{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:07:03Z","timestamp":1772168823837,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/f1000research.11063.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2017,9,1]],"date-time":"2017-09-01T00:00:00Z","timestamp":1504224000000}}],"reference-count":31,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2017,9,1]],"date-time":"2017-09-01T00:00:00Z","timestamp":1504224000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sharon Stewart Aniridia Research Trust"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background:<\/ns4:bold>\n                    Aniridia is a disorder predominately caused by heterozygous loss-of-function mutations of the\n                    <ns4:italic>PAX6<\/ns4:italic>\n                    gene, which is a transcriptional regulator necessary for normal eye and brain development. \u00a0The ocular abnormalities of aniridia have been well characterized, but mounting evidence has implicated brain-related phenotypes as a prominent feature of this disorder as well.\u00a0 Investigations using neuroimaging in aniridia patients have shown reductions in discrete brain structures and changes in global grey and white matter.\u00a0 However, limited sample sizes and substantive heterogeneity of structural phenotypes in the brain remain a challenge.\u00a0\n                    <ns4:bold>Methods:<\/ns4:bold>\n                    Here, we examined brain structure in a new population sample in an effort to add to the collective understanding of anatomical abnormalities in aniridia.\u00a0 The current study used 3T magnetic resonance imaging to acquire high-resolution structural data in 12 persons with aniridia and 12 healthy demographically matched comparison subjects.\u00a0\n                    <ns4:bold>Results:<\/ns4:bold>\n                    We examined five major structures: the anterior commissure, the posterior commissure, the pineal gland, the corpus callosum, and the optic chiasm.\u00a0 The most consistent reductions were found in the anterior commissure and the pineal gland; however, abnormalities in all of the other structures examined were present in at least one individual.\u00a0\n                    <ns4:bold>Conclusions:<\/ns4:bold>\n                    Our results indicate that the anatomical abnormalities in aniridia are variable and largely individual-specific.\u00a0 These findings suggest that future studies investigate this heterogeneity further, and that normal population variation should be considered when evaluating structural abnormalities.\n                  <\/ns4:p>","DOI":"10.12688\/f1000research.11063.2","type":"journal-article","created":{"date-parts":[[2017,9,1]],"date-time":"2017-09-01T05:45:28Z","timestamp":1504244728000},"page":"255","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Structural brain abnormalities in 12 persons with aniridia"],"prefix":"10.12688","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2135-3302","authenticated-orcid":false,"given":"Madison K.","family":"Grant","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasia M.","family":"Bobilev","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordan E.","family":"Pierce","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jon","family":"DeWitte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James D.","family":"Lauderdale","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2017,9,1]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"915-920","DOI":"10.1093\/hmg\/2.7.915","article-title":"PAX6 mutations in aniridia.","volume":"2","author":"I Hanson","year":"1993","journal-title":"Hum Mol Genet."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"11-18","DOI":"10.1007\/s004390100529","article-title":"Population-based risk estimates of Wilms tumor in sporadic aniridia. A comprehensive mutation screening procedure of PAX6 identifies 80% of mutations in aniridia.","volume":"109","author":"K Gr\u00f8nskov","year":"2001","journal-title":"Hum Genet."},{"key":"ref-3","doi-asserted-by":"publisher","first-page":"621-42","DOI":"10.1016\/0039-6257(84)90184-X","article-title":"Aniridia. A review.","volume":"28","author":"L Nelson","year":"1984","journal-title":"Surv Ophthalmol."},{"key":"ref-4","doi-asserted-by":"publisher","first-page":"842-847","DOI":"10.1016\/0002-9394(74)90308-0","article-title":"Progressive changes in the angle in congenital aniridia, with development of glaucoma.","volume":"78","author":"W Grant","year":"1974","journal-title":"Am J Ophthalmol."},{"key":"ref-5","doi-asserted-by":"publisher","first-page":"762-764","DOI":"10.1038\/sj.eye.6701642","article-title":"Aniridia and optic nerve hypoplasia.","volume":"19","author":"T McCulley","year":"2005","journal-title":"Eye (Lond)."},{"key":"ref-6","doi-asserted-by":"publisher","first-page":"368-375","DOI":"10.1016\/S0002-9394(14)72167-1","article-title":"Ocular surface abnormalities in aniridia.","volume":"120","author":"K Nishida","year":"1995","journal-title":"Am J Ophthalmol."},{"key":"ref-7","doi-asserted-by":"publisher","first-page":"1075-1079","DOI":"10.1016\/j.ajo.2005.07.035","article-title":"A progressive anterior fibrosis syndrome in patients with postsurgical congenital aniridia.","volume":"140","author":"J Tsai","year":"2005","journal-title":"Am J Ophthalmol."},{"key":"ref-8","doi-asserted-by":"publisher","first-page":"1216-1218","DOI":"10.1212\/01.WNL.0000118298.81140.62","article-title":"Cognitive functioning in humans with mutations of the PAX6 gene.","volume":"62","author":"P Thompson","year":"2004","journal-title":"Neurology."},{"key":"ref-9","doi-asserted-by":"publisher","first-page":"503-509","DOI":"10.1002\/ana.20227","article-title":"Deficient auditory interhemispheric transfer in patients with PAX6 mutations.","volume":"56","author":"D Bamiou","year":"2004","journal-title":"Ann Neurol."},{"key":"ref-10","doi-asserted-by":"publisher","first-page":"669-77","DOI":"10.1111\/cge.12708","article-title":"Assessment of PAX6 alleles in 66 families with aniridia.","volume":"89","author":"A Bobilev","year":"2016","journal-title":"Clin Genet."},{"key":"ref-11","doi-asserted-by":"publisher","first-page":"2581-90","DOI":"10.1167\/iovs.08-2827","article-title":"Detailed ophthalmologic evaluation of 43 individuals with PAX6 mutations.","volume":"50","author":"M Hingorani","year":"2009","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"ref-12","doi-asserted-by":"publisher","first-page":"486-505","DOI":"10.1016\/j.ydbio.2005.12.041","article-title":"Analysis of Pax6 expression using a BAC transgene reveals the presence of a paired-less isoform of Pax6 in the eye and olfactory bulb.","volume":"292","author":"J Kim","year":"2006","journal-title":"Dev Biol."},{"key":"ref-13","doi-asserted-by":"publisher","first-page":"387-393","DOI":"10.1016\/j.brainresbull.2005.02.006","article-title":"Role of Pax6 in forebrain regionalization.","volume":"66","author":"M Manuel","year":"2005","journal-title":"Brain Res Bull."},{"key":"ref-14","doi-asserted-by":"publisher","first-page":"1041-1051","DOI":"10.1002\/bies.10174","article-title":"Pax6; a pleiotropic player in development.","volume":"24","author":"T Simpson","year":"2002","journal-title":"Bioessays."},{"key":"ref-15","doi-asserted-by":"crossref","first-page":"1985-1997","DOI":"10.1242\/dev.124.10.1985","article-title":"Pax-6 functions in boundary formation and axon guidance in the embryonic mouse forebrain.","volume":"124","author":"G Mastick","year":"1997","journal-title":"Development."},{"key":"ref-16","doi-asserted-by":"publisher","first-page":"163-174","DOI":"10.1620\/tjem.193.163","article-title":"The role of Pax6 in brain patterning.","volume":"193","author":"N Osumi","year":"2001","journal-title":"Tohoku J Exp Med."},{"key":"ref-17","doi-asserted-by":"publisher","first-page":"214-216","DOI":"10.1038\/90042","article-title":"PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans.","volume":"28","author":"S Sisodiya","year":"2001","journal-title":"Nat Genet."},{"key":"ref-18","doi-asserted-by":"publisher","first-page":"658-663","DOI":"10.1002\/ana.10576","article-title":"Polymicrogyria and absence of pineal gland due to PAX6 mutation.","volume":"53","author":"T Mitchell","year":"2003","journal-title":"Ann Neurol."},{"key":"ref-19","doi-asserted-by":"publisher","first-page":"463-469","DOI":"10.1001\/archpedi.161.5.463","article-title":"Auditory interhemispheric transfer deficits, hearing difficulties, and brain magnetic resonance imaging abnormalities in children with congenital aniridia due to PAX6 mutations.","volume":"161","author":"D Bamiou","year":"2007","journal-title":"Arch Pediatr Adolesc Med."},{"key":"ref-20","first-page":"2074-83","article-title":"PAX6 aniridia and interhemispheric brain anomalies.","volume":"15","author":"H Abouzeid","year":"2009","journal-title":"Mol Vis."},{"key":"ref-21","doi-asserted-by":"publisher","first-page":"2281-2290","DOI":"10.1016\/j.neuroimage.2003.07.001","article-title":"Quantitative MR image analysis in subjects with defects in the PAX6 gene.","volume":"20","author":"S Free","year":"2003","journal-title":"Neuroimage."},{"key":"ref-22","doi-asserted-by":"publisher","first-page":"1505-12","DOI":"10.1111\/j.1460-9568.2004.03236.x","article-title":"Heterozygous PAX6 mutation, adult brain structure and fronto-striato-thalamic function in a human family.","volume":"19","author":"Z Ellison-Wright","year":"2004","journal-title":"Eur J Neurosci."},{"key":"ref-23","doi-asserted-by":"publisher","first-page":"314-30","DOI":"10.1002\/acn3.297","article-title":"PAX6, brain structure and function in human adults: advanced MRI in aniridia.","volume":"3","author":"M Yogarajah","year":"2016","journal-title":"Ann Clin Transl Neurol."},{"key":"ref-24","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.3389\/fnhum.2014.01013","article-title":"Increased functional connectivity in intrinsic neural networks in individuals with aniridia.","volume":"8","author":"J Pierce","year":"2014","journal-title":"Front Hum Neurosci."},{"key":"ref-25","doi-asserted-by":"publisher","first-page":"162-73","DOI":"10.1006\/cbmr.1996.0014","article-title":"AFNI: software for analysis and visualization of functional magnetic resonance neuroimages.","volume":"29","author":"R Cox","year":"1996","journal-title":"Comput Biomed Res."},{"key":"ref-26","doi-asserted-by":"publisher","first-page":"179-194","DOI":"10.1006\/nimg.1998.0395","article-title":"Cortical surface-based analysis. I. Segmentation and surface reconstruction.","volume":"9","author":"A Dale","year":"1999","journal-title":"Neuroimage."},{"key":"ref-27","doi-asserted-by":"publisher","first-page":"341-55","DOI":"10.1016\/S0896-6273(02)00569-X","article-title":"Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain.","volume":"33","author":"B Fischl","year":"2002","journal-title":"Neuron."},{"key":"ref-28","doi-asserted-by":"publisher","first-page":"16-22","DOI":"10.1111\/jsr.12345","article-title":"Pineal hypoplasia, reduced melatonin and sleep disturbance in patients with PAX6 haploinsufficiency.","volume":"25","author":"A Hanish","year":"2016","journal-title":"J Sleep Res."},{"key":"ref-29","article-title":"PROS AND CONS OF 1.5 T MRI VERSUS 3.0 T MRI","author":"R Wood"},{"key":"ref-30","doi-asserted-by":"publisher","first-page":"169-179","DOI":"10.1001\/archneur.55.2.169","article-title":"Sex differences in brain aging. a quantitative magnetic resonance imaging study.","volume":"55","author":"C Coffey","year":"1998","journal-title":"Arch Neurol."},{"key":"ref-31","doi-asserted-by":"publisher","DOI":"10.5256\/f1000research.11063.d153799","article-title":"Dataset 1 in: Structural brain abnormalities in 12 persons with aniridia.","author":"M Grant","year":"2017","journal-title":"F1000Research."}],"container-title":["F1000Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/6-255\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/6-255\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/6-255\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T22:05:03Z","timestamp":1659391503000},"score":1,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/6-255\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,1]]},"references-count":31,"URL":"https:\/\/doi.org\/10.12688\/f1000research.11063.2","relation":{"has-review":[{"id-type":"doi","id":"10.5256\/f1000research.13553.r25602","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.13553.r25602","asserted-by":"object"}]},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,1]]},"assertion":[{"value":"Indexed","URL":"https:\/\/f1000research.com\/articles\/6-255\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.11931.r21598, Veronica van Heyningen, Institute of Ophthalmology, University College London, London, UK, 06 Apr 2017, version 1, 1 approved, 1 approved with reservations","URL":"https:\/\/f1000research.com\/articles\/6-255\/v1#referee-response-21598","order":0,"name":"referee-response-21598","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Madison Grant<\/b>; <i>Posted: 23 Aug 2017<\/i>; <b>Reviewer: Veronica van Heyningen<\/b>,&nbsp;Institute of Ophthalmology, University College London, London, UK&nbsp;&nbsp;We thank Dr. van Heyningen for the helpful comments and suggestions, which improved the manuscript. Our responses are listed below.&nbsp;Comments to the Author:Minor comments In the Introduction the PAX6 mutations are described as mostly \u201csingle nucleotide polymorphisms\u201d. This is incorrect the changes are extremely rare variants. There are no polymorphisms of any note in the extremely highly conserved PAX6 gene.-&nbsp;The text was modified to read: \u201cThe majority of these variants are nonsense mutations, which lead to a premature termination codon, and are found across the <i>PAX6<\/i> locus.\u201d&nbsp; It is a pity that the patient numbering is different in earlier fMRI work from this group (ref 24). Indeed it is not made clear that ref 24 studies the same cohort as observed in the current paper.-&nbsp;Numbering of patients has been amended to reflect the same numbering used in the previous paper (ref 24).&nbsp; We have additionally added a supplementary table (Supplementary Table 2) that matches DICOM file names to patient ID from this paper and previous papers using the same patient group.&nbsp; Additionally, we have added a sentence in methods (Subjects) to state that this study and ref 24 used the same patients.&nbsp; It would help to have the protein effects of the mutations in Table 1.-&nbsp;Protein effects have been added to Table 1.&nbsp; Can the olfactory bulb status be observed with the current cohort? It would be interesting to see that reported.-&nbsp;While we agree that the olfactory bulb would be an interesting and important addition, we elected not to pursue this structure because constraints inherent to our data.&nbsp; We have amended methods (MRI data analysis) to discuss explain why we decided not to investigate olfactory bulb in this patient sample.","URL":"https:\/\/f1000research.com\/articles\/6-255\/v2#referee-comment-2973","order":1,"name":"referee-comment-2973","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.13553.r25602, Lutz J\u00e4ncke, Department of Psychology (Neuropsychology) and INAPIC, University of Zurich, Zurich, Switzerland, 26 Sep 2017, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/6-255\/v2#referee-response-25602","order":2,"name":"referee-response-25602","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This research was supported by a grant from the Sharon Stewart Aniridia Research Trust to AMB and JDL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Data associated with the article are available under the terms of the Creative Commons Zero \"No rights reserved\" data waiver (CC0 1.0 Public domain dedication).","order":0,"name":"copyright-info","label":"Copyright"}]}}