title: VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans.
abstract: Vax1 and Vax2 have been implicated in eye development and the closure of the choroid fissure in mice and zebrafish. We sequenced the coding exons of VAX1 and VAX2 in 70 patients with anophthalmia/microphthalmia (A/M). In VAX1, we observed homozygosity for two successive nucleotide substitutions c.453G>A and c.454C>A, predicting p.Arg152Ser, in a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis. This mutation affects an invariant residue in the homeodomain of VAX1 and was absent from 96 Egyptian controls. It is likely that the mutation results in a loss of function, as the mutation results in a phenotype similar to the Vax1 homozygous null mouse. We did not identify any mutations in VAX2. This is the first description of a phenotype associated with a VAX1 mutation in humans and establishes VAX1 as a new causative gene for A/M.
authors.affiliation: Department of Pediatrics, Division of Genetics, University of California, San Francisco, California 94143-0748, USA. slavotia@peds.ucsf.edu
authors.forename: Anne M
authors.initials: AM
authors.lastname: Slavotinek
authors.forename: Ryan
authors.initials: R
authors.lastname: Chao
authors.forename: Tomas
authors.initials: T
authors.lastname: Vacik
authors.forename: Mani
authors.initials: M
authors.lastname: Yahyavi
authors.forename: Hana
authors.initials: H
authors.lastname: Abouzeid
authors.forename: Tanya
authors.initials: T
authors.lastname: Bardakjian
authors.forename: Adele
authors.initials: A
authors.lastname: Schneider
authors.forename: Gary
authors.initials: G
authors.lastname: Shaw
authors.forename: Elliott H
authors.initials: EH
authors.lastname: Sherr
authors.forename: Greg
authors.initials: G
authors.lastname: Lemke
authors.forename: Mohammed
authors.initials: M
authors.lastname: Youssef
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schorderet
mesh_terms: D061085:Agenesis of Corpus Callosum / Q000235:genetics*; D019943:Amino Acid Substitution; D002675:Child, Preschool; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D005091:Exons; D005787:Gene Frequency; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008850:Microphthalmos / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; C572055:VAX1 protein, human; C492362:VAX2 protein, human
references.citation: Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10729-34
references.pmid: 10485894
references.citation: Hum Mutat. 2005 Apr;25(4):334-42
references.pmid: 15776446
references.citation: Arch Pediatr Adolesc Med. 2007 May;161(5):463-9
references.pmid: 17485622
references.citation: J Biol Chem. 2004 Nov 5;279(45):47272-7
references.pmid: 15322073
references.citation: Hum Mutat. 1998;12(3):153-71
references.pmid: 9711873
references.citation: Am J Med Genet A. 2003 Jan 30;116A(3):215-21
references.pmid: 12503095
references.citation: Development. 2002 Feb;129(3):805-13
references.pmid: 11830579
references.citation: Eur J Hum Genet. 2006 Sep;14(9):999-1008
references.pmid: 16736036
references.citation: Development. 2011 Mar;138(5):873-8
references.pmid: 21247964
references.citation: Eur J Neurosci. 2004 Mar;19(6):1505-12
references.pmid: 15066147
references.citation: Genes Dev. 2005 May 15;19(10):1249-59
references.pmid: 15905411
references.citation: Acta Neuropathol. 1993;86(2):126-35
references.pmid: 8213068
references.citation: Genes Cells. 1999 May;4(5):267-76
references.pmid: 10421837
references.citation: Neuron. 1999 Nov;24(3):541-53
references.pmid: 10595508
references.citation: Orphanet J Rare Dis. 2007 Nov 26;2:47
references.pmid: 18039390
references.citation: Genes Dev. 1999 Dec 1;13(23):3092-105
references.pmid: 10601035
references.citation: Development. 2004 Dec;131(24):6131-40
references.pmid: 15548580
references.citation: Am J Med Genet A. 2005 Aug 15;137(1):36-40
references.pmid: 16007635
references.citation: Development. 2003 Mar;130(5):955-68
references.pmid: 12538521
references.citation: Eur J Hum Genet. 2009 Jun;17(6):831-9
references.pmid: 19142206
references.citation: Mech Dev. 2010 Jan-Feb;127(1-2):62-72
references.pmid: 19854269
references.citation: Am J Med Genet A. 2007 Aug 15;143A(16):1900-5
references.pmid: 17632789
references.citation: Dev Biol. 1999 Jan 1;205(1):79-97
references.pmid: 9882499
references.citation: Mol Vis. 2009 Oct 17;15:2074-83
references.pmid: 19862335
references.citation: Development. 2002 Feb;129(3):797-804
references.pmid: 11830578
references.citation: Mech Dev. 2001 Dec;109(2):215-24
references.pmid: 11731235
references.citation: Eye (Lond). 2007 Oct;21(10):1290-300
references.pmid: 17914432
references.citation: Genes Dev. 2011 Sep 1;25(17):1783-95
references.pmid: 21856776
references.citation: Genes Dev. 1999 Dec 1;13(23):3106-14
references.pmid: 10601036