title: A novel loss-of-function mutation in OTX2 in a patient with anophthalmia and isolated growth hormone deficiency.
abstract: Heterozygous mutations of the gene encoding transcription factor OTX2 were recently shown to be responsible for ocular as well as pituitary abnormalities. Here, we describe a patient with unilateral anophthalmia and short stature. Endocrine evaluation of the hypothalamic-pituitary axis revealed isolated growth hormone deficiency (IGHD) with small anterior pituitary gland, invisible stalk, ectopic posterior lobe, and right anophthalmia on brain magnetic resonance imaging. DNA was analyzed for mutations in the HESX1, SOX2, and OTX2 genes. Molecular analysis yielded a novel heterozygous OTX2 mutation (c.270A>T, p.R90S) within the homeodomain. Functional analysis revealed that the mutation inhibited both the DNA binding and transactivation activities of the protein. This novel loss-of-function mutation is associated with anophthalmia and IGHD in a patient of Sephardic Jewish descent. We recommend that patients with GH deficiency and ocular malformation in whom genetic analysis for classic transcription factor genes (PROP1, POU1F1, HESX1, and LHX4) failed to identify alterations should be checked for the presence of mutations in the OTX2 gene.
authors.affiliation: The Jesse Z and Sara Lea Shafer Institute of Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, 14 Kaplan Street, 49202 Petach Tikva, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Ashkenazi-Hoffnung
authors.forename: Yael
authors.initials: Y
authors.lastname: Lebenthal
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wyatt
authors.forename: Nicola K
authors.initials: NK
authors.lastname: Ragge
authors.forename: Sumito
authors.initials: S
authors.lastname: Dateki
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
authors.forename: Moshe
authors.initials: M
authors.lastname: Phillip
authors.forename: Galia
authors.initials: G
authors.lastname: Gat-Yablonski
mesh_terms: D000853:Anophthalmos / Q000235:genetics*; D002675:Child, Preschool; D005124:Eye Abnormalities / Q000235:genetics; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics; D019382:Human Growth Hormone / Q000172:deficiency*; D006801:Humans; D060850:LIM-Homeodomain Proteins; D008297:Male; D020125:Mutation, Missense; D051857:Otx Transcription Factors / Q000235:genetics*; D010903:Pituitary Gland, Anterior / Q000002:abnormalities; D014157:Transcription Factors / Q000235:genetics
chemical_list: C489736:HESX1 protein, human; D018398:Homeodomain Proteins; C486362:LHX4 protein, human; D060850:LIM-Homeodomain Proteins; C497659:OTX2 protein, human; D051857:Otx Transcription Factors; D014157:Transcription Factors; D019382:Human Growth Hormone
references.citation: J Clin Endocrinol Metab. 2010 Feb;95(2):756-64
references.pmid: 19965921
references.citation: Development. 1995 Oct;121(10):3279-90
references.pmid: 7588062
references.citation: J Clin Invest. 2006 Sep;116(9):2442-55
references.pmid: 16932809
references.citation: Science. 1992 Aug 21;257(5073):1115-8
references.pmid: 1509262
references.citation: Nat Genet. 1998 Feb;18(2):147-9
references.pmid: 9462743
references.citation: J Mol Med (Berl). 2006 Jul;84(7):604-15
references.pmid: 16607563
references.citation: Eur J Hum Genet. 2007 Aug;15(8):898-901
references.pmid: 17406642
references.citation: Br J Ophthalmol. 2007 Nov;91(11):1471-6
references.pmid: 17522144
references.citation: J Clin Endocrinol Metab. 2008 Nov;93(11):4351-9
references.pmid: 18728160
references.citation: Nat Genet. 2000 Jun;25(2):182-6
references.pmid: 10835633
references.citation: J Clin Endocrinol Metab. 2009 Jan;94(1):314-9
references.pmid: 18854396
references.citation: Biochemistry. 2005 May 24;44(20):7497-511
references.pmid: 15895993
references.citation: Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
references.pmid: 9254694
references.citation: Proteins. 2004 Jul 1;56(1):143-56
references.pmid: 15162494
references.citation: Genomics. 1994 Jul 1;22(1):41-5
references.pmid: 7959790
references.citation: Am J Hum Genet. 2001 Nov;69(5):961-8
references.pmid: 11567216
references.citation: Cell. 1995 Sep 8;82(5):709-19
references.pmid: 7671301
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5408-13
references.pmid: 18385377
references.citation: Genes Dev. 1995 Nov 1;9(21):2646-58
references.pmid: 7590242
references.citation: Mol Genet Metab. 2000 Sep-Oct;71(1-2):43-50
references.pmid: 11001794
references.citation: Development. 1996 Jan;122(1):243-52
references.pmid: 8565836
references.citation: Clin Genet. 2006 Jun;69(6):459-70
references.pmid: 16712695
references.citation: Hum Mol Genet. 2004 Nov 15;13(22):2727-35
references.pmid: 15459176
references.citation: Nat Genet. 1996 Dec;14(4):392-9
references.pmid: 8944018
references.citation: J Clin Endocrinol Metab. 2008 Oct;93(10):3697-702
references.pmid: 18628516
references.citation: J Clin Endocrinol Metab. 2006 Sep;91(9):3329-36
references.pmid: 16735499
references.citation: Hum Mutat. 2008 Nov;29(11):E278-83
references.pmid: 18781617
references.citation: Mol Vis. 2009 Nov 21;15:2442-7
references.pmid: 19956411
references.citation: Am J Hum Genet. 2005 Jun;76(6):1008-22
references.pmid: 15846561
references.citation: Nat Genet. 2004 Mar;36(3):247-55
references.pmid: 14981518
references.citation: Curr Opin Genet Dev. 2005 Jun;15(3):332-40
references.pmid: 15917210
references.citation: Nat Genet. 1998 Jun;19(2):125-33
references.pmid: 9620767
references.citation: Nat Genet. 2003 Apr;33(4):461-3
references.pmid: 12612584
references.citation: Horm Res. 2009;72(5):302-9
references.pmid: 19844116