Alternative titles; symbols
HGNC Approved Gene Symbol: OTX2
SNOMEDCT: 718761007;
Cytogenetic location: 14q22.3 Genomic coordinates (GRCh38) : 14:56,799,905-56,810,479 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q22.3 | Microphthalmia, syndromic 5 | 610125 | Autosomal dominant | 3 |
| Pituitary hormone deficiency, combined, 6 | 613986 | Autosomal dominant | 3 | |
| Retinal dystrophy, early-onset, with or without pituitary dysfunction | 610125 | Autosomal dominant | 3 |
OTX2 is a homeobox family gene related to a Drosophila gene expressed in the developing head. Simeone et al. (1992) identified rodent OTX2. Homologs are also found in the chicken, zebrafish, and Xenopus.
Dateki et al. (2010) noted that full-length human OTX2 contains 297 amino acids and contains an N-terminal paired type homeodomain, a SIWSPA conserved motif, and 2 tandem tail motifs within a C-terminal transactivation domain. An alternative splice acceptor site at the boundary of intron 3 and exon 4 results in a shorter isoform of 289 amino acids. PCR analysis of human tissues detected the shorter isoform as the major product with strong expression in pituitary gland, thalamus, and hypothalamus, and whole brain. There was not expression of either isoform in spinal cord, kidney, leukocytes, and skin fibroblasts. Western blot analysis detected OTX2 at an apparent molecular mass of 31.6 kD. Subcellular localization analysis showed that OTX2 localized to the nucleus.
Dateki et al. (2010) noted that the OTX2 gene contains 5 exons. The first 2 exons are noncoding.
Kastury et al. (1994) mapped the human OTX2 gene to 14q21-q22 by fluorescence in situ hybridization using a cosmid containing the gene.
Wyatt et al. (2008) noted that the OTX2 gene maps to chromosome 14q22.3.
Boncinelli et al. (1993) showed that Otx2 is expressed in the dorsal and most of the ventral regions of the telencephalon, diencephalon, and mesencephalon of developing mouse brain embryos. Its pattern of expression is wider than that of Otx1 (600036). Developmentally, Otx2 is expressed first, followed by Otx1, Emx2 (600035), and finally by Emx1 (600034).
Florell et al. (1996) described the association of aprosencephaly, absence of optic chiasm, absent mesencephalon, poorly formed metencephalon, and severely dysplastic cerebellum in 2 sibs; see 601374. Although this complex matched the expression profile of the OTX2 gene, no sequence variations of this gene were identified in the tissues of these fetuses.
Tenascin-C (TNC; 187380), an extracellular matrix glycoprotein with time- and site-restricted expression during CNS development, has binding sites for neural cells and supports neuronal migration and neurite formation. Gherzi et al. (1997) found that the TNC gene is subject to transcriptional control by OTX2. In cotransfected mammalian cells, OTX2 directly bound with high affinity to a motif in the human TNC promoter and reduced the transcriptional activity of the TNC promoter.
The Gnrh gene (152760) is expressed exclusively in a highly restricted population of approximately 800 neurons in the mediobasal hypothalamus in the mouse. The Otx2 homeoprotein colocalizes with Gnrh in embryonic mouse brain. Kelley et al. (2000) identified a highly conserved bicoid-related Otx target sequence within the proximal promoter region of the Gnrh gene from several species. This element from the rat Gnrh promoter binds baculovirus-expressed Otx2 protein and Otx2 protein in nuclear extracts of a hypothalamic Gnrh-expressing mouse neuronal cell line, GT1-7. Transient transfection assays indicated that the Gnrh promoter Otx/bicoid site is required for specific expression of the Gnrh gene in GT1-7 cells. Thus, the Gnrh proximal promoter is regulated by the Otx2 homeoprotein. The authors concluded that Otx2 is important in the development of the Gnrh neuron and/or in the maintenance of Gnrh expression in the adult mouse hypothalamus.
Using a transgenic mouse strain under conditional Otx2 gene ablation, Nishida et al. (2003) found that Otx2 deficiency converted differentiating photoreceptor cells to amacrine-like neurons, reflecting a change in progenitor cell fate, and led to a total lack of pinealocytes in the pineal gland. Expression studies suggested that Otx2 is a direct upstream regulator of another cone-rod homeobox-containing gene, Crx (602225), via binding to specific consensus sequences in the Crx promoter. The findings identified Otx2 as a key regulatory gene in photoreceptor cell development.
Martinez-Morales et al. (2003) showed that mouse Otx2, like Mitf (156845), could induce the pigmented phenotype in quail neural retinal cells. Otx2 specifically bound to a bicoid motif present in the promoter regions of genes encoding melanosome glycoproteins, leading to their transactivation, and induction was enhanced by Mitf. Otx2 colocalized with Mitf in the nuclei of retinal pigmented cells, and the 2 proteins interacted in vitro. Because Otx2 and Mitf did not appear to regulate each other's expression, Martinez-Morales et al. (2003) proposed that the 2 transcription factors operate at the same hierarchical level to establish the identity of retinal pigment epithelium.
Akagi et al. (2004) reported that CRX and OTX2 effectively induced the generation of photoreceptor-specific phenotypes from ciliary- and iris-derived cells of adult rat. More than 90% of the CRX- and OTX2-transfected ciliary- and iris-derived cells exhibited rod opsin immunoreactivity, whereas few of the similarly transfected mesencephalon-derived neural stem cells from embryonic rat expressed rod opsin. At least 2 additional key components of the phototransduction cascade, recoverin (179618) and G-delta-T1, were expressed by CRX- and OTX2-transfected iris-derived cells. Akagi et al. (2004) concluded that CRX and OTX2 induced phenotype generation in cells derived from iris or ciliary tissue, which may suggest an approach to photoreceptor cell preparation for retinal transplantation.
Hever et al. (2006) reviewed the expression patterns and complex interactions of 3 genes associated with the development of the eye, SOX2 (184429), OTX2, and PAX6 (607108), noting that these interactions may explain the significant phenotypic overlap between mutations at these 3 loci.
In studies in Xenopus oocytes, Danno et al. (2008) demonstrated specific binding of endogenous OTX2 and SOX2 proteins to a conserved noncoding sequence (CNS1) located approximately 2 kb upstream of the RAX (601881) promoter; reporter assays in Xenopus and HEK93T cells revealed that OTX2 and SOX2 synergistically activated RAX transcription via CNS1. GST pull-down and coimmunoprecipitation assays showed that OTX2 and SOX2 physically interacted, and this interaction was affected by missense mutations located in helices 2 and 3 of the SOX2 HMG domain (R74P, 184429.0008; L97P, 184429.0004, respectively), resulting in reduced induction of transcription via RAX CNS1. Danno et al. (2008) concluded that direct interaction between OTX2 and SOX2 proteins coordinate RAX expression in eye development.
Panman et al. (2014) found that Sox6 (607257), Otx2, and Nolz1 (ZNF503; 613902) were selectively expressed in distinct subpopulations of mouse embryonic and adult midbrain dopamine (mDA) neurons that were at the neural progenitor cell stage. Sox6 selectively localized to substantia nigra pars compacta (SNc) mDA neurons, whereas Otx2 and Nolz1 localized to a subset of ventral tegmental area (VTA) mDA neurons. Otx2 restricted Sox6 expression in mDA neuron progenitors and suppressed Sox6 expression in postmitotic SNc mDA neurons. Sox6, on the other hand, suppressed VTA-specific characteristics in mDA neurons, promoted SNc-specific differentiation of mDA neurons, and maintained the characteristics of postmitotic SNc neurons. Immunohistochemical analysis showed that SOX6 expression in human mDA neurons appeared to recapitulate the characteristics seen in mice.
Early life stress increases risk for depression. Pena et al. (2017) established a 2-hit stress model in mice wherein stress at a specific postnatal period increases susceptibility to adult social defeat stress and causes long-lasting transcriptional alterations that prime the ventral tegmental area (VTA), a brain reward region, to be in a depression-like state. Pena et al. (2017) identified a role for the developmental transcription factor Otx2 as an upstream mediator of these enduring effects. Transient juvenile, but not adult, knockdown of Otx2 in VTA mimics early life stress by increasing stress susceptibility, whereas its overexpression reverses the effects of early life stress. Pena et al. (2017) concluded that their work established a mechanism by which early life stress encodes lifelong susceptibility to stress via long-lasting transcriptional programming in VTA mediated by Otx2.
Syndromic Microphthalmia 5
Using a candidate gene approach, Ragge et al. (2005) analyzed 333 patients with ocular malformation spectrum defects and identified heterozygous mutations in the OTX2 gene in 11 affected individuals from 8 families (see MCOPS5, 610125). In 2 families, the mutations occurred de novo in severely affected offspring (600037.0001 and 600037.0002, respectively), and in 2 other families, the mutations were inherited from a gonosomal mosaic parent (600037.0003 and 600037.0004, respectively). Ragge et al. (2005) stated that data from these 4 families supported a simple model in which OTX2 heterozygous loss-of-function mutations cause ocular malformations. The other 4 families displayed complex inheritance patterns, suggesting that OTX2 mutations alone may not lead to consistent phenotypes.
Wyatt et al. (2008) analyzed the OTX2 gene in 165 patients with ocular malformations, primarily clinical anophthalmia, microphthalmia, and/or coloboma, and identified heterozygosity for 2 whole gene deletions, involving OTX2 and several other genes, and 2 nonsense and 2 frameshift mutations, in 8 patients from 6 families.
In an 8.5-year-old Japanese girl with bilateral clinical anophthalmia, short stature, developmental delay, and partial growth hormone deficiency, who was negative for mutation in the HESX1 (601802) and POU1F1 (173110) genes, Dateki et al. (2008) identified a de novo heterozygous frameshift mutation in the OTX2 gene (600037.0005).
In a 6-year-old Japanese boy with bilateral clinical anophthalmia, short stature, and combined pituitary hormone deficiency, Tajima et al. (2009) identified a de novo heterozygous frameshift mutation in the OTX2 gene (600037.0007).
Dateki et al. (2010) analyzed the OTX2 gene in 16 patients with ocular anomalies, short stature, and pituitary dysfunction, 12 patients with ocular anomalies with or without short stature in whom pituitary function was not investigated, and 66 patients with pituitary dysfunction without ocular anomalies. The patients were negative for mutation in genes known to be associated with their respective phenotypes. Dateki et al. (2010) identified 3 heterozygous OTX2 truncation mutations in 4 unrelated patients (see, e.g., 600037.0009 and 600037.0010) and a microdeletion involving the OTX2 gene in 1 patient. The authors concluded that OTX2 mutations are associated with variable pituitary phenotype, with no genotype-phenotype correlations.
In a 13.5-year-old boy with unilateral clinical anophthalmia, short stature, and isolated GH deficiency, Ashkenazi-Hoffnung et al. (2010) analyzed the HESX1, SOX2 (184429), and OTX2 genes, and identified heterozygosity for a missense mutation in the OTX2 DNA-binding domain (600037.0011).
In a large 4-generation French family in which 17 individuals had microphthalmia or clinical anophthalmia, Chassaing et al. (2012) identified a heterozygous 1-bp deletion in the OTX2 gene (316delC; 600037.0012) that segregated with disease. Included in the pedigree were 3 deceased offspring with otocephaly (see 202650), from whom DNA was unavailable; however, a deceased male infant with an intermediate phenotype was also found to be heterozygous for the 1-bp deletion. Because of the phenotypic variability observed in the French family, Chassaing et al. (2012) screened 5 additional candidate genes known to play a role in vertebrate otocephalic malformations, including PRRX1 (167420), but did not detect any likely pathogenic variants. The authors concluded that loss-of-function OTX2 mutations do not sufficiently explain the complex anatomic defects in patients with otocephaly/dysgnathia, suggesting the requirement for a second genetic hit.
In a mother with unilateral severe microphthalmia and her male fetus with agnathia-otocephaly complex, Patat et al. (2013) identified heterozygosity for a nonsense mutation in the OTX2 gene (R97X; 600037.0013). The fetus also carried a heterozygous synonymous OTX2 variant (c.525C-G) that was inherited from his asymptomatic father; however, the authors stated that it was unlikely that the silent variant explained the intrafamilial phenotypic variability.
Combined Pituitary Hormone Deficiency 6
In 19 patients with hypopituitarism (CPHD6; 613986), Diaczok et al. (2008) analyzed 8 genes encoding pituitary-specific transcription factors, including HESX1, LHX3 (600577), LHX4 (602146), OTX2, PITX2 (601542), POU1F1, PROP1 (601538), and SIX6 (606326), and identified heterozygosity for a missense mutation in the OTX2 gene (600037.0006) in 2 unrelated patients. One was a 6-year-old boy with deficiency of GH, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH), who on MRI had an ectopic neurohypophysis, along with a hypoplastic adenohypophysis and absent or severely hypoplastic pituitary stalk. The other patient was a 14-year-old girl with deficiency of TSH, ACTH, and GH, in whom MRI at age 2 months showed hypoplasia of the pituitary with a posterior bright spot. Neither patient had midline or optic nerve abnormalities.
Early-Onset Retinal Dystrophy with or without Pituitary Dysfunction
Henderson et al. (2009) analyzed DNA samples from 142 patients with Leber congenital amaurosis (LCA; see 204000) or severe childhood-onset retinal dystrophy (RD; see 613341) using an 'LCA chip' involving 8 LCA- and RD-associated genes, as well as screening the OTX2 gene. In a 7-year-old boy with early-onset retinal dystrophy, who was negative for all variants assayed by the LCA chip, they identified heterozygosity for a de novo nonsense mutation in the OTX2 gene (600037.0008). The patient also had failure to thrive and subsequent short stature (see 610125), and growth hormone deficiency was suggested indirectly due to low levels of IGF1 (147440) and IGFBP3 (146732). Henderson et al. (2009) stated that the phenotypic spectrum observed in this patient was consistent with the assigned multiple roles of OTX2 in the development and function of both the retinal pigment epithelium (RPE) and neural retina, as well as in the pituitary.
In affected individuals from 2 Caucasian Canadian families segregating autosomal dominant pattern retinal dystrophy without pituitary dysfunction, Vincent et al. (2014) identified heterozygosity for a missense mutation in the OTX2 gene (E79K; 600037.0014).
The mid/hindbrain junction can act as an organizer to direct the development of the midbrain and anterior hindbrain. In mice, Otx2 is expressed in the forebrain and midbrain and Gbx2 (601135) is expressed in the anterior hindbrain, with a shared border at the level of the mid/hindbrain organizer. Millet et al. (1999) demonstrated that in Gbx2 -/- mutants, the earliest phenotype is a posterior expansion of the Otx2 domain during early somite stages. Furthermore, organizer genes are expressed at the shifted Otx2 border, but not in a normal spatial relationship. To test whether Gbx2 is sufficient to position the mid/hindbrain organizer, Millet et al. (1999) transiently expressed Gbx2 in the caudal Otx2 domain and found that the Otx2 caudal border was indeed shifted rostrally, and a normal-appearing organizer formed at this new Otx2 border. Transgenic embryos then showed an expanded hindbrain and a reduced midbrain at embryonic day 9.5 to 10. Millet et al. (1999) proposed that the formation of a normal mid/hindbrain organizer depends on a sharp Otx2 caudal border and that Gbx2 is required to position and sharpen this border.
By ectopically expressing Otx2 in the murine presumptive anterior hindbrain using a knockin strategy into the En1 (131290) locus, Broccoli et al. (1999) investigated whether the caudal limit of Otx2 expression is instrumental in positioning the isthmic organizer (midbrain/hindbrain junction) and in specifying midbrain versus hindbrain fate. Transgenic offspring displayed a cerebellar ataxia. Morphologic and histologic studies of adult transgenic brains revealed that most of the anterior cerebellar vermis is missing, whereas the inferior colliculus is complementarily enlarged. During early neuronal pattern formation, expression of the midbrain markers Wnt1 (164820) and ephrin A5 (601535), the isthmic organizer markers Pax2 (167409) and Fgf8 (600483), and the hindbrain marker Gbx2 are shifted caudally in the presumptive hindbrain territory. Broccoli et al. (1999) concluded that the caudal limit of Otx2 expression is sufficient for positioning the isthmic organizer and encoding caudal midbrain fate within the mid/hindbrain domain.
Kimura-Yoshida et al. (2005) found that Otx2 deficiency resulted in defective conversion of the mouse embryonic axis from the proximal-distal orientation to a prospective anterior-posterior polarity. Defective axis conversion was rescued by expression of Dkk1 (605189), a Wnt (see WNT1; 164820) antagonist, or following removal of 1 copy of the beta-catenin gene (see CTNNB1; 116806). Furthermore, the asymmetric distribution of beta-catenin localization was impaired in Otx2-deficient embryos.
Chassaing et al. (2012) transiently suppressed the zebrafish ortholog of OTX2. At 5 days postfertilization, the zebrafish showed mild microphthalmia and shortening of the pharyngeal skeleton that increased in penetrance in a dose-dependent manner. Combined suppression of otx2 and other otocephaly-associated genes, including prrx1 (167420), pgap1 (611655), and msx1 (142983), demonstrated a synergistic exacerbation of the phenotypes: pairwise suppression resulted in increased mortality and a new class of embryos that displayed severe microphthalmia, eye fusion along the midline, and severe disorganization of mandibular cartilage. Chassaing et al. (2012) concluded that suppression of otx2, in combination with loss of function of other loci contributing to otocephaly phenotypes, can modulate phenotypic severity in the manifestation of craniofacial malformations.
In mouse, Zhang et al. (2018) showed that downregulation of Otx2 precedes the initiation of the primordial germ cell (PGC) program both in vitro and in vivo. Deletion of Otx2 in vitro markedly increased the efficiency of PGC-like cell differentiation and prolonged the period of PGC competence. In the absence of Otx2 activity, differentiation of PGC-like cells became independent of the otherwise essential cytokine signals, with germline entry initiating even in the absence of the PGC transcription factor Blimp1 (603423). Deletion of Otx2 in vivo increased primordial germ cell numbers. Zhang et al. (2018) concluded that OTX2 functions repressively upstream of PGC transcription factors, acting as a roadblock to limit entry of epiblast cells to the germline to a small window in space and time, thereby ensuring correct numerical segregation of germline cells from the soma.
In a boy with right clinical anophthalmia and left microphthalmia and associated features (MCOPS5; 610125), Ragge et al. (2005) identified heterozygosity for a de novo 2-bp insertion (464GC) in exon 5 of the OTX2 gene, predicted to result in a nonsense codon 22 amino acids downstream. Based on numbering from the first residue of the initiation codon as +1, the 635insGC mutation is renumbered as 464insGC, and exon numbering includes the first 2 noncoding exons (Dateki et al., 2008). The patient also had left-sided persistent pupillary membrane, iris coloboma, high hypermetropia, and chorioretinal coloboma. MRI scan at age 1 month showed partial agenesis of the corpus callosum with a normal-sized pituitary gland, absent right optic nerve and small left optic nerve, thin chiasm, and malformation of the hippocampi bilaterally. Examination at age 4 years revealed marked developmental delay, generalized hypotonia, increased joint laxity, and microcephaly. Neither the parents nor the unaffected brother carried the mutation.
In a boy with asymmetric microphthalmia and associated features (MCOPS5; 610125), Ragge et al. (2005) identified heterozygosity for a de novo 265C-G transversion in exon 5 of the OTX2 gene, resulting in an arg89-to-gly (R89G) substitution in the homeodomain. On an MRI at age 3 weeks, there was bilateral optic nerve aplasia, the chiasm was not visualized, and there was thinning of the corpus callosum anteriorly; when repeated at 2 years of age, no optic chiasm was seen but the corpus callosum appeared normal. Horizontal corneal diameters were 6.5 mm and 8.0 mm on the right and left, respectively. The only systemic abnormalities at birth were midline dermoid cysts on the forehead and nasal bridge. Cognitive and language skills were normal at age 4.
Based on numbering from the initiation codon, 346C-G is renumbered as 265C-G, and exon numbering includes the first 2 noncoding exons (Dateki et al., 2008).
In a female infant with bilateral severe microphthalmia and associated features (MCOPS5; 610125), Ragge et al. (2005) identified heterozygosity for a 1-bp deletion (81delC) in exon 3 of the OTX2 gene, predicted to result in a termination codon in exon 4. CT scan revealed a thickened septum pellucidum and slightly enlarged lateral ventricles. A fetus, terminated after ultrasound revealed bilateral microphthalmia and agenesis of the corpus callosum, also carried the mutation. The phenotypically normal mother was found to be a gonosomal mosaic carrier of the mutation.
Based on numbering from the first residue of initiation codon as +1, the 252delC mutation is renumbered as 81delC, and exon numbering includes the first 2 noncoding exons (Dateki et al., 2008).
In a sister and brother with bilateral microphthalmia and associated features (MCOPS5; 610125), Ragge et al. (2005) identified heterozygosity for a 537T-A transversion in exon 5 of the OTX2 gene, resulting in a tyr179-to-ter (Y179X) substitution in the C-terminal domain. The sister also had bilateral colobomas and microcornea, left-sided cataract, bilateral fifth finger clinodactyly, severe learning difficulties, and a seizure disorder. The brother, who had borderline microphthalmic eyes, was given a diagnosis of Leber congenital amaurosis (LCA; see 204000) at birth; examination at age 26 years revealed pale optic discs, thin retinal vessels, atrophic maculae, and large clumps of pigment in the midperiphery, consistent with the diagnosis of LCA. ERG was absent, and he had nystagmus, bilateral peripheral anterior synechiae, and a right-sided hearing loss. The mother was found to be a gonosomal mosaic carrier of the mutation; examination of her eyes revealed retinal dystrophy comparable to that seen in her son, night blindness, and extensive peripheral field loss bilaterally.
Based on numbering from the initiation codon as +1, 708T-A is renumbered as 537T-A, and exon numbering includes the first 2 noncoding exons (Dateki et al., 2008).
In an 8.5-year-old Japanese girl with bilateral clinical anophthalmia, short stature, developmental delay, and partial growth hormone deficiency (MCOPS5; 610125), Dateki et al. (2008) identified heterozygosity for a de novo 1-bp insertion (402insC) in exon 5 of the OTX2 gene, predicted to cause a frameshift and premature termination codon resulting in retention of the homeodomain but loss of the transactivation domain as well as the SIWSPA motif. The mutation was not found in either parent. Functional studies showed that both wildtype and mutant protein localized to the nucleus; however, wildtype OTX2 markedly transactivated the reporters for the IRBP (180290), HESX1 (601802), and POU1F1 (173110) genes, whereas mutant OTX2 barely retained transactivation activities and had no dominant-negative effects.
In 2 unrelated patients with multiple pituitary hormone deficiencies (CPHD6; 613986), Diaczok et al. (2008) identified heterozygosity for a 698A-G transition in exon 5 of the OTX2 gene, resulting in an asn233-to-ser (N233S) substitution in the transcription factor region. Electrophoretic mobility shift assay (EMSA) with murine Otx2 demonstrated that both wildtype and mutant Otx2 bound equally well to 2 specific sites in the 5-prime flanking region of the HESX1 gene (601802). Functional studies in 293T cells showed that the mutant Otx2 had a dominant negative effect on the proximal promoter region of HESX1 and a multiple bicoid binding site reporter construct, and studies in the GH-producing GH3 cells showed that N233S Otx2 repressed reporter expression. Diaczok et al. (2008) concluded that the heterozygous N233S OTX2 mutation acts as a dominant inhibitor of the HESX1 gene.
In a 6-year-old boy with bilateral clinical anophthalmia, short stature, and combined pituitary hormone deficiency (MCOPS5; 610125), Tajima et al. (2009) identified a de novo heterozygous 2-bp insertion (576insCT) in exon 5 of the OTX2 gene, causing a frameshift and premature termination codon, resulting in a protein lacking the C-terminal region. The mutation was not found in the unaffected parents or in 50 Japanese controls. Functional analysis in mice revealed that the mutant protein localized to the nucleus, but activation of the promoters of the HESX1 (601802) and POU1F1 (173110) genes was absent or less than 50% of wildtype, respectively.
In a 7-year-old boy with severe childhood-onset retinal dystrophy and growth hormone deficiency (see 610125), Henderson et al. (2009) identified heterozygosity for a de novo 413C-G transversion in the OTX2 gene, resulting in a ser138-to-ter (S138X) substitution. The patient, who was noted to have poor vision and nyctalopia during his first year of life, also had failure to thrive and growth hormone deficiency. The mutation was not found in his unaffected parents or in 181 controls.
In a 3-year-old boy with right clinical anophthalmia and left microphthalmia, who had developmental delay, short stature, and growth hormone deficiency (MCOPS5; 610125), Dateki et al. (2010) identified heterozygosity for a de novo 16-bp deletion (221_236del) in exon 4 of the OTX2 gene, predicted to cause a frameshift and premature termination codon. The deletion was not found in the unaffected parents or in 100 controls. Functional analysis revealed that the mutant protein had no transactivation functions for 4 promoters that were transactivated by wildtype OTX2; no dominant-negative effect was observed. Brain MRI revealed pituitary hypoplasia and ectopic posterior pituitary. The patient also had right-sided retractile testis.
In a 15-year-old boy and an unrelated 10-year-old boy, both of whom had bilateral microphthalmia and developmental delay (MCOPS5; 610125), Dateki et al. (2010) identified heterozygosity for a 562G-T transversion in exon 5 of the OTX2 gene, predicted to cause a gly188-to-ter (G188X) substitution. The mutation was not found in 100 controls; the parents refused molecular studies. Functional analysis revealed that the mutant protein had reduced transactivation function (approximately 50% of wildtype) for the 4 promoters tested, with no dominant-negative effect. The 15-year-old patient had deficiency of the pituitary hormones GH, TSH, PRL, LH, and FSH, and brain MRI revealed pituitary hypoplasia and ectopic posterior pituitary. The 10-year-old patient, who also had seizures, had 'no discernible pituitary dysfunction' and did not undergo brain MRI.
In a 13.5-year-old boy of Sephardic Jewish descent who had unilateral clinical anophthalmia, short stature, and isolated GH deficiency (MCOPS5; 610125), Ashkenazi-Hoffnung et al. (2010) identified heterozygosity for a 270A-T transversion in exon 3 of the OTX2 gene, resulting in an arg90-to-ser (R90S) substitution in the DNA-binding homeodomain. His father, who had short stature but normal eye structure and unknown endocrine status, was also heterozygous for the mutation. The mutation was not present in the unaffected mother or an unaffected brother, and had not previously been found in 261 controls (Ragge et al., 2005; Wyatt et al., 2008). Functional analysis revealed that the R90S mutation did not affect the expression or nuclear localization of the protein, but inhibited its DNA-binding activity as well as its transactivation capability, thus rendering it nonfunctional. No dominant-negative effect was observed.
In affected members of a large 4-generation French family in which 17 individuals had microphthalmia or clinical anophthalmia, 3 of whom also exhibited moderate to severe mental retardation (MCOPS5; 610125), Chassaing et al. (2012) identified a heterozygous 1-bp deletion (c.316delC, NM_021728.2) in the OTX2 gene, causing a frameshift predicted to result in premature termination (Gln106AsnfsTer11) within the glutamine stretch. Included in the pedigree were 3 deceased offspring with otocephaly, from whom DNA was unavailable; however, 2 were sibs born of an affected mother who carried the deletion, and another deceased male infant who exhibited clinical features overlapping both microphthalmia and otocephaly was also found to be heterozygous for the 1-bp deletion. Chassaing et al. (2012) stated that loss-of-function OTX2 mutations do not sufficiently explain the complex anatomic defects in patients with otocephaly/dysgnathia, suggesting the requirement for a second genetic hit.
In a mother with unilateral severe microphthalmia and her male fetus with agnathia-otocephaly complex (see MCOPS5, 610125), Patat et al. (2013) identified heterozygosity for a c.289C-T transition (c.289C-T, NM_021728.2) in the OTX2 gene, resulting in an arg97-to-ter (R97X) substitution. The fetus also carried a heterozygous synonymous OTX2 variant (c.525C-G) that was inherited from his asymptomatic father; however, the authors stated that it was unlikely that the silent variant explained the intrafamilial phenotypic variability.
In affected individuals from 2 Caucasian Canadian families segregating autosomal dominant pattern retinal dystrophy without pituitary dysfunction (see 610125), Vincent et al. (2014) identified heterozygosity for a c.235G-A transition (c.235G-A, NM_001270523.1) in exon 4 of the OTX2 gene, resulting in a glu79-to-lys (E79K) substitution at a highly conserved residue in the homeobox domain. Haplotype analysis revealed a 19.68-cM shared haplotype between SNPs rs17107459 and rs710050; the number of generations between a common ancestor and affected individuals in the youngest generation in each family was estimated to be 5, making them fourth cousins. Of the 7 patients who underwent ocular examination, 3 exhibited a butterfly pattern of retinal dystrophy, 2 showed a grouped pigmentation pattern, 1 showed an annular pattern, and 1 showed only a dull foveal reflex with no apparent pattern.
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