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Human Molecular Genetics Advance Access originally published online on September 22, 2004
Human Molecular Genetics 2004 13(22):2841-2851; doi:10.1093/hmg/ddh306
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Human Molecular Genetics, Vol. 13, No. 22 © Oxford University Press 2004; all rights reserved

Polyalanine expansion in HOXA13: three new affected families and the molecular consequences in a mouse model

Jeffrey W. Innis1,2,*, Douglas Mortlock2,{dagger}, Zhi Chen3,{ddagger}, Michael Ludwig4, Melissa E. Williams2, Thomas M. Williams2, Colleen D. Doyle2, Zhihong Shao2, Michael Glynn2, Davor Mikulic5, Katarina Lehmann6, Stefan Mundlos6 and Boris Utsch1,§

1Department of Pediatrics, 2Department of Human Genetics and 3Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA, 4Department of Clinical Biochemistry, University of Bonn, Bonn, Germany, 5Zentrum fuer Kinder und Jugendmedizin, Kreiskrankenhaus, Luedenscheid, Germany and 6Department of Medical Genetics, Humboldt University, Berlin, Germany

Received July 26, 2004; Accepted September 15, 2004

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 (HOXA13ALA28). 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 HOXA13ALA28 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.

* To whom correspondence should be addressed at: Department of Human Genetics, 4811 Med Sciences II, Box 0618, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0618, USA. Email: innis{at}umich.edu


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