Polyalanine expansion in HOXA13: three new affected families and the molecular consequences in a mouse model.
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.
Innis
Jeffrey W
JW
Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA. innis@umich.edu
Mortlock
Douglas
D
Chen
Zhi
Z
Ludwig
Michael
M
Williams
Melissa E
ME
Williams
Thomas M
TM
Doyle
Colleen D
CD
Shao
Zhihong
Z
Glynn
Michael
M
Mikulic
Davor
D
Lehmann
Katarina
K
Mundlos
Stefan
S
Utsch
Boris
B
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
D018398:Homeodomain Proteins; D010455:Peptides; D012333:RNA, Messenger; C099959:homeobox protein HOXA13; C019529:polyalanine