February 2015
Volume 56, Issue 2
Research Highlight  |   February 2015
Networks of Genes Governing the Development of Optic and Otic Vesicles: Implications for Eye and Ear Development
Investigative Ophthalmology & Visual Science February 2015, Vol.56, 892. doi:https://doi.org/10.1167/iovs.15-16420
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      Marc M. Abitbol; Networks of Genes Governing the Development of Optic and Otic Vesicles: Implications for Eye and Ear Development. Invest. Ophthalmol. Vis. Sci. 2015;56(2):892. https://doi.org/10.1167/iovs.15-16420.

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      © ARVO (1962-2015); The Authors (2016-present)

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A homozygous 26 nucleotide deletion in the first exon of the HMX1 gene, generating a truncating protein that lacked the complete homeodomain, was shown to cause a complex oculo-auricular syndrome associating congenital cataract, anterior segment dysgenesis, iris coloboma, early-onset retinal dystrophy, and abnormal external ear cartilage in affected family members.1 In this issue, Gillespie et al.2 report a homozygous c.650A>C; p.(Gln217Pro) missense mutation within the highly conserved homeodomain of the HMX1 gene, causing the same syndrome and demonstrating convincingly the pathogenicity of this mutation. To our knowledge, this is only the second identified genetic alteration causing this syndrome. The confirmation that different mutations in the same gene cause the same genetic syndrome or disease is important from an epistemological point of view, as it confirms and strengthens the validity of the first discovery; from a clinical point of view, since it contributes to further delineate this rare syndrome; and from a developmental genetics point of view, as it highlights the importance of the structural integrity of the HMX1 homeodomain for the normal development of the otic and optic vesicles in mammals. More importantly, it stresses our insufficient knowledge about the gene and protein networks involved in the development of these vesicles. In mammals, a network variably composed of genes belonging to the PAX, SIX, EYA, and DACH families has a key regulatory role in the development of multiple organs, including the eye, muscle, ears, heart, lungs, endocrine glands, placodes, pharyngeal pouches, craniofacial skeleton, and parathyroid.3 The sequential expression of select homeotic gene families governs the morphogenetic program leading to the constitution of normal eyes. The expression of several distinct homeotic genes in the dorsolateral region of the otic placode triggers the development of the vestibular system, and the expression of different specific genes in the ventromedial region of the otic placode is associated with the development of the auditory sensory organ.4 Of utmost importance, this work suggests that HMX1 might belong to the network of genes involved in the pathophysiology of coloboma. Indeed, HMX1 has been identified recently as a target of miR-204, a microRNA that has been implicated in optic fissure closure, lens differentiation, optic cup development, and subsequent dorsoventral patterning of the retina by way of Meis2 gene dosage and subsequent misregulation of genes in the Pax6 pathway.5 It remains to determine whether miR204 has any important role in HMX1 expression in the otic placode, and to identify thoroughly the network of regulatory genes and proteins involved in eye and ear development. 
Schorderet DF Nichini O Boisset G Mutation in the human homeobox gene NKX5-3 causes an oculo-auricular syndrome. Am J Hum Genet. 2008; 82: 1178–1184. [CrossRef] [PubMed]
Gillespie RL Urquhart J Lovell SC Abrogation of HMX1 function causes rare oculo-auricular syndrome associated with congenital cataract, anterior segment dysgenesis, and retinal dystrophy. Invest Ophthalmol Vis Sci. 2015; 56: 883–891. [CrossRef] [PubMed]
Tadjuidje E Hegde RS. The Eyes Absent proteins in development and disease. Cell Mol Life Sci. 2013; 70: 1897–1913. [CrossRef] [PubMed]
Represa J Frenz DA Van De Water TR. Genetic patterning of embryonic inner ear development. Acta Otolaryngol. 2000; 120: 5–10. [PubMed]
Conte I Carrella S Avellino R miR-204 is required for lens and retinal development via Meis2 targeting. Proc Natl Acad Sci U S A. 2010; 107: 15491–15496. [CrossRef] [PubMed]

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