Abstract
We identified homozygous truncating mutations in HOXA1 in three genetically isolated human populations. The resulting phenotype includes horizontal gaze abnormalities, deafness, facial weakness, hypoventilation, vascular malformations of the internal carotid arteries and cardiac outflow tract, mental retardation and autism spectrum disorder. This is the first report to our knowledge of viable homozygous truncating mutations in any human HOX gene and of a mendelian disorder resulting from mutations in a human HOX gene critical for development of the central nervous system.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lufkin, T., Dierich, A., LeMeur, M., Mark, M. & Chambon, P. Cell 66, 1105–1119 (1991).
Chisaka, O., Musci, T.S. & Capecchi, M.R. Nature 355, 516–520 (1992).
Mark, M. et al. Development 119, 319–338 (1993).
Chariot, A., Moreau, L., Senterre, G., Sobel, M.E. & Castronovo, V. Biochem. Biophys. Res. Commun. 215, 713–720 (1995).
Goodman, F.R. Am. J. Med. Genet. 112, 256–265 (2002).
Shrimpton, A.E. et al. Am. J. Hum. Genet. 75, 92–96 (2004).
Thompson, A.A. & Nguyen, L.T. Nat. Genet. 26, 397–398 (2000).
Murphy, P. & Hill, R.E. Development 111, 61–74 (1991).
Holve, S. et al. Am. J. Med. Genet. A 120, 169–173 (2003).
Gavalas, A. et al. Development 125, 1123–1136 (1998).
del Toro, E.D. et al. J. Neurosci. 21, 5637–5642 (2001).
Etchevers, H.C., Vincent, C., Le Douarin, N.M. & Couly, G.F. Development 128, 1059–1068 (2001).
McClintock, J.M. et al. Dev. Genes Evol. 213, 399–406 (2003).
Rodier, P.M., Ingram, J.L., Tisdale, B., Nelson, S. & Romano, J. J. Comp. Neurol. 370, 247–261 (1996).
Ingram, J.L. et al. Teratology 62, 393–405 (2000).
Acknowledgements
We thank the family members for their participation; H. Kinney, R. Robertson, K. Yamada, H. Etchevers, J. Tischfield and C. Walsh for discussions and manuscript review; and C. Dow for technical expertise. This work was supported by the US National Institutes of Health (E.C.E.) and the Muscular Dystrophy Association and the Holslaw Family Professorship (R.P.E.).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Fig. 1
HOXA1 syndrome pedigrees and electropherograms. (PDF 1108 kb)
Supplementary Table 1
Clinical summary of BSAS patients. (PDF 53 kb)
Supplementary Table 2
Primer sequences. (PDF 62 kb)
Supplementary Table 3
Two-point lod scores between the BSAS locus and 7p markers. (PDF 47 kb)
Rights and permissions
About this article
Cite this article
Tischfield, M., Bosley, T., Salih, M. et al. Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development. Nat Genet 37, 1035–1037 (2005). https://doi.org/10.1038/ng1636
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng1636
This article is cited by
-
A distant global control region is essential for normal expression of anterior HOXA genes during mouse and human craniofacial development
Nature Communications (2024)
-
Modeling of large-scale hoxbb cluster deletions in zebrafish uncovers a role for segmentation pathways in atrioventricular boundary specification
Cellular and Molecular Life Sciences (2023)
-
Variations in the poly-histidine repeat motif of HOXA1 contribute to bicuspid aortic valve in mouse and zebrafish
Nature Communications (2023)
-
CircTRRAP (hsa_circ_0081234) participates in prostate cancer progression and glycolysis by HOXA1 via functioning as a miR-515-5p sponge
Applied Biological Chemistry (2022)
-
Clinical and genetic characteristics of Chinese patients with congenital cranial dysinnervation disorders
Orphanet Journal of Rare Diseases (2022)
