Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA-protein interaction

Purpose: Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions. Methods: We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGUeye) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants. Results: Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease. Conclusion: Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants

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Gamma and He Ion Radiolysis of Copper Oxides

Two copper oxides, cuprous and cupric oxide, were characterized using a variety of surface techniques including scanning electron microscopy, temperature-programmed desorption, diffuse reflectance infrared Fourier transform spectroscopy, Raman spectroscopy, X-ray photoelectron spectroscopy, and X-ray diffraction to analyze changes in the oxide surface following irradiation with γ-rays and 5 MeV ⁴He ions. The radiation chemical yield for molecular hydrogen was also measured for copper oxide powders with adsorbed water as well as with slurries containing various amounts of water. The yield of hydrogen was found to be slightly greater than the yield expected for bulk water radiolysis, indicating some small radiation chemical effect of the oxide surface on water. X-ray photoelectron spectroscopy indicated that the amount of OH groups present on the cuprous oxide surface decreased as a result of the irradiation while the cupric oxide surface had an increase in OH groups on the surface. This result suggests that the mechanism for the formation of H₂ differs based on the surface composition and structure of the oxide