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Pou6f2 is a genetic connection between central corneal thickness (CCT) in the mouse and a risk factor for developing primary open-angle glaucoma. POU6F2 is also a risk factor for several conditions in humans, including glaucoma, myopia, and dyslexia. Recent findings demonstrate that POU6F2-positive retinal ganglion cells (RGCs) comprise a number of RGC subtypes in the mouse, some of which also co-stain for Cdh6 and Hoxd10. These POU6F2-positive RGCs appear to be novel of ON-OFF directionally selective ganglion cells (ooDSGCs) that do not co-stain with CART or SATB2 (typical ooDSGCs markers). These POU6F2-positive cells are sensitive to damage caused by elevated intraocular pressure. In the DBA/2J mouse glaucoma model, heavily-labeled POU6F2 RGCs decrease by 73% at 8 months of age compared to only 22% loss of total RGCs (labeled with RBPMS). Additionally, Pou6f2 -/- mice suffer a significant loss of acuity and spatial contrast sensitivity along with an 11.4% loss of total RGCs. In the rhesus macaque retina, POU6F2 labels the large parasol ganglion cells that form the magnocellular (M) pathway. The association of POU6F2 with the M-pathway may reveal in part its role in human glaucoma, myopia, and dyslexia., (© 2024. The Author(s).)

Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) form a clinical continuum associating progressive muscle weakness with additional multi-systemic anomalies of the bones, skin, spleen, and platelets. TAM/STRMK arises from excessive extracellular Ca 2+ entry due to gain-of-function mutations in the Ca 2+ sensor STIM1 or the Ca 2+ channel ORAI1. Currently, no treatment is available. Here we assessed the therapeutic potential of ORAI1 downregulation to anticipate and reverse disease development in a faithful mouse model carrying the most common TAM/STRMK mutation and recapitulating the main signs of the human disorder. To this aim, we crossed Stim1 R304W/+ mice with Orai1 +/- mice expressing 50% of ORAI1. Systematic phenotyping of the offspring revealed that the Stim1 R304W/+ Orai1 +/- mice were born with a normalized ratio and showed improved postnatal growth, bone architecture, and partly ameliorated muscle function and structure compared with their Stim1 R304W/+ littermates. We also produced AAV particles containing Orai1 -specific shRNAs, and intramuscular injections of Stim1 R304W/+ mice improved the skeletal muscle contraction and relaxation properties, while muscle histology remained unchanged. Altogether, we provide the proof-of-concept that Orai1 silencing partially prevents the development of the multi-systemic TAM/STRMK phenotype in mice, and we also established an approach to target Orai1 expression in postnatal tissues.

Dyslexia is a common heritable developmental disorder involving impaired reading abilities. Its genetic underpinnings are thought to be complex and heterogeneous, involving common and rare genetic variation. Multigenerational families segregating apparent monogenic forms of language-related disorders can provide useful entrypoints into biological pathways. In the present study, we performed a genome-wide linkage scan in a three-generational family in which dyslexia affects 14 of its 30 members and seems to be transmitted with an autosomal dominant pattern of inheritance. We identified a locus on chromosome 7q21.11 which cosegregated with dyslexia status, with the exception of two cases of phenocopy (LOD = 2.83). Whole-genome sequencing of key individuals enabled the assessment of coding and noncoding variation in the family. Two rare single-nucleotide variants (rs144517871 and rs143835534) within the first intron of the SEMA3C gene cosegregated with the 7q21.11 risk haplotype. In silico characterization of these two variants predicted effects on gene regulation, which we functionally validated for rs144517871 in human cell lines using luciferase reporter assays. SEMA3C encodes a secreted protein that acts as a guidance cue in several processes, including cortical neuronal migration and cellular polarization. We hypothesize that these intronic variants could have a cis-regulatory effect on SEMA3C expression, making a contribution to dyslexia susceptibility in this family.

