A novel loss-of-function mutation in OTX2 in a patient with anophthalmia and isolated growth hormone deficiency.
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.
Ashkenazi-Hoffnung
Liat
L
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.
Lebenthal
Yael
Y
Wyatt
Alexander W
AW
Ragge
Nicola K
NK
Dateki
Sumito
S
Fukami
Maki
M
Ogata
Tsutomu
T
Phillip
Moshe
M
Gat-Yablonski
Galia
G
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
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
J Clin Endocrinol Metab. 2010 Feb;95(2):756-64
19965921
Development. 1995 Oct;121(10):3279-90
7588062
J Clin Invest. 2006 Sep;116(9):2442-55
16932809
Science. 1992 Aug 21;257(5073):1115-8
1509262
Nat Genet. 1998 Feb;18(2):147-9
9462743
J Mol Med (Berl). 2006 Jul;84(7):604-15
16607563
Eur J Hum Genet. 2007 Aug;15(8):898-901
17406642
Br J Ophthalmol. 2007 Nov;91(11):1471-6
17522144
J Clin Endocrinol Metab. 2008 Nov;93(11):4351-9
18728160
Nat Genet. 2000 Jun;25(2):182-6
10835633
J Clin Endocrinol Metab. 2009 Jan;94(1):314-9
18854396
Biochemistry. 2005 May 24;44(20):7497-511
15895993
Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
9254694
Proteins. 2004 Jul 1;56(1):143-56
15162494
Genomics. 1994 Jul 1;22(1):41-5
7959790
Am J Hum Genet. 2001 Nov;69(5):961-8
11567216
Cell. 1995 Sep 8;82(5):709-19
7671301
Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5408-13
18385377
Genes Dev. 1995 Nov 1;9(21):2646-58
7590242
Mol Genet Metab. 2000 Sep-Oct;71(1-2):43-50
11001794
Development. 1996 Jan;122(1):243-52
8565836
Clin Genet. 2006 Jun;69(6):459-70
16712695
Hum Mol Genet. 2004 Nov 15;13(22):2727-35
15459176
Nat Genet. 1996 Dec;14(4):392-9
8944018
J Clin Endocrinol Metab. 2008 Oct;93(10):3697-702
18628516
J Clin Endocrinol Metab. 2006 Sep;91(9):3329-36
16735499
Hum Mutat. 2008 Nov;29(11):E278-83
18781617
Mol Vis. 2009 Nov 21;15:2442-7
19956411
Am J Hum Genet. 2005 Jun;76(6):1008-22
15846561
Nat Genet. 2004 Mar;36(3):247-55
14981518
Curr Opin Genet Dev. 2005 Jun;15(3):332-40
15917210
Nat Genet. 1998 Jun;19(2):125-33
9620767
Nat Genet. 2003 Apr;33(4):461-3
12612584
Horm Res. 2009;72(5):302-9
19844116