Abstract
Hypodactyly (Hd) is a semidominant mutation in mice that maps in a genetic interval overlapping the Hoxa cluster. The profound deficiency of digital arch structures in Hd/Hd mice is consistent with a defect in a gene activated late in limb morphogenesis. We have determined the structure of the Hoxa13 gene and describe a 50–base pair deletion in the first exon of the Hd allele that probably arose from unequal recombination or misalignment between triplet repeats. It is predicted that no Hoxa13 protein is made from Hd mRNA. The hypodactyly limb phenotype is similar to that of Hoxd13–deficient mice in sharing defects along multiple axes and alterations in cartilage maturation; however, the overall effects on digital arch formation are more severe in Hd/Hd mice. Our results confirm the critical role of AbdB–like Hox genes in the development of the autopod, and add to the spectrum of mutations involving triplet repeats
Similar content being viewed by others
References
Laufer, E., Nelson, C.E., Johnson, R.L., Morgan, B.A. & Tabin, C. Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud. Cell 79, 993–1003 (1994).
Tabin, C. The initiation of the limb bud: growth factors, Hox genes, and retinoids. Cell 80, 671–674 (1995).
Cohn, M.J., Izpisúa-Belmonte, J.C., Abud, H., Heath, J.K. & Tickle, C. Fibroblast growth factors induce additional limb development from the flank of chick embryos. Cell 80, 739–746 (1995).
Duboule, D. The vertebrate limb: a model system to study the Hox/HOM gene network during development and evolution. Bio Essays. 14, 375–384 (1992).
Yokouchi, Y., Sasaki, H. & Kuroiwa, A. Homeobox gene expression correlated with the bifurcation process of limb cartilage development. Nature 353, 443–445 (1991).
Haack, H. & Gruss, P. The establishment of murine Hox-7 expression domains during patterning of the limb. Dev. Biol. 157, 410–422 (1993).
Small, K.M. & Potter, S.S. Homeotic transformations and limb defects in Hoxa11 mutant mice. Genes Dev. 7, 2318–2328 (1993).
Satokata, I., Benson, G. & Maas, R. Sexually dimorphic sterility phenotypes in Hoxa10-deficient mice. Nature 374, 460–463 (1995).
Rijli, F.M. et al. Cryptorchidism and homeotic transformations of spinal nerves and vertebrae in Hoxa-10 mutant mice. Proc. Natl. Acad. Sci. USA. 92, 8185–8189 (1995).
Hsieh-Li, H.M. et al. Hoxa11 structure, extensive antisense transcription, and function in male and female fertility. Development 121, 1373–1385 (1995).
Dolle, P. et al. Disruption of the Hoxd-13 gene induces localized heterochrony leading to mice with neotenic limbs. Cell 75, 431–441 (1993).
Davis, A.R., White, D.R., Hsieh-Li, H.M., Potter, S.S. & Capecchi, M.R. Absence of radius and ulna in mice lacking hoxa-11 and hoxd-11 . Nature 375, 791–795 (1995).
Davis, A.P. & Capecchi, M.R. Axial homeosis and appendicular skeleton defects in mice with a targeted disruption of hoxd-11. Development 120, 2187–2198 (1994).
Yokouchi, Y. et al. Misexpression of Hoxa-13 induces cartilage homeotic transformation and changes cell adhesiveness in chick limb buds. Genes Dev. 9, 2509–2522 (1995).
Morgan, B.A. & Tabin, C. Hox genes and growth: early and lates roles in limb bud morphogenesis. Development Suppl. 181–186 (1994).
Roberts, D.J. & Tabin, C. The genetics of human limb development. Am. J. Hum. Gen. 55, 1–6 (1994).
Redline, R.W., Neish, A., Holmes, L.B. & Collins, T. Biology of disease: homeobox genes and congenital malformations. Lab. Invest. 66, 659–670 (1992).
Krumlauf, R. Hox genes in vertebrate development. Cell 78, 191–201 (1994).
Muragaki, Y., Mundtos, S., Upton, J. & Olsen, B.R. Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13. Science 272, 548–551 (1996).
Hummel, K., Hypodactyly, a semidominant lethal mutation in mice. J. Heread. 61, 219–220 (1970).
Innis, J.W., Kazen-Giltespie, K., Post, L.C. & McGorman, J.M. High-resolution genetic mapping of the hypodactyly (Hd) locus on mouse chromosome 6. Mamm. Genome 7, 2–5 (1996).
Innis, J.W. et al. Orientation of the Hoxa complex and placement of the Hd locus distal to Hoxa2 on mouse chromosome 6. Mamm. Genome 7, 216–217 (1996).
Gardiner, D.M., Blumberg, B., Komine, Y., & Bryant, S.V. Regulation of Hoxa expression in developing and regenerating axolotl limbs. Development 121, 1731–1741 (1995).
Rogina, B. & Uphott, W.B. Cloning of full coding chicken cDNAs for the homeobox-containing gene Hoxd-13 . Nucl. Acids Res. 21, 1316 (1993).
van der Hoeven, F., Sordino, P., Fraudeau, N., Izpisùa-Belmonte, J.-C. & Duboule, D. Genbank ♯X87752, direct submission. (1995).
Kozak, M. Point mutations close to the AUG initiator codon affect the efficiency of translation of rat preproinsulin in vivo . Nature 308, 241–246 (1984).
Kozak, M. Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes. Cell 44, 283–293 (1986).
