title: Heterozygous mutations of OTX2 cause severe ocular malformations.
abstract: Major malformations of the human eye, including microphthalmia and anophthalmia, are examples of phenotypes that recur in families yet often show no clear Mendelian inheritance pattern. Defining loci by mapping is therefore rarely feasible. Using a candidate-gene approach, we have identified heterozygous coding-region changes in the homeobox gene OTX2 in eight families with ocular malformations. The expression pattern of OTX2 in human embryos is consistent with the eye phenotypes observed in the patients, which range from bilateral anophthalmia to retinal defects resembling Leber congenital amaurosis and pigmentary retinopathy. Magnetic resonance imaging scans revealed defects of the optic nerve, optic chiasm, and, in some cases, brain. In two families, the mutations appear to have occurred de novo in severely affected offspring, and, in two other families, the mutations have been inherited from a gonosomal mosaic parent. Data from these four families support a simple model in which OTX2 heterozygous loss-of-function mutations cause ocular malformations. Four additional families display complex inheritance patterns, suggesting that OTX2 mutations alone may not lead to consistent phenotypes. The high incidence of mosaicism and the reduced penetrance have implications for genetic counseling.
authors.affiliation: Department of Adnexal Surgery, Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Nicola K
authors.initials: NK
authors.lastname: Ragge
authors.forename: Alison G
authors.initials: AG
authors.lastname: Brown
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Poloschek
authors.forename: Birgit
authors.initials: B
authors.lastname: Lorenz
authors.forename: R Alex
authors.initials: RA
authors.lastname: Henderson
authors.forename: Michael P
authors.initials: MP
authors.lastname: Clarke
authors.forename: Isabelle
authors.initials: I
authors.lastname: Russell-Eggitt
authors.forename: Alistair
authors.initials: A
authors.lastname: Fielder
authors.forename: Dianne
authors.initials: D
authors.lastname: Gerrelli
authors.forename: Juan Pedro
authors.initials: JP
authors.lastname: Martinez-Barbera
authors.forename: Piers
authors.initials: P
authors.lastname: Ruddle
authors.forename: Jane
authors.initials: J
authors.lastname: Hurst
authors.forename: J Richard O
authors.initials: JR
authors.lastname: Collin
authors.forename: Alison
authors.initials: A
authors.lastname: Salt
authors.forename: Simon T
authors.initials: ST
authors.lastname: Cooper
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Thompson
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Sisodiya
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Williamson
authors.forename: David R
authors.initials: DR
authors.lastname: Fitzpatrick
authors.forename: Veronica
authors.initials: V
authors.lastname: van Heyningen
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Hanson
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000853:Anophthalmos / Q000235:genetics; D001921:Brain / Q000000981:diagnostic imaging; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D005124:Eye Abnormalities / Q000235:genetics* / Q000473:pathology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D014644:Genetic Variation; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008957:Models, Genetic; D009030:Mosaicism; D009154:Mutation; D016366:Open Reading Frames; D051857:Otx Transcription Factors; D010375:Pedigree; D019683:Penetrance; D017434:Protein Structure, Tertiary; D011859:Radiography; D017422:Sequence Analysis, DNA
chemical_list: D018398:Homeodomain Proteins; C497659:OTX2 protein, human; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse