ArticlePDF Available

Pineal Gland Agenesis: Review and Case Illustration

Authors:
Marcus A Cox
Marcus A Cox
Marcus A Cox
  • This person is not on ResearchGate, or hasn't claimed this research yet.
Michele Davis
Michele Davis
Michele Davis
  • This person is not on ResearchGate, or hasn't claimed this research yet.
Vlad Voin at St. George's University
Vlad Voin
Mohammadali M Shoja at Nova Southeastern University
Mohammadali M Shoja
Show all 7 authorsHide
Download full-text PDF
Read full-text
Download citation

Abstract and Figures

Agenesis of the pineal gland has rarely been reported in the medical literature. Herein, we report a cadaveric specimen found to have agenesis of the pineal gland. The remaining gross examination of the brain was normal. A review of the literature was performed on this unusual finding.
Figures - available via license: Creative Commons Attribution 3.0 Unported
Content may be subject to copyright.
Available via license: CC BY 3.0
Content may be subject to copyright.
Received 05/23/2017
Review began 05/28/2017
Review ended 05/30/2017
Published 06/05/2017
© Copyright 2017
Cox et al. This is an open access
article distributed under the terms of
the Creative Commons Attribution
License CC-BY 3.0., which permits
unrestricted use, distribution, and
reproduction in any medium,
provided the original author and
source are credited.
Pineal Gland Agenesis: Review and Case
Illustration
Marcus A. Cox , Michele Davis , Vlad Voin , Mohammadali M. Shoja , Rod J. Oskouian ,
Marios Loukas , R. Shane Tubbs
1. Internal Medicine, Saint Michael's Medical Center 2. Department of Anatomical Sciences, St. George's
University School of Medicine, Grenada, West Indies 3. Research Fellow, Seattle Science Foundation 4.
Department of Surgery, University of Texas Medical Branch at Galveston 5. Swedish Neuroscience
Institute 6. Department of Anatomical Sciences, St. George's University School of Medicine, Grenada,
West Indies 7. Neurosurgery, Seattle Science Foundation
Corresponding author: Michele Davis, mdavis4@sgu.edu
Disclosures can be found in Additional Information at the end of the article
Abstract
Agenesis of the pineal gland has rarely been reported in the medical literature. Herein, we
report a cadaveric specimen found to have agenesis of the pineal gland. The remaining gross
examination of the brain was normal. A review of the literature was performed on this unusual
finding.
Categories: Endocrinology/Diabetes/Metabolism, Neurology, Neurosurgery
Keywords: pineal gland, embryology, brain, diencephalon, aplasia, variation
Introduction
The pineal gland is a neuroendocrine organ which develops from the diencephalon. Although
the primary function is the secretion of melatonin, the role in human growth and development
has not been clearly defined. Although exceptionally rare, the absence of the pineal gland has
been recorded as an incidental finding on magnetic resonance imaging (MRI). It has been
linked to the PAX6 gene mutation, which is a transcription factor [1-2]. In this article, we will
review rare cases of pineal agenesis and their associated syndromes, with special attention to
ocular and brain abnormalities in patients with PAX6 mutations. A cadaveric specimen with
pineal gland agenesis will be presented as an illustration.
Case Presentation
During routine dissection of a Caucasian male cadaver (79 years old at death), the absence of
the pineal gland was noted (Figure 1). The patient had a history of hypertension, osteoarthritis,
and glaucoma. He expired due to a myocardial infarction. No other medical history was
reported including any syndromes or previous intracranial surgery. The patient had a left
inguinal region incision and had undergone a left knee replacement.
1 2 3 4 5
6 7
Open Access Case
Report DOI: 10.7759/cureus.1314
How to cite this article
Cox M A, Davis M, Voin V, et al. (June 05, 2017) Pineal Gland Agenesis: Review and Case Illustration.
Cureus 9(6): e1314. DOI 10.7759/cureus.1314
FIGURE 1: Absent Pineal Gland
Left posterolateral view of the brain of the case illustration herein. Notice the absence of the
pineal gland.
During the dissection of the cranium and its contents, no other intracranial anatomical
variations were noted. Specifically, the other diencephalic derived brain structures (e.g.,
thalamus, optic nerves, hypothalamus, posterior pituitary gland) were all within normal limits.
No pathology of the brain was noted such as hydrocephalus or ectopic tissues.
Discussion
The pineal gland develops as an evagination of the neuroepithelium from the dorsal
diencephalon, above the future third ventricle, and has been attributed as the main producer of
melatonin. The shape of the pineal gland in mammals is variable but usually presents as a
lobular structure. From early human life the pineal gland begins to calcify and calcification
increases with age, which may correlate with the age-related decline in melatonin production.
Decreases in the night time levels of this hormone may be responsible for fragmented sleep-
wake patterns [3].
Pineal gland agenesis has been observed in murine and humans with mutations in the paired
box gene 6 (PAX6), where the pineal gland along with other brain and eye abnormalities has
been observed [1, 4-5]. PAX6 is expressed in the telencephalon, diencephalon, caudal part of
the rhombencephalon, myelencephalon, the spinal cord and pancreas, explaining the various
phenotypes observed in individuals with mutations in this gene [1, 4-5]. PAX6 has been shown
to play an important role as a regulatory gene in cortical developmental processes including
cellular proliferation, neuronal migration, and axonal guidance [1, 6-7]. The mechanism by
which PAX6 expression influences structural formation is unknown, but one explanation is that
PAX6 regulates expression of a gene directing synthesis of R-cadherin and other cell surface
2017 Cox et al. Cureus 9(6): e1314. DOI 10.7759/cureus.1314 2 of 4
recognition molecules [8]. Mapping results of the PAX6 gene by Thakurela, et al., demonstrated
a dual function of PAX6 upon neuronal commitment where it mediates the activation of
neuronal genes while concurrently suppressing the mesodermal and endodermal genes to
ensure the unidirectionality toward neuronal differentiation [9]. They also concluded that PAX6
induces critical signaling pathways that further work together in guiding critical neurogenic
events such as neurogenesis, neuronal differentiation, and lens development [9].
In mice, PAX6 is critical for survival. PAX6 null mice die immediately after birth [5-6].
Heterozygote mice have a subtle form of cortical and eye abnormalities. There have only been a
few cases reported in humans with mutations in both PAX6 alleles. In these cases, patients had
severe brain and eye abnormalities reported [5, 7]. Human heterozygotes have a variety of
anomalies [1-2, 6-7]. Studies have been performed using imaging techniques in patients with
PAX6 mutation to identify the extent of these abnormalities.
High-resolution MRIs performed on 24 individuals with ocular abnormalities and positive
PAX6 mutations showed 13 individuals had absent pineal glands (54%), four had structurally
normal pineal glands (17%) and the remaining seven had pineal glands which were difficult to
visualize and were deemed “hypoplastic” (29%) [1]. Although this study shows a link between
PAX6 mutations, aniridia, and pineal agenesis, it is limited by the small sample size and the
possibility that pineal tissue may be demonstrable histopathologically while not being
visualized on MRIs. Abouzeid, et al. showed that out of 10 patients from three different families
in Egypt who had PAX6 mutations, all 10 had bilateral aniridia while three had absent pineal
glands (30%) [4]. This was much less than the 54% in the study of Mitchell, et al. who had both
pineal agenesis and ocular abnormalities [1]. All patients in the study published by Abouzeid, et
al. had a full ophthalmic and neurological examinations performed at the time and showed no
major neurodevelopmental delays [4]. Although the sample size remains small, the current
evidence points to a distinct link between ocular abnormalities and pineal agenesis with PAX6
mutations.
Yogarajah, et al. investigated MRI parameters in 19 adults with known PAX6 mutations to
understand the importance that the PAX6 gene plays in the maintenance of brain integrity.
They found in people with heterozygous mutation in PAX6, there was exaggerated cortical
thinning with age, a reduction in cortical thickness that correlated with a decline in working
memory, and abnormalities of cortical patterning. They concluded that these findings could
play an important role in understanding neurodegenerative disorders and modulation of PAX6
may offer new therapeutic strategies in fighting these diseases [5].
