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

Human Molecular Genetics
Jeffrey W InnisBoris Utsch

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.

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Citations

Nov 1, 2016·Human Molecular Genetics·Tessa MattiskeCheryl Shoubridge
Jun 18, 2014·American Journal of Medical Genetics. Part a·Eri ImagawaNoriko Miyake
Mar 28, 2013·American Journal of Medical Genetics. Part a·Kailey M OwensJeffrey W Innis
Oct 16, 2007·American Journal of Medical Genetics. Part a·Boris UtschJeffrey W Innis
Oct 22, 2010·Genome Génome / Conseil National De Recherches Canada·Wilfried Haerty, G Brian Golding
Jun 9, 2016·American Journal of Medical Genetics. Part a·Adeline JacquinetAnna Lehman
Feb 17, 2016·Journal of Developmental Biology·João Leite-CastroRenata Freitas
Jun 1, 2013·Birth Defects Research. Part C, Embryo Today : Reviews·M SylvaM J B van den Hoff
Sep 21, 2016·American Journal of Medical Genetics. Part a·Emir TasSelma Feldman Witchel
Jul 1, 2017·Obstetrical & Gynecological Survey·Bala BhagavathSteven R Lindheim
Jul 13, 2006·Nature Reviews. Genetics·Dagmar Wilhelm, Peter Koopman
Oct 16, 2008·Journal of Molecular Evolution·Tiana KohlsdorfGünter P Wagner
Nov 7, 2015·American Journal of Medical Genetics. Part a·Antoine B ChristiaensCatherine Nyssen-Behets
Dec 17, 2008·Molecular Biology and Evolution·Zhe WangShuyi Zhang

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