title: Polyalanine expansion in HOXA13: three new affected families and the molecular consequences in a mouse model.
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.
authors.affiliation: Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA. innis@umich.edu
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Innis
authors.forename: Douglas
authors.initials: D
authors.lastname: Mortlock
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Ludwig
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Williams
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Williams
authors.forename: Colleen D
authors.initials: CD
authors.lastname: Doyle
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Shao
authors.forename: Michael
authors.initials: M
authors.lastname: Glynn
authors.forename: Davor
authors.initials: D
authors.lastname: Mikulic
authors.forename: Katarina
authors.initials: K
authors.lastname: Lehmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Boris
authors.initials: B
authors.lastname: Utsch
mesh_terms: D000818:Animals; D001483:Base Sequence; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005532:Foot Deformities, Congenital / Q000235:genetics*; D006228:Hand Deformities, Congenital / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D010375:Pedigree; D010455:Peptides / Q000235:genetics*; D014176:Protein Biosynthesis; D011489:Protein Denaturation; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics; D011995:Recombination, Genetic; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013577:Syndrome; D018911:Trinucleotide Repeats
chemical_list: D018398:Homeodomain Proteins; D010455:Peptides; D012333:RNA, Messenger; C099959:homeobox protein HOXA13; C019529:polyalanine