Originally published as Genetics Published Articles Ahead of Print on June 22, 2009.

Genetics, Vol. 183, 23-30, September 2009, Copyright © 2009
doi:10.1534/genetics.109.104695

Fork Stalling and Template Switching As a Mechanism for Polyalanine Tract Expansion Affecting the DYC Mutant of HOXD13, a New Murine Model of Synpolydactyly

Olivier Cocquempot*,{dagger},1, Véronique Brault*,{dagger}, Charles Babinet{ddagger} and Yann Herault*,{dagger},§,2

* Université d'Orléans, UMR6218, Molecular Immunology and Embryology, 45071 Orléans, France {dagger} Centre National de la Recherche Scientifique (CNRS), UMR6218, MIE, 3B rue de la Férollerie, 45071 Orleans Cedex 2, France, {ddagger} Unité de Biologie du Développement, URA 1960, CNRS, Institut Pasteur, 25 rue du Docteur Roux 75015 Paris, France and § CNRS, UPS44, TAAM, Institut de Transgenose, 45071 Orléans, France

2 Corresponding author: UMR6218, IEM, Uni Orléans, CNRS, UPS44, TAAM, Institut de Transgénose, 3B rue de la Férollerie, 45071 Orléans Cedex 2 France.
E-mail: herault{at}cnrs-orleans.fr

Polyalanine expansion diseases are proposed to result from unequal crossover of sister chromatids that increases the number of repeats. In this report we suggest an alternative mechanism we put forward while we investigated a new spontaneous mutant that we named "Dyc" for "Digit in Y and Carpe" phenotype. Phenotypic analysis revealed an abnormal limb patterning similar to that of the human inherited congenital disease synpolydactyly (SPD) and to the mouse mutant model Spdh. Both human SPD and mouse Spdh mutations affect the Hoxd13 gene within a 15-residue polyalanine-encoding repeat in the first exon of the gene, leading to a dominant negative HOXD13. Genetic analysis of the Dyc mutant revealed a trinucleotide expansion in the polyalanine-encoding region of the Hoxd13 gene resulting in a 7-alanine expansion. However, unlike the Spdh mutation, this expansion cannot result from a simple duplication of a short segment. Instead, we propose the fork stalling and template switching (FosTeS) described for generation of nonrecurrent genomic rearrangements as a possible mechanism for the Dyc polyalanine extension, as well as for other polyalanine expansions described in the literature and that could not be explained by unequal crossing over.