Background/objective: The "neural noise" hypothesis suggests that individuals with dyslexia have high glutamate concentrations associated with their reading challenges. Different reading intervention programs have showed low GLX (a combined measure for glutamine and glutamate obtained with in vivo magnetic resonance spectroscopy) in association with reading improvement. Several studies demonstrated improved reading and increased activation in the anterior cingulate cortex following an-executive-function (EF)-based reading intervention. The goals of the current study are two-fold: 1) to determine if the effect of the EF-based reading program extends also to the metabolite concentrations and in particular, on the GLX concentrations in the anterior cingulate cortex; 2) to expand the neural noise hypothesis in dyslexia also to neural networks supporting additional parts of the reading networks, i.e. in specific regions related to executive function skills., Methods: Children with dyslexia and typical readers were trained on the EF-based reading program. Reading ability was assessed before and after training while spectroscopy data was obtained at the end of the program. The association between change in reading scores following intervention and GLX concentrations was examined., Results: Greater "gains" in word reading were associated with low GLX, Glu, Cr, and NAA concentrations for children with dyslexia compared to typical readers., Conclusions: These results suggest that the improvement reported following the EF-based reading intervention program also involved a low GLX concentration, as well as additional metabolites previously associated with better reading ability (Glx, Cr, NAA) which may point at the decreased neural noise, especially in the anterior cingulate cortex, as a possible mechanism for the effect of this program., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Tubular aggregate myopathy (TAM) is a progressive disorder characterized by muscle weakness, cramps, and myalgia. TAM clinically overlaps with Stormorken syndrome (STRMK), combining TAM with miosis, thrombocytopenia, hyposplenism, ichthyosis, short stature, and dyslexia. TAM and STRMK arise from gain-of-function mutations in STIM1 (stromal interaction molecule 1) or ORAI1, both encoding key regulators of Ca 2+ homeostasis, and mutations in either gene result in excessive extracellular Ca 2+ entry. The pathomechanistic similarities and differences between TAM and STRMK are only partially understood. Here we provide functional in vitro experiments demonstrating that STIM1 harboring the TAM D84G or the STRMK R304W mutation similarly cluster and exert a dominant effect on the wild-type protein. Both mutants recruit ORAI1 to the clusters, increase cytosolic Ca 2+ levels, promote major nuclear import of the Ca 2+ -dependent transcription factor NFAT (nuclear factor of activated T cells), and trigger the formation of circular membrane stacks. In conclusion, the analyzed TAM and STRMK mutations have a comparable impact on STIM1 protein function and downstream effects of excessive Ca 2+ entry, highlighting that TAM and STRMK involve a common pathomechanism., (© 2020 Japanese Society of Neuropathology.)

Introduction: Japanese is unique, as it features two distinct writing systems that share the same sound and meaning: syllabic Hiragana and logographic Kanji scripts. Acquired reading difficulties in Hiragana and Kanji have been examined in older patients with brain lesions. However, the precise mechanisms underlying deficits in developmental dyslexia (DD) remain unclear. Materials and Methods: The neural signatures of Japanese children with DD were examined by using resting-state functional magnetic resonance imaging. We examined 22 dyslexic and 46 typically developing (TD) children, aged 7-14 years. Results: Reading performance in each writing system was correlated with neural connectivity in TD children. In contrast, in children with DD, weak associations between neural connectivity and reading performance were observed. In TD children, Hiragana-reading fluency was positively correlated with the left fusiform gyrus network. No significant correlations between Hiragana fluency and neural connectivity were observed in children with DD. Correspondingly, there were fewer correlations between Kanji accuracy and strength of reading-related connectivity in children with DD, whereas positive correlations with the bilateral fronto-parietal network and negative correlations with the left fusiform network were found in TD children. Discussion: These data suggest that positive and negative coupling with neural connectivity is associated with developing Japanese reading skills. Further, different neural connectivity correlations between Hiragana fluency and Kanji accuracy were detected in TD children but less in children with DD. Conclusion: The two writing systems may exert differential effects and deficits on reading in healthy children and in children with DD, respectively.

Developmental dyslexia (DD) is a neurodevelopmental condition with complex genetic mechanisms. A number of candidate genes have been identified, some of which are linked to neuronal development and migration and to ciliary functions. However, expression and regulation of these genes in human brain development and neuronal differentiation remain uncharted. Here, we used human long-term self-renewing neuroepithelial stem (lt-NES, here termed NES) cells derived from human induced pluripotent stem cells to study neuronal differentiation in vitro. We characterized gene expression changes during differentiation by using RNA sequencing and validated dynamics for selected genes by qRT-PCR. Interestingly, we found that genes related to cilia were significantly enriched among upregulated genes during differentiation, including genes linked to ciliopathies with neurodevelopmental phenotypes. We confirmed the presence of primary cilia throughout neuronal differentiation. Focusing on dyslexia candidate genes, 33 out of 50 DD candidate genes were detected in NES cells by RNA sequencing, and seven candidate genes were upregulated during differentiation to neurons, including DYX1C1 (DNAAF4), a highly replicated DD candidate gene. Our results suggest a role of ciliary genes in differentiating neuronal cells and show that NES cells provide a relevant human neuronal model to study ciliary and DD candidate genes.

Cortisol is the main end product of hypothalamic-pituitary-adrenal gland (HPA axis), and melatonin (MT) has a regulating effect on HPA axis, and both are closely related to individual behavior and cognitive function. We aimed to evaluate cortisol and MT roles on children dyslexia in this study.A total of 72 dyslexic children and 72 controls were recruited in this study. Saliva samples were collected in the morning, afternoon, and night, respectively. The levels of saliva cortisol and MT were measured by enzyme-linked immunosorbent assay method. