Association for Research in Vision and Ophthalmology, Investigative Ophthalmology & Visual Science, 2(56), p. 883-891
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Purpose: To define the phenotypic manifestation, confirm the genetic basis and delineate the pathogenic mechanisms underlying an oculo-auricular syndrome (OAS). Methods: Two individuals from a consanguineous family underwent comprehensive clinical phenotyping and electrodiagnostic testing (EDT). Genome-wide microarray analysis and Sanger sequencing of the candidate gene were used to identify the likely causal variant. Protein modelling, Western blotting, and dual luciferase assays were used to assess the pathogenic effect of the variant in vivo. Results: Complex developmental ocular abnormalities of congenital cataract, anterior segment dysgenesis, iris coloboma, early-onset retinal dystrophy and abnormal external ear cartilage presented in the affected family members. Genetic analyses identified a homozygous c.650A>C; p.(Gln217Pro) missense mutation within the highly conserved homeodomain of the H6 family homeobox 1 (HMX1) gene. Protein modelling suggested the variant would have a detrimental effect on protein folding and/or stability. In vitro analyses were able to confirm that the mutation has no effect on protein expression but adversely alters function. Conclusions: OAS is an autosomal recessive condition that has a profound effect on the development of the external ear, anterior segment and retina, leading to significant visual loss at an early age. This study has delineated the phenotype and confirmed HMX1 as the gene causative of OAS, enabling the description of only the second family with the condition. HMX1 is a key player in ocular development, possibly in both the pathway responsible for lens and retina development, and via the gene network integral to optic fissure closure. ; Gillespie, Rachel L Urquhart, Jill Lovell, Simon C Biswas, Susmito Parry, Neil R A Schorderet, Daniel F Lloyd, I Chris Clayton-Smith, Jill Black, Graeme C ENG 2015/01/13 06:00 Invest Ophthalmol Vis Sci. 2015 Jan 8. pii: IOVS-14-15861. doi: 10.1167/iovs.14-15861.