Duboule, D. Guidebook to the Homeobox Genes . (Oxford University Press, New York, 1994).
Han, K. & Manley, J.L. Transcriptional repression by the Drosophila Even-skipped protein: definition of a minimal repression domain. Genes Dev. 7, 492–503 (1993).
Han, K. & Manley, J.L. Functional domains of the Drosophila Engrailed protein. EMBO J. 12, 2723–2733 (1993).
Licht, J.D., Grossel, M.J., Figge, J. & Hansen, U.M., Drosophila Kruppel protein is a transcriptional represser. Nature 346, 76–79 (1990).
Dover, G. Slippery DNA runs on and on and on … Nature Genet. 10, 254–256 (1995).
Kunkel, T.A. Slippery DNA and diseases. Nature 365, 207–208 (1993).
Shubin, N.H. & Alberch, P.A morphogenetic approach to the origin and basic organization of the tetrapod limb. Evol. Biol. 20, 319–387 (1986).
Oster, G.F., Murray, J.D. & Maini, P.K. A model for chondrogenic condensations in the developing limb: the role of extracellular matrix and cell tractions. J. Embryol. Exp. Morph. 89, 93–112 (1985).
Condie, B.G. & Capecchi, M.R. Mice with targeted disruptions in the paralogous genes hoxa-3 and hoxd-3 reveal synergistic interactions. Nature 370, 304–307 (1994).
Rancourt, D.E., Tsuzuki, T. & Capecchi, M.R. Genetic interaction between hoxb-5 and hoxb-6 is revealed by nonaltelic noncomplementation. Genes Dev. 9, 108–122 (1995).
Favier, B., Meur, M.L., Chambon, P. & Dollé, P. Axial skeleton homeosis and forelimb malformations in Hoxd-11 mutant mice. Proc. Natl. Acad. Sci. USA 92, 310–314 (1995).
Dollé, P., Izpisúa-Belmonte, J.-C., Boncinelli, E. & Duboule, D., The Hox-4.8 gene is localised at the 5′ extremity of the HOX-4 complex and is expressed in the most posterior parts of the body during development. Mech. Dev. 36, 3–14 (1991).
Yokouchi, Y., Sakiyama, J. & Kuroiwa, A. A Coordinated expression of Abd-B subfamily genes of the Hoxa cluster in the developing digestive tract of chick embryo. Dev. Biol. 169, 76–89 (1995).
Copp, A.J. Death before birth: clues from gene knockouts and mutations. Trends Genet. 11, 87–93 (1995).
Bates, G. & Lehrach, H. Trinucleotide repeat expansions and human genetic disease. Bio Essays 16, 277–284 (1994).
Lupski, J.R., Roth, J.R. & Weinstock, G.M. Chromosomal duplications in bacteria, fruit flies, and humans. Am. J. Hum. Gen. 58, 21–27 (1996).
Tautz, D. & Schlötterer, C. Simple Sequences. Curr. Opin. Gen. Dev. 4, 832–837 (1994).
Magli, M.C., Barba, P., Celetti, A., Vita, G.d. & Cillo, C. Coordinate regulation of HOX genes in human hematopoietic cells. Proc. Natl. Acad. Sci. USA 88, 6348–6352 (1991).
Redline, R.W., Hudock, P., MacFee, M. & Patternson, P. Expression of AbdB-type homeobox genes in human tumors. Lab. Invest. 71, 663–670 (1994).
Stern, A.M. et al. The hand–foot–uterus syndrome. J. Pediat. 77, 109–116 (1970).
Poznanski, A.K., Stern, A.S. & Gall, J.C. Radiographic findings in the hand–foot–uterus syndrome(HFUS). Radiology 95, 129–134 (1970).
Halal, F., The Hand–foot–genital(hand–foot–uterus) syndrome: family report and update. Am. J. Med. Gen. 30, 793–803 (1988).
Kimmel, C.A. & Trammell, C. A rapid procedure for routine double staining of cartilage and bone in fetal and adult animals. Stain Technol. 56, 271–273 (1981).
Ausubel, F.M. et al. Current protocols in molecular biology. (Greene Publishing Associates and Wiley-lnterscience, 1991).
Valdes, J.M., Tagle, D., Elmer, L. & Collins, F. A simple non-radioactive method for diagnosis of Huntington's disease. Hum. Mol. Genet. 2, 633–634 (1993).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Mortlock, D., Post, L. & Innis, J. The molecular basis of hypodactyly (Hd): a deletion in Hoxa13 leads to arrest of digital arch formation. Nat Genet 13, 284–289 (1996). https://doi.org/10.1038/ng0796-284
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0796-284
- Springer Nature America, Inc.
This article is cited by
-
De novo t(12;17)(p13.3;q21.3) translocation with a breakpoint near the 5′ end of the HOXB gene cluster in a patient with developmental delay and skeletal malformations
European Journal of Human Genetics (2007)
-
Digit ratios (2D:4D), secondary sexual characters and cell-mediated immunity in house sparrows Passer domesticus
Behavioral Ecology and Sociobiology (2007)
-
Human digit ratios depend on birth order and sex of older siblings and predict maternal fecundity
Behavioral Ecology and Sociobiology (2006)
-
Developmental genetics of the female reproductive tract in mammals
Nature Reviews Genetics (2003)
-
Hox in hair growth and development
Naturwissenschaften (2003)