Ellison-Wright, et al. demonstrated significant reductions of white matter in the anterior and
posterior corpus callosum, local excesses of grey matter in regions including the hippocampus,
ventral striatum, insula, and cerebellum in humans with heterozygous PAX6 mutation [8]. Free,
et al. established variations in cortical structures in patients with a PAX6 abnormality using
quantitative MRI analysis [7]. Sisodiya, et al. observed that patients with the PAX6 mutation
had cerebral malformation and olfactory dysfunctions [10]. These findings show there is a link
between people with PAX6 mutations and abnormal brain development.
Being a transcription factor, PAX6 interacts with several brain developmental genes and other
transcription factors. With the development of high-resolution MRIs, the extent of
abnormalities in these patients is being examined more closely.
Conclusions
The extent to which pineal agenesis affects human growth and development has not been
explored in the articles reviewed. Extensive neurological, endocrine, and sleep studies on these
2017 Cox et al. Cureus 9(6): e1314. DOI 10.7759/cureus.1314 3 of 4
patients might help provide further insight into the function of this gland in normal human
growth and development. Also, the PAX6 gene plays an important role in brain development
and formation. While the correlation between PAX6 gene mutation and pineal agenesis is not
definite, there seems to be a link between patients with pineal agenesis and mutations in the
PAX6 gene. Further study of this gene could lead to novel treatments and our understanding of
neurodegenerative diseases.
Additional Information
Disclosures
Human subjects: All authors have confirmed that this study did not involve human
participants or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure
form, all authors declare the following: Payment/services info: All authors have declared that
no financial support was received from any organization for the submitted work. Financial
relationships: All authors have declared that they have no financial relationships at present or
within the previous three years with any organizations that might have an interest in the
submitted work. Other relationships: All authors have declared that there are no other
relationships or activities that could appear to have influenced the submitted work.
References
1. Mitchell TN, Free SL, WIlliamson KA, et al.: Polymicrogyria and absence of pineal gland due
to PAX6 mutation. Ann Neurol. 2003, 53:658–663. 10.1002/ana.10576
2. Al-Owain M, Al-Zahrani J, Al-Bakhett A, et al.: A novel syndrome of abnormal striatum and
congenital cataract: evidence for linkage to chromosomes 11. Clin Genet. 2013, 84:258–264.
10.1111/cge.12066
3. Sapède D, Cau E: The pineal gland from development to function . Curr Top Dev Biol. 2013,
106:171–215. 10.1016/B978-0-12-416021-7.00005-5
4. Abouzeid H, Youssef MA, ElShakankiri N, et al.: PAX6 aniridia and interhemispheric brain
anomalies. Mol Vis. 2009, 15:2074–2083.
5. Yogarajah M, Matarin M, Vollmar C, et al.: PAX6, brain structure and function in human
adults: advanced MRI in aniridia. Ann Clin Transl Neurol. 2016, 3:314–330. 10.1002/acn3.297
6. Thompson PJ, Mitchell TN, Free SL, et al.: Cognitive functioning in humans with mutations of
the PAX6 gene. Neurology. 2004, 62:1216–1218. 10.1212/01.WNL.0000118298.81140.62
7. Free SL, Mitchell TN, Williamson KA, et al.: Quantitative MR image analysis in subjects with
defects in the PAX6 gene. Neuroimage. 2003, 20:2281–2290.
10.1016/j.neuroimage.2003.07.001
8. Ellison-Wright Z, Heyman I, Frampton I, et al.: Heterozygous PAX6 mutation, adult brain
structure and fronto-striato-thalamic function in a human family. Eur J Neurosci. 2004,
19:1505–1512. 10.1111/j.1460-9568.2004.03236.x
9. Thakurela S, Tiwari N, Schick S, et al.: Mapping gene regulatory circuitry of Pax6 during
neurogenesis. Cell Discov. 2016, 2:15045. 10.1038/celldisc.2015.45
10. Sisodiya SM, Free SL, Williamson KA, et al.: PAX6 haploinsufficiency causes cerebral
malformation and olfactory dysfunction in humans. Nat Genet. 2001, 28:214-216.
10.1038/90042
2017 Cox et al. Cureus 9(6): e1314. DOI 10.7759/cureus.1314 4 of 4
... The cause of the phenotypes in all 7 syndromic cases are intragenic PAX6 loss-offunction variants. Other systems involvement in PAX6-associated AN is widely discussed and even observed in rare AN cases [15][16][17][18][19]. In the whole sample there were 21 AN syndromic cases. ...
Epidemiology of PAX6 Gene Pathogenic Variants and Expected Prevalence of PAX6-Associated Congenital Aniridia across the Russian Federation: A Nationwide Study
Article
Full-text available
  • Nov 2023
This study investigates the distribution of PAX6-associated congenital aniridia (AN) and WAGR syndrome across Russian Federation (RF) districts while characterizing PAX6 gene variants. We contribute novel PAX6 pathogenic variants and 11p13 chromosome region rearrangements to international databases based on a cohort of 379 AN patients (295 families, 295 probands) in Russia. We detail 100 newly characterized families (129 patients) recruited from clinical practice and specialized screening studies. Our methodology involves multiplex ligase-dependent probe amplification (MLPA) analysis of the 11p13 chromosome, PAX6 gene Sanger sequencing, and karyotype analysis. We report novel findings on PAX6 gene variations, including 67 intragenic PAX6 variants and 33 chromosome deletions in the 100 newly characterized families. Our expanded sample of 295 AN families with 379 patients reveals a consistent global PAX6 variant spectrum, including CNVs (copy number variants) of the 11p13 chromosome (31%), complex rearrangements (1.4%), nonsense (25%), frameshift (18%), and splicing variants (15%). No genetic cause of AN is defined in 10 patients. The distribution of patients across the Russian Federation varies, likely due to sample completeness. This study offers the first AN epidemiological data for the RF, providing a comprehensive PAX6 variants spectrum. Based on earlier assessment of AN prevalence in the RF (1:98,943) we have revealed unexamined patients ranging from 55% to 87%, that emphases the need for increased awareness and comprehensive diagnostics in AN patient care in Russia.
View
... autopsy. Rarely, such injury can cause loss of consciousness, chronic headache, sensory and corticospinal impairment and even sudden death (13,45,49). SD caused by compression by a pineal gland cyst is very rare, and there are few cases described in the literature. ...
Sudden Death In Adults Caused By Intracranial Pathology: A Systematic Review
Article
Full-text available
  • Feb 2023
  • TURK NEUROSURG
Objective: The study aimed to review the literature and was designed with the objective of elucidating the intracranial pathologies that cause sudden deaths in adults. Methods: The systematic review was carried out in concordance with the PRISMA checklist. Results: Epilepsy and intracranial hemorrhage have been found to be the two main causes of sudden and unexplained deaths in adults due to intracranial pathologies. Intracranial neoplasms are not among the two main causes of SD, as they are usually discovered before fatality, so their rate of SD is not so extensive. It is noticed that the highest incidence of this type of death is also related to the abusive use of alcohol and other drugs, such as cocaine, heroin and nicotine. There is a possibility that the actual incidence of SD in adults due to intracranial pathologies is even greater, since there is a lack of reliability in autopsies and the fact that most SD in adults are not witnessed. Conclusion: The most recurrent etiologies of SD in adults are epilepsy, intracranial hemorrhage, meningitis or purulent abscess and tumors. Thus, it represents real challenge for neurosurgeons, since their understanding, accurate diagnosis and adequate treatment of these pathologies, in addition to healthy lifestyle habits by people can reduce the possibility of SD.
View
... The pineal gland's primary function is the nighttime secretion of melatonin (Fig. 11) [19]. Histological studies have indicated that pineal gland calcification starts early in life and progresses with age [23]. Whitehead et al. [18] found a 5% prevalence of pineal calcification in CT examinations of 500 children ranging from 0 to 9 years of age. ...
Intracranial calcifications in childhood: Part 1
Article
Full-text available
  • Sep 2020
  • PEDIATR RADIOL
This article is the first of a two-part series on intracranial calcification in childhood. Intracranial calcification can be either physiological or pathological. Physiological intracranial calcification is not an expected neuroimaging finding in the neonatal or infantile period but occurs, as children grow older, in the pineal gland, habenula, choroid plexus and occasionally the dura mater. Pathological intracranial calcification can be broadly divided into infectious, congenital, endocrine/metabolic, vascular and neoplastic. The main goals in Part 1 are to discuss the chief differences between physiological and pathological intracranial calcification, to discuss the histological characteristics of intracranial calcification and how intracranial calcification can be detected across neuroimaging modalities, to emphasize the importance of age at presentation and intracranial calcification location, and to propose a comprehensive neuroimaging approach toward the differential diagnosis of the causes of intracranial calcification. Finally, in Part 1 the authors discuss the most common causes of infectious intracranial calcification, especially in the neonatal period, and congenital causes of intracranial calcification. Various neuroimaging modalities have distinct utilities and sensitivities in the depiction of intracranial calcification. Age at presentation, intracranial calcification location, and associated neuroimaging findings are useful information to help narrow the differential diagnosis of intracranial calcification. Intracranial calcification can occur in isolation or in association with other neuroimaging features. Intracranial calcification in congenital infections has been associated with clastic changes, hydrocephalus, chorioretinitis, white matter abnormalities, skull changes and malformations of cortical development. Infections are common causes of intracranial calcification, especially neonatal TORCH (toxoplasmosis, other [syphilis, varicella-zoster, parvovirus B19], rubella, cytomegalovirus and herpes) infections.
View
... There is a known link with a mutation of the PAX6 gene [68,69]. PAX6 is expressed in the telencephallus, diencephallus, caudal part of rhombencephallus, mielencephallus, spinal chord and pancreas [70]. ...
The morphological and functional characteristics of the pineal gland
Article
Full-text available
  • May 2019
Introduction: The pineal gland is a photo-neuro-endocrine organ situated inside the brain, that secretes serotonin, melatonin and N,N-dymethyltriptamine. This narrative review will address the latest information gathered on this function of the gland as well as the unknown roles it may have. The different histological and pathological findings of the pineal gland have demonstrated a role in clinical manifestations of numerous endocrine, neurological and psychiatric pathologies. Materials: For this narrative review we used the NCBI website database PubMed. The search terms were "Pineal Gland" AND/OR "histology, melatonin, DMT, pathology". Total number of articles included were 86. Results: We have reviewed physiological information of melatonin and DMT, anatomical, histological and histopathological information on the pineal gland and its role in endocrine, neurological and psychiatric pathology. Conclusion: The role of melatonin in immunity and its potential therapeutic effects show promising potential for further research. DMT seems to have a role in psychiatric pathology and potential therapeutic effects. Proper tumoral screening and diagnostic protocol are required.
View
... This syndrome can be classified as primary, dependent on factors that directly affect the pineal gland and/or its innervation, and secondary, developed as a consequence of a primary event, such as a systemic disease (e.g. hyperglycemia) or environmental factor (e.g light at night) (44)(45)(46)(47)(48)(49)(50). ...
A brief review about melatonin, a pineal hormone
Article
Full-text available
  • Sep 2018
Melatonin is a ubiquitous molecule in nature, being locally synthesized in several cells and tissues, besides being a hormone that is centrally produced in the pineal gland of vertebrates, particularly in mammals. Its pineal synthesis is timed by the suprachiasmatic nucleus, that is synchronized to the light-dark cycle via the retinohypothalamic tract, placing melatonin synthesis at night, provided its dark. This unique trait turns melatonin into an internal synchronizer that adequately times the organism’s physiology to the daily and seasonal demands. Besides being amphiphilic, melatonin presents specific mechanisms and ways of action devoted to its role as a time-giving agent, being widely spread in the organism. The present review aims to focus on melatonin as a pineal hormone with specific mechanisms and ways of action, besides presenting the clinical syndromes related to its synthesis and/or function disruptions. © 2018, Sociedade Brasileira de Endocrinologia e Metabologia. All rights reserved.
View
... it is dependent on factors that directly affect the pineal or its innervation, embryonic formation, pineal melatonin synthesis as a result of a genetic or innate disease. It might be dependent on pineal agenesis or hypoplasia; sympathetic pineal innervation agenesis; and biochemical defects in pineal melatonin synthesis as is the case in gene polymorphisms linked to the enzymes involved in the melatonin synthesis pathway (TPH, or AANAT or ASMT) (498)(499)(500)(501)(502)(503)(504)(505)(506)(507)(508)(509)(510)(511). The absence of circulating melatonin that follows surgical pinealectomy should be considered primary hypomelatoninemia as well (512). ...
Melatonin as a Hormone: New Physiological and Clinical Insights
Article
Full-text available
  • Sep 2018
Melatonin is a ubiquitous molecule present in almost every live being from bacteria to humans. In vertebrates, besides being produced in peripheral tissues and acting as an autocrine and paracrine signal, melatonin is centrally synthetized by a neuroendocrine organ, the pineal gland. Independently of the considered specie, pineal hormone melatonin is always produced during the night and its production and secretory episode duration is directly dependent on the length of the night. As its production is tightly linked to the light/dark cycle, melatonin main hormonal systemic integrative action is to coordinate behavioral and physiological adaptations to the environmental geophysical day and season. The circadian signal is dependent on its daily production regularity, on the contrast between day and night concentrations and on specially developed ways of action. During its daily secretory episode, melatonin coordinates the night adaptive physiology through immediate effects and primes the day adaptive responses through prospective effects that will only appear at daytime, when melatonin is absent. Similarly, the annual history of the daily melatonin secretory episode duration primes the central nervous/endocrine system to the seasons to come. Remarkably, maternal melatonin programs the fetuses’ behavior and physiology to cope with the environmental light/dark cycle and season after birth. These unique ways of action turn melatonin into a biological time-domain acting molecule. The present review focus on the above considerations, proposes a putative classification of clinical melatonin dysfunctions and discuss general guidelines to the therapeutic use of melatonin.
View
PAX6, brain structure and function in human adults: Advanced MRI in aniridia
Article
Full-text available
  • Mar 2016
Objective PAX6 is a pleiotropic transcription factor essential for the development of several tissues including the eyes, central nervous system, and some endocrine glands. Recently it has also been shown to be important for the maintenance and functioning of corneal and pancreatic tissues in adults. We hypothesized that PAX6 is important for the maintenance of brain integrity in humans, and that adult heterozygotes may have abnormalities of cortical patterning analogous to those found in mouse models. Methods We used advanced magnetic resonance imaging techniques, including surface-based morphometry and region-of-interest analysis in adult humans heterozygously mutated for PAX6 mutations (n = 19 subjects and n = 21 controls). Using immunohistochemistry, we also studied PAX6 expression in the adult brain tissue of healthy subjects (n = 4) and patients with epilepsy (n = 42), some of whom had focal injuries due to intracranial electrode track placement (n = 17). Results There were significant reductions in frontoparietal cortical area after correcting for age and intracranial volume. A greater decline in thickness of the frontoparietal cortex with age, in subjects with PAX6 mutations compared to controls, correlated with age-corrected, accelerated decline in working memory. These results also demonstrate genotypic effects: those subjects with the most severe genotypes have the most widespread differences compared with controls. We also demonstrated significant increases in PAX6-expressing cells in response to acute injury in the adult human brain. Interpretation These findings suggest a role for PAX6 in the maintenance and consequent functioning of the adult brain, homologous to that found in other tissues. This has significant implications for the understanding and treatment of neurodegenerative diseases.
View
PAX6 aniridia and interhemispheric brain anomalies
Article
Full-text available
  • Oct 2009
  • MOL VIS
To report the clinical and genetic study of patients with autosomal dominant aniridia. We studied ten patients with aniridia from three families of Egyptian origin. All patients underwent full ophthalmologic, general and neurological examination, and blood drawing. Cerebral magnetic resonance imaging was performed in the index case of each family. Genomic DNA was prepared from venous leukocytes, and direct sequencing of all the exons and intron-exon junctions of the Paired Box gene 6 (PAX6) was performed after PCR amplification. Phenotype description, including ophthalmic and cerebral anomalies, mutation detection in PAX6 and phenotype-genotype correlation was acquired. Common features observed in the three families included absence of iris tissue, corneal pannus with different degrees of severity, and foveal hypoplasia with severely reduced visual acuity. In Families 2 and 3, additional findings, such as lens dislocation, lens opacities or polar cataract, and glaucoma, were observed. We identified two novel (c.170-174delTGGGC [p.L57fs17] and c.475delC [p.R159fs47]) and one known (c.718C>T [p.R240X]) PAX6 mutations in the affected members of the three families. Systemic and neurological examination was normal in all ten affected patients. Cerebral magnetic resonance imaging showed absence of the pineal gland in all three index patients. Severe hypoplasia of the brain anterior commissure was associated with the p.L57fs17 mutation, absence of the posterior commissure with p.R159fs47, and optic chiasma atrophy and almost complete agenesis of the corpus callosum with p.R240X. We identified two novel PAX6 mutations in families with severe aniridia. In addition to common phenotype of aniridia and despite normal neurological examination, absence of the pineal gland and interhemispheric brain anomalies were observed in all three index patients. The heterogeneity of PAX6 mutations and brain anomalies are highlighted. This report emphasizes the association between aniridia and brain anomalies with or without functional impact, such as neurodevelopment delay or auditory dysfunction.
View
Mapping gene regulatory circuitry of Pax6 during neurogenesis
Article
  • Feb 2016
Pax6 is a highly conserved transcription factor among vertebrates and is important in various aspects of the central nervous system development. However, the gene regulatory circuitry of Pax6 underlying these functions remains elusive. We find that Pax6 targets a large number of promoters in neural progenitors cells. Intriguingly, many of these sites are also bound by another progenitor factor, Sox2, which cooperates with Pax6 in gene regulation. A combinatorial analysis of Pax6-binding data set with transcriptome changes in Pax6-deficient neural progenitors reveals a dual role for Pax6, in which it activates the neuronal (ectodermal) genes while concurrently represses the mesodermal and endodermal genes, thereby ensuring the unidirectionality of lineage commitment towards neuronal differentiation. Furthermore, Pax6 is critical for inducing activity of transcription factors that elicit neurogenesis and repress others that promote non-neuronal lineages. In addition to many established downstream effectors, Pax6 directly binds and activates a number of genes that are specifically expressed in neural progenitors but have not been previously implicated in neurogenesis. The in utero knockdown of one such gene, Ift74, during brain development impairs polarity and migration of newborn neurons. These findings demonstrate new aspects of the gene regulatory circuitry of Pax6, revealing how it functions to control neuronal development at multiple levels to ensure unidirectionality and proper execution of the neurogenic program.
View
View
The Pineal Gland from Development to Function
Article
  • Dec 2013
The pineal gland is a small neuroendocrine organ whose main and most conserved function is the nighttime secretion of melatonin. In lower vertebrates, the pineal gland is directly photosensitive. In contrast, in higher vertebrates, the direct photosensitivity of the pineal gland had been lost. Rather, the action of this gland as a relay between environmental light conditions and body functions involves reception of light information by the retina. In parallel to this sensory regression, the pineal gland (and its accessory organs) appears to have lost several functions in relation to light and temperature, which are important in lower vertebrate species. In humans, the functions of the pineal gland overlap with the functions of melatonin. They are extremely widespread and include general effects both on cell protection and on more precise functions, such as sleep and immunity. Recently, the role of melatonin has received a considerable amount of attention due to increased cancer risk in shift workers and the discovery that patients suffering from neurodegenerative diseases, autism, or depression exhibit abnormal melatonin rhythms.
View
A novel syndrome of abnormal striatum and congenital cataract: Evidence for linkage to chromosomes 11
Article
We report a consanguineous family of three girls and one boy affected with a novel syndrome involving the lens and the basal ganglia. The phenotype is strikingly similar between affected siblings with cognitive impairment, attention deficit hyperactivity disorder (ADHD), microcephaly, growth retardation, congenital cataract, and dystonia. The MRI showed unusual pattern of swelling of the caudate heads and thinning of the putamina with severe degree of hypometabolism on the [18F] deoxyglucose positron emission tomography (FDG PET). Furthermore, the clinical assessment provides the evidence that the neurological phenotype is very slowly progressive. We utilized the 10K SNP microarray genotyping for linkage analysis. Genome-wide scan indicated a 45.9 Mb region with a 4.2353 LOD score on chromosome 11. Affymetrix genome-wide human SNP array 6.0 assay did not show any gross chromosomal abnormality. Targeted sequencing of two candidate genes within the linkage interval (PAX6 and B3GALTL) as well as mtDNA genome sequencing did not reveal any putative mutations.
View
PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans
Article
  • Aug 2001
PAX6 is widely expressed in the central nervous system. Heterozygous PAX6 mutations in human aniridia cause defects that would seem to be confined to the eye. Magnetic resonance imaging (MRI) and smell testing reveal the absence or hypoplasia of the anterior commissure and reduced olfaction in a large proportion of aniridia cases, which shows that PAX6 haploinsuffiency causes more widespread human neuro developmental anomalies.
View
Polymicrogyria and absence of pineal gland due to PAX6 mutation
Article
  • May 2003
Identification of genes involved in human cerebral development is important for our understanding of disorders with potential neurodevelopmental causes such as epilepsy and learning disability. Murine models suggest that PAX6 plays a key role in human brain development. With magnetic resonance imaging in 24 humans heterozygous for defined PAX6 mutations, we demonstrated widespread structural abnormalities including absence of the pineal gland and unilateral polymicrogyria. Ann Neurol 2003;53:658–663
View
Quantitative MR image analysis in subjects with defects in the PAX6 gene
Article
  • Jan 2004
Cerebral development is governed by genetic and environmental factors. Animal models provide much of our knowledge about genetic influences in the brain but it is not clear how similar or relevant these are to the human brain. The investigation of human subjects with mutations in genes known to be expressed in the developing brain is an alternative approach to improving our understanding of the role of genetic factors in brain development. We investigated 24 subjects with known mutations in the PAX6 gene (including representatives of all the known mutations of the gene) which are associated with characteristic ocular abnormalities in humans and animals. We have quantified MRI data using several techniques to assess qualities of cerebral structure which are difficult to interpret visually. Abnormalities were identified using voxel-based morphometry, statistical morphometrics, and measurement of corpus callosum cross-sectional area when comparing data from subjects with PAX6 abnormality and 72 age-and sex-matched control subjects. These abnormalities include grey matter changes in the cerebellum and occipital poles and white matter loss in the corpus callosum, alteration of sulcal orientation in the occipital lobe, and alteration to overall neuronal connectivity. These abnormalities complement and exceed the changes seen in the mouse models, and those seen on visual inspection alone of the human MRI data. Structural differences were also identified between the two largest genotype mutation subgroups.
View
Heterozygous PAX6 mutation, adult brain structure and fronto-striato-thalamic function in a human family
Article
  • Apr 2004
Recent progress in developmental neurobiology and neuroimaging can be drawn together to provide new insight into the links between genetically specified processes of embryonic brain development and adult human brain structure and function. We used magnetic resonance imaging (MRI) to show that individuals with aniridia and deficits in executive and social cognition, due to heterozygous mutation of the neurodevelopmental control gene PAX6, have structural abnormalities of grey matter in anterior cingulate cortex, cerebellum and medial temporal lobe, as well as white matter deficits in corpus callosum. Functional MRI demonstrated reduced activation of fronto-striato-thalamic systems during performance of overt verbal fluency and nonsense sentence completion; the most consistent abnormality of verbal executive activation was located in the thalamus. These results provide the first evidence for brain functional differences in humans with PAX6 mutation that are compatible both with anatomical abnormalities in the same subjects and, more circumstantially, with the known roles of murine Pax6 in regional differentiation, axonal guidance and other aspects of early forebrain development. Highly conserved homeobox genes may be critical for normal ontogenesis of large-scale neurocognitive networks supporting phylogenetically advanced mental functions.
View