Heterozygous mutations of OTX2 cause severe ocular malformations.
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.
Ragge
Nicola K
NK
Department of Adnexal Surgery, Moorfields Eye Hospital, London, United Kingdom.
Brown
Alison G
AG
Poloschek
Charlotte M
CM
Lorenz
Birgit
B
Henderson
R Alex
RA
Clarke
Michael P
MP
Russell-Eggitt
Isabelle
I
Fielder
Alistair
A
Gerrelli
Dianne
D
Martinez-Barbera
Juan Pedro
JP
Ruddle
Piers
P
Hurst
Jane
J
Collin
J Richard O
JR
Salt
Alison
A
Cooper
Simon T
ST
Thompson
Pamela J
PJ
Sisodiya
Sanjay M
SM
Williamson
Kathleen A
KA
Fitzpatrick
David R
DR
van Heyningen
Veronica
V
Hanson
Isabel M
IM
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
D018398:Homeodomain Proteins; C497659:OTX2 protein, human; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse