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.
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Acknowledgments
We thank Dr Dave Robinson and Dr Dave Bunyan for the MLPA work, Prof. L. Kornreich from the imaging department, SCMC, for interpretation of MRI scans and Adva Yeheskel from the Bioinformatics Unit of the George S. Wise Faculty of Life Sciences at Tel Aviv University for her bioinformatics analysis of the mutation. We thank Gloria Ginzach for her editorial assistance. This study was supported by the Public Committee for the Allocation of Estate Funds, Ministry of Health, Israel. Alexander Wyatt is supported through grants from the Polak Trust, and VICTA, Nicola Ragge is the recipient of a Senior Surgical Scientist Award through the Academy of Medical Sciences/The Health Foundation.
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L. Ashkenazi-Hoffnung and Y. Lebenthal contributed equally to this work.
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Ashkenazi-Hoffnung, L., Lebenthal, Y., Wyatt, A.W. et al. A novel loss-of-function mutation in OTX2 in a patient with anophthalmia and isolated growth hormone deficiency. Hum Genet 127, 721–729 (2010). https://doi.org/10.1007/s00439-010-0820-9
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DOI: https://doi.org/10.1007/s00439-010-0820-9