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Review
. 2017 Nov 21;3(6):a002162.
doi: 10.1101/mcs.a002162. Print 2017 Nov.

Novel NR2F1 variants likely disrupt DNA binding: molecular modeling in two cases, review of published cases, genotype-phenotype correlation, and phenotypic expansion of the Bosch-Boonstra-Schaaf optic atrophy syndrome

Charu Kaiwar  1 , Michael T Zimmermann  2 , Matthew J Ferber  3   4 , Zhiyv Niu  3   4 , Raul A Urrutia  5   6 , Eric W Klee  2   4   5 , Dusica Babovic-Vuksanovic  4   5
Affiliations
Review

Novel NR2F1 variants likely disrupt DNA binding: molecular modeling in two cases, review of published cases, genotype-phenotype correlation, and phenotypic expansion of the Bosch-Boonstra-Schaaf optic atrophy syndrome

Charu Kaiwar et al. Cold Spring Harb Mol Case Stud. .

Abstract

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a recently described autosomal dominant disorder caused by mutations in the NR2F1 gene. There are presently 28 cases of BBSOAS described in the literature. Its common features include developmental delay, intellectual disability, hypotonia, optic nerve atrophy, attention deficit disorder, autism spectrum disorder, seizures, hearing defects, spasticity, and thinning of the corpus callosum. Here we report two unrelated probands with novel, de novo, missense variants in NR2F1 The first is a 14-yr-old male patient with hypotonia, intellectual disability, optic nerve hypoplasia, delayed bone age, short stature, and altered neurotransmitter levels on cerebrospinal fluid testing. The second is a 5-yr-old female with severe developmental delay, motor and speech delay, and repetitive motion behavior. Whole-exome sequencing identified a novel missense NR2F1 variant in each case, Cys86Phe in the DNA-binding domain in Case 1, and a Leu372Pro in the ligand-binding domain in Case 2. The presence of clinical findings compatible with BBSOAS along with structural analysis at atomic resolution using homology-based molecular modeling and molecular dynamic simulations, support the pathogenicity of these variants for BBSOAS. Short stature, abnormal CNS neurotransmitters, and macrocephaly have not been previously reported for this syndrome and may represent a phenotypic expansion of BBSOAS. A review of published cases along with new evidence from this report support genotype-phenotype correlations for this disorder.

Keywords: amblyopia; aplasia/hypoplasia of the optic nerve; cortical visual impairment; decreased CSF homovanillic acid (HVA); microretrognathia; optic disc hypoplasia; oromotor apraxia; relative macrocephaly; severe muscular hypotonia; short stature.

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Figures

Figure 1.
Figure 1.
Phenotype of Case 1 with Bosch–Boonstra–Schaaf optic atrophy syndrome. (A) Facial features: deep-set eyes, midface hypoplasia, simplified ear lobules, protruding ears, micrognathia, and retrognathia. (B) Height chart and (C) weight chart. Yellow crosses indicate serial measurements of the patient's height and weight. All marks fall consistently below the third percentile.
Figure 2.
Figure 2.
Phenotype of Case 2 with Bosch–Boonstra–Schaaf optic atrophy syndrome. (A) Facial features: hypertelorism, prominent synorphrys, simplified cupped ear helices, and large head. (B) Height chart and (C) weight chart. Yellow crosses indicate serial measurements of the patient's height and weight.
Figure 3.
Figure 3.
C86F leads to distortion of the zinc-binding site. The zinc-finger domain of NR2F1 and bound DNA are shown in cartoon representation. Solvent atoms are hidden for clarity, and zinc ions are represented by purple spheres. (A) Molecular model of NR2F1 zinc-finger (ZF) domains shows the structural role of C86. (B) A representative from among the largest deviations in wt simulations is shown. Although the zinc ion has moved, the geometry of the binding site is preserved. (C) Throughout simulations of F86, the geometry of the zinc-binding site is significantly altered and zinc ion interacts with residues outside of the binding site. (D) Plotting each frame from the simulation as a point in the dominant principal component (PC) subspace, the two proteins adopted different conformations. (E,F) The distance (Å) between the Cα atom of residue 86 and of two of the other zinc-coordinating residues. Both measures showed stability for the duplicate wt simulations, but instability for C86F. (G) The distance (Å) between zinc-coordinating residues across apo simulations. Probability density plots and structural representatives (inset) show that across triplicate simulations of apo-NR2F1 at 300 K and 360 K, C86F led to greater instability around the ion-binding site.
Figure 4.
Figure 4.
Pathogenic variants in the DBD lead to greater separation from DNA. Four previously reported pathogenic variants were simulated similarly to C86F and wt. We measured the distance between the center of mass (COM) of NR2F1 and of the bound DNA fragment. The separation between the COM of each molecule was monitored, and all pathogenic variants lead to a significant increase. However, the two variants that directly altered zinc-binding residues, C128R and C86F, exhibited the greatest effect.
Figure 5.
Figure 5.
L372P destabilizes the ligand-binding domain (LBD) dimer interface. (A) Examination of our model of the LBD dimer revealed that L372 is in the center of the α-helix that makes up much of the dimer interface. (B) The dimerization helices from each monomer are arranged in parallel, leading to the L372P and G368D residues from each to be facing one another. (C) We observed loss of α-helical content within the dimerization helices after MD simulation. (D) L372P also leads to alteration of binding helix conformation as quantified by larger RMSDs.
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