title: Abrogation of HMX1 function causes rare oculoauricular syndrome associated with congenital cataract, anterior segment dysgenesis, and retinal dystrophy.
abstract: OBJECTIVE
  To define the phenotypic manifestation, confirm the genetic basis, and delineate the pathogenic mechanisms underlying an oculoauricular 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 vitro.
  
  
  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 predicts that the variant may have a detrimental effect on protein folding and/or stability. In vitro analyses were able to demonstrate that the mutation has no effect on protein expression but adversely alters function.
  
  
  CONCLUSIONS
  Oculoauricular syndrome 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.
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Gillespie
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: Jill
authors.initials: J
authors.lastname: Urquhart
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Lovell
authors.affiliation: Manchester Royal Eye Hospital, Manchester Academic Health Science Centre, The University of Manchester, Central Manchester Foundation Trust, Manchester, United Kingdom.
authors.forename: Susmito
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Manchester Royal Eye Hospital, Manchester Academic Health Science Centre, The University of Manchester, Central Manchester Foundation Trust, Manchester, United Kingdom.
authors.forename: Neil R A
authors.initials: NR
authors.lastname: Parry
authors.affiliation: School of Life Science, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schorderet
authors.affiliation: Manchester Royal Eye Hospital, Manchester Academic Health Science Centre, The University of Manchester, Central Manchester Foundation Trust, Manchester, United Kingdom.
authors.forename: I Chris
authors.initials: IC
authors.lastname: Lloyd
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Saint Mary's Hospital, Manchester, United Kingdom Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Saint Mary's Hospital, Manchester, United Kingdom Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: Graeme C
authors.initials: GC
authors.lastname: Black
mesh_terms: D000015:Abnormalities, Multiple; D000869:Anterior Eye Segment / Q000002:abnormalities*; D015153:Blotting, Western; D002386:Cataract / Q000151:congenital / Q000175:diagnosis / Q000235:genetics*; D002478:Cells, Cultured; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004423:Ear / Q000002:abnormalities*; D005124:Eye Abnormalities / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D005820:Genetic Testing; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D058499:Retinal Dystrophies / Q000151:congenital / Q000175:diagnosis* / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D004247:DNA
keywords: anterior segment dysgenesis; coloboma; congenital cataract; early-onset retinal dystrophy; oculoauricular syndrome