NR2F1 mutations cause optic atrophy with intellectual disability.
Optic nerve atrophy and hypoplasia can be primary disorders or can result from trans-synaptic degeneration arising from cerebral visual impairment (CVI). Here we report six individuals with CVI and/or optic nerve abnormalities, born after an uneventful pregnancy and delivery, who have either de novo heterozygous missense mutations in NR2F1, also known as COUP-TFI, or deletions encompassing NR2F1. All affected individuals show mild to moderate intellectual impairment. NR2F1 encodes a nuclear receptor protein that regulates transcription. A reporter assay showed that missense mutations in the zinc-finger DNA-binding domain and the putative ligand-binding domain decrease NR2F1 transcriptional activity. These findings indicate that NR2F1 plays an important role in the neurodevelopment of the visual system and that its disruption can lead to optic atrophy with intellectual disability.
Department of Human Genetics, Radboud university medical center, 6500 HB Nijmegen, the Netherlands; Bartiméus, Institute for the Visually Impaired, 3700 BA Zeist, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud university medical center, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud university medical center, 6500 HB Nijmegen, the Netherlands.
Daniëlle G M
DG
Bosch
Bartiméus, Institute for the Visually Impaired, 3700 BA Zeist, the Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud university medical center, 6500 HB Nijmegen, the Netherlands.
F Nienke
FN
Boonstra
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Claudia
C
Gonzaga-Jauregui
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Mafei
M
Xu
Department of Human Genetics, Radboud university medical center, 6500 HB Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud university medical center, 6500 HB Nijmegen, the Netherlands; Institute for Genetic and Metabolic Disease, Radboud university medical center, 6500 HB Nijmegen, the Netherlands.
Joep
J
de Ligt
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Shalini
S
Jhangiani
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
Wojciech
W
Wiszniewski
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Donna M
DM
Muzny
Department of Human Genetics, Radboud university medical center, 6500 HB Nijmegen, the Netherlands.
Helger G
HG
Yntema
Department of Human Genetics, Radboud university medical center, 6500 HB Nijmegen, the Netherlands.
Rolph
R
Pfundt
Department of Human Genetics, Radboud university medical center, 6500 HB Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud university medical center, 6500 HB Nijmegen, the Netherlands; Institute for Genetic and Metabolic Disease, Radboud university medical center, 6500 HB Nijmegen, the Netherlands.
Lisenka E L M
LE
Vissers
Department of Human Genetics, Radboud university medical center, 6500 HB Nijmegen, the Netherlands; Research Institute for Oncology, Radboud university medical center, 6500 HB Nijmegen, the Netherlands.
Liesbeth
L
Spruijt
Department of Human Genetics, Radboud university medical center, 6500 HB Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud university medical center, 6500 HB Nijmegen, the Netherlands.
Ellen A W
EA
Blokland
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
Chun-An
CA
Chen
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Richard A
RA
Lewis
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Sophia Y
SY
Tsai
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Richard A
RA
Gibbs
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Ming-Jer
MJ
Tsai
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
James R
JR
Lupski
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USA; Department of Neuroscience, Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
Huda Y
HY
Zoghbi
Department of Human Genetics, Radboud university medical center, 6500 HB Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud university medical center, 6500 HB Nijmegen, the Netherlands.
Frans P M
FP
Cremers
Department of Human Genetics, Radboud university medical center, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud university medical center, 6500 HB Nijmegen, the Netherlands; Institute for Genetic and Metabolic Disease, Radboud university medical center, 6500 HB Nijmegen, the Netherlands. Electronic address: Bert.deVries@radboudumc.nl.
Bert B A
BB
de Vries
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: schaaf@bcm.edu.
Christian P
CP
Schaaf
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D051838:COUP Transcription Factor I / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009896:Optic Atrophy / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D055815:Young Adult; D016335:Zinc Fingers / Q000235:genetics
D051838:COUP Transcription Factor I; D004268:DNA-Binding Proteins; C497589:NR2F1 protein, human