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: Liat Ashkenazi-Hoffnung, Yael Lebenthal, Alexander W Wyatt, Nicola K Ragge, Sumito Dateki, Maki Fukami, Tsutomu Ogata, Moshe Phillip, Galia Gat-Yablonski
• Journal: Human genetics (Hum Genet) Vol. 127 Issue 6 Pg. 721-9 (Jun 2010) ISSN: 1432-1203 [Electronic] Germany
• PMID: 20396904 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HESX1 protein, human
• Homeodomain Proteins
• LHX4 protein, human
• LIM-Homeodomain Proteins
• OTX2 protein, human
• Otx Transcription Factors
• Transcription Factors
• Human Growth Hormone

Topics

• Anophthalmos (genetics)
• Child, Preschool
• Eye Abnormalities (genetics)
• Heterozygote
• Homeodomain Proteins (genetics)
• Human Growth Hormone (deficiency)
• Humans
• LIM-Homeodomain Proteins
• Male
• Mutation, Missense
• Otx Transcription Factors (genetics)
• Pituitary Gland, Anterior (abnormalities)
• Transcription Factors (genetics)