A novel heterozygous SOX2 mutation causing congenital bilateral anophthalmia, hypogonadotropic hypogonadism and growth hormone deficiency

Macchiaroli, Annamaria; Kelberman, Daniel; Auriemma, Renata S.; Drury, Suzanne; Islam, Lily; Galimberti, Sara; Ironi, Gabriele; Lench, Nicholas; Sowden, Jane C.; Colao, Annamaria; Pivonello, Rosario; Cavallo, Luciano; Gasperi, Maurizio; Faienza, Maria Felicia

doi:10.1016/j.gene.2013.10.043

Cited by 24 publications

(12 citation statements)

References 19 publications

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“…These can pose significant challenges for treatment, especially when linked to other clinical problems. For example, heterozygous loss-of-function mutations in SOX2 in humans are associated with severe eye defects, ranging from micropthalmia to anopthalmia, but affected individuals also exhibit other congenital defects including hypopituitarism that can affect everything from height to puberty ( Macchiaroli et al, 2014 ; Suzuki et al, 2014 ). However, the role of SOX2 in the developing pituitary is not well understood.…”

Section: Discussionmentioning

confidence: 99%

SOX2 is sequentially required for progenitor proliferation and lineage specification in the developing pituitary

2016

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Sox2 mutations are associated with pituitary hormone deficiencies and the protein is required for pituitary progenitor proliferation, but its function has not been well characterized in this context. SOX2 is known to activate expression of Six6, encoding a homeodomain transcription factor, in the ventral diencephalon. Here, we find that the same relationship likely exists in the pituitary. Moreover, because Six6 deletion is associated with a similar phenotype as described here for loss of Sox2, Six6 appears to be an essential downstream target of SOX2 in the gland. We also uncover a second role for SOX2. Whereas cell differentiation is reduced in Sox2 mutants, some endocrine cells are generated, such as POMC-positive cells in the intermediate lobe. However, loss of SOX2 here results in complete downregulation of the melanotroph pioneer factor PAX7, and subsequently a switch of identity from melanotrophs to ectopic corticotrophs. Rescuing proliferation by ablating the cell cycle negative regulator p27 (also known as Cdkn1b) in Sox2 mutants does not restore melanotroph emergence. Therefore, SOX2 has two independent roles during pituitary morphogenesis; firstly, promotion of progenitor proliferation, and subsequently, acquisition of melanotroph identity.

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Section: Discussionmentioning

confidence: 99%

SOX2 is sequentially required for progenitor proliferation and lineage specification in the developing pituitary

2016

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“…Other evidence shows that the Wnt/β-catenin pathway also plays a clinically relevant role in hypothalamic patterning, as SOD patients with variants in the Wnt effector TCF7L1 have been identified (Gaston-Massuet et al, 2016). Multiple additional genes have been linked to developmental disorders of the hypothalamus that lead to hypopituitarism (Mehta and Dattani, 2008), including SOX2 and SOX3 (Woods et al, 2005;Macchiaroli et al, 2014).…”

Section: Box 1 Hypothalamic Dysfunctionmentioning

confidence: 99%

Development of the hypothalamus: conservation, modification and innovation

2017

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The hypothalamus, which regulates fundamental aspects of physiological homeostasis and behavior, is a brain region that exhibits highly conserved anatomy across vertebrate species. Its development involves conserved basic mechanisms of induction and patterning, combined with a more plastic process of neuronal fate specification, to produce brain circuits that mediate physiology and behavior according to the needs of each species. Here, we review the factors involved in the induction, patterning and neuronal differentiation of the hypothalamus, highlighting recent evidence that illustrates how changes in Wnt/β-catenin signaling during development may lead to species-specific form and function of this important brain structure.

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“…In humans, mutations in several transcription factor genes have been reported to cause disruption of vertebrate eye development or maintenance. [ 10 11 12 13 14 15 27 28 29 30 31 32 ] This led to the hypothesis that polymorphisms in these genes may also predispose towards the risk of congenital eye disorders. In our previous studies on mutation screening in candidate genes for congenital cataract and microphthalmia, we observed that the frequency of two polymorphisms FOXE3 -p.Ala170Ala and PITX3 -p.Ile95Ile was higher in congenital cataract and microphthalmia cases as compared to controls.…”

Section: Discussionmentioning

confidence: 99%

Association of FOXE3-p.Ala170Ala and PITX3-p.Ile95Ile polymorphisms with congenital cataract and microphthalmia

Vidya¹,

Ganatra

Vasavada

et al. 2018

J Ophthalmic Vis Res

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Purpose:To investigate the association of FOXE3-p.Ala170Ala (rs34082359) and PITX3-p.Ile95Ile (rs2281983) polymorphisms with congenital cataract and microphthalmia in a western Indian population.Methods:FOXE3-p.Ala170Ala (c.510C>T) and PITX3-p.Ile95Ile (c.285C>T) polymorphisms were genotyped in 561 subjects consisting of 242 cases with congenital cataract, 52 with microphthalmia, and 267 controls using polymerase chain reaction-restriction fragment length polymorphism. Approximately 10% of samples were randomly sequenced for each single nucleotide polymorphism to confirm the genotypes. The prediction of mRNA secondary structure for polymorphism FOXE3-p.Ala170Ala and PITX3-p.Ile95Ile was performed.Results:A significantly high frequency of T allele and a borderline significance in the frequency of TT genotype of FOXE3-p.Ala170Ala was observed in microphthalmia cases, as compared to controls [T allele: OR: [CI] = 1.8 [1.15-2.72], P = 0.0115; TT: OR [CI] = 2.9 [1.14-7.16], P = 0.0291). The frequency of CC genotype was significantly low in microphthalmia cases when compared to controls (CC: OR [CI] = 0.5 [0.24-0.86, P = 0.0150). There was no significant difference in the allele and genotype frequencies of PITX3-p.Ile95Ile between cases and controls. A slight free energy change was observed in the secondary structure of mRNA between the FOXE3-p.Ala170Ala C-allele (-917.60 kcal/mol) and T-allele (-916.80 kcal/mol) and between PITX3-p.Ile95Ile C-allele (-659.80 kcal/mol) and T-allele (-658.40 kcal/mol).Conclusion:The present findings indicate that FOXE3-p.Ala170Ala ‘T’ allele and ‘TT’ genotype could be predisposing factors for microphthalmia while ‘CC’ genotype might play a protective role against it. A reduction in the free energy change associated with FOXE3-p.Ala170Ala ‘T’ allele could further contribute towards disease risk.

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A novel heterozygous SOX2 mutation causing congenital bilateral anophthalmia, hypogonadotropic hypogonadism and growth hormone deficiency

Cited by 24 publications

References 19 publications

SOX2 is sequentially required for progenitor proliferation and lineage specification in the developing pituitary

SOX2 is sequentially required for progenitor proliferation and lineage specification in the developing pituitary

Development of the hypothalamus: conservation, modification and innovation

Association of FOXE3-p.Ala170Ala and PITX3-p.Ile95Ile polymorphisms with congenital cataract and microphthalmia

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