyclic hair-loss and regrowth in transgenic mice overexpressing an intermediate filament gene. EMBO J. 1990 May;9(5):1485–1493. doi: 10.1002/j.1460-2075.1990.tb08266.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rogers M. A., Winter H., Langbein L., Wolf C., Schweizer J. Characterization of a 300 kbp region of human DNA containing the type II hair keratin gene domain. J Invest Dermatol. 2000 Mar;114(3):464–472. doi: 10.1046/j.1523-1747.2000.00910.x. [DOI] [PubMed] [Google Scholar]
- Siracusa L. D., Washburn L. L., Swing D. A., Argeson A. C., Jenkins N. A., Copeland N. G. Hypervariable yellow (Ahvy), a new murine agouti mutation: Ahvy displays the largest variation in coat color phenotypes of all known agouti alleles. J Hered. 1995 Mar-Apr;86(2):121–128. doi: 10.1093/oxfordjournals.jhered.a111541. [DOI] [PubMed] [Google Scholar]
- Telenius H., Carter N. P., Bebb C. E., Nordenskjöld M., Ponder B. A., Tunnacliffe A. Degenerate oligonucleotide-primed PCR: general amplification of target DNA by a single degenerate primer. Genomics. 1992 Jul;13(3):718–725. doi: 10.1016/0888-7543(92)90147-k. [DOI] [PubMed] [Google Scholar]
- Vassar R., Coulombe P. A., Degenstein L., Albers K., Fuchs E. Mutant keratin expression in transgenic mice causes marked abnormalities resembling a human genetic skin disease. Cell. 1991 Jan 25;64(2):365–380. doi: 10.1016/0092-8674(91)90645-f. [DOI] [PubMed] [Google Scholar]
- Winter H., Langbein L., Praetzel S., Jacobs M., Rogers M. A., Leigh I. M., Tidman N., Schweizer J. A novel human type II cytokeratin, K6hf, specifically expressed in the companion layer of the hair follicle. J Invest Dermatol. 1998 Dec;111(6):955–962. doi: 10.1046/j.1523-1747.1998.00456.x. [DOI] [PubMed] [Google Scholar]
- Winter H., Rogers M. A., Gebhardt M., Wollina U., Boxall L., Chitayat D., Babul-Hirji R., Stevens H. P., Zlotogorski A., Schweizer J. A new mutation in the type II hair cortex keratin hHb1 involved in the inherited hair disorder monilethrix. Hum Genet. 1997 Dec;101(2):165–169. doi: 10.1007/s004390050607. [DOI] [PubMed] [Google Scholar]
- Winter H., Rogers M. A., Langbein L., Stevens H. P., Leigh I. M., Labrèze C., Roul S., Taieb A., Krieg T., Schweizer J. Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix. Nat Genet. 1997 Aug;16(4):372–374. doi: 10.1038/ng0897-372. [DOI] [PubMed] [Google Scholar]
- Wojcik S. M., Bundman D. S., Roop D. R. Delayed wound healing in keratin 6a knockout mice. Mol Cell Biol. 2000 Jul;20(14):5248–5255. doi: 10.1128/mcb.20.14.5248-5255.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wojcik S. M., Imakado S., Seki T., Longley M. A., Petherbridge L., Bundman D. S., Bickenbach J. R., Rothnagel J. A., Roop D. R. Expression of MK6a dominant-negative and C-terminal mutant transgenes in mice has distinct phenotypic consequences in the epidermis and hair follicle. Differentiation. 1999 Oct;65(2):97–112. doi: 10.1046/j.1432-0436.1999.6520097.x. [DOI] [PubMed] [Google Scholar]
- Wolff G. L. Influence of maternal phenotype on metabolic differentiation of agouti locus mutants in the mouse. Genetics. 1978 Mar;88(3):529–539. doi: 10.1093/genetics/88.3.529. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wong P., Colucci-Guyon E., Takahashi K., Gu C., Babinet C., Coulombe P. A. Introducing a null mutation in the mouse K6alpha and K6beta genes reveals their essential structural role in the oral mucosa. J Cell Biol. 2000 Aug 21;150(4):921–928. doi: 10.1083/jcb.150.4.921. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wu C., Zhu S., Simpson S., de Jong P. J. DOP-vector PCR: a method for rapid isolation and sequencing of insert termini from PAC clones. Nucleic Acids Res. 1996 Jul 1;24(13):2614–2615. doi: 10.1093/nar/24.13.2614. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yoon S. J., LeBlanc-Straceski J., Ward D., Krauter K., Kucherlapati R. Organization of the human keratin type II gene cluster at 12q13. Genomics. 1994 Dec;24(3):502–508. doi: 10.1006/geno.1994.1659. [DOI] [PubMed] [Google Scholar]
