Polyalanine Expansion in HOXA13: Three New Affected Families and the Molecular Consequences in a Mouse Model

Author(s)

Jeffrey W. Innis, University of Michigan-Ann Arbor
Douglas Mortlock, University of Michigan-Ann Arbor
Zhi Chen, University of Michigan-Ann Arbor
Michael Ludwig, University of Bonn
Melissa E. Williams, University of Michigan-Ann Arbor
Thomas M. Williams, University of DaytonFollow
Colleen D. Doyle, University of Michigan-Ann Arbor
Zhihong Shao, University of Michigan-Ann Arbor
Michael Glynn, University of Michigan-Ann Arbor
Davor Mikulic, Zentrum fuer Kinder und Jugendmedizin, Kreiskrankenhaus
Katarina Lehmann, Humboldt University
Stefan Mundlos, Humboldt University
Boris Utsch, University of Michigan-Ann Arbor

Document Type

Article

Publication Date

11-2004

Publication Source

Human Molecular Genetics

Abstract

Polyalanine expansions in two of three large imperfect trinucleotide repeats encoded by the first exon of HOXA13 have been reported in hand–foot–genital syndrome (HFGS). Here we report additional families with expansions in the third repeat of 11 and 12 alanine residues, the latter being the largest expansion reported. We also report a patient with a novel, de novo 8-alanine expansion in the first large repeat. Thus, expansions in all three large HOXA13 polyalanine repeats can cause HFGS. To determine the molecular basis for impaired HOXA13 function, we performed homologous recombination in ES cells in mice to expand the size of the third largest polyalanine tract by 10 residues (HOXA13^ALA28). Mutant mice were indistinguishable from Hoxa13 null mice. Mutant limb buds had normal steady-state HOXA13 RNA expression, normal mRNA splicing and reduced levels of steady-state protein. In vitro translation efficiency of the HOXA13^ALA28 protein was normal. Thus, loss of function is secondary to a reduction in the in vivo abundance of the expanded protein likely due to degradation.

Inclusive pages

2841-2851

ISBN/ISSN

0964-6906

Comments

Permission documentation is on file.

Copyright

Copyright © 2004, Oxford University Press. All rights reserved.

Publisher

Oxford University Press

Volume

13

Peer Reviewed

yes

Issue

22

eCommons Citation

Innis, Jeffrey W.; Mortlock, Douglas; Chen, Zhi; Ludwig, Michael; Williams, Melissa E.; Williams, Thomas M.; Doyle, Colleen D.; Shao, Zhihong; Glynn, Michael; Mikulic, Davor; Lehmann, Katarina; Mundlos, Stefan; and Utsch, Boris, "Polyalanine Expansion in HOXA13: Three New Affected Families and the Molecular Consequences in a Mouse Model" (2004). Biology Faculty Publications. 170.
https://ecommons.udayton.edu/bio_fac_pub/170