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NR2F1 mutations cause optic atrophy with intellectual disability

Publicatie van: Bosch DG(1), Boonstra FN(2), Gonzaga-Jauregui C(3), Xu M(4), de Ligt J(5), Jhangiani S(6), Wiszniewski W(7), Muzny DM(6), Yntema HG(8), Pfundt R(8), Vissers LE(5), Spruijt L(9), Blokland EA(10), Chen CA(11); Baylor-Hopkins Center for Mendelian Genomics, Lewis RA(12), Tsai SY(4), Gibbs RA(13), Tsai MJ(4), Lupski JR(14), Zoghbi HY(15), Cremers FP(10), de Vries BB(16), Schaaf CP(17).


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. 

In: Am J Hum Genet. 2014 Feb 6;94(2):303-9. doi: 10.1016/j.ajhg.2014.01.002. Epub 2014 Jan 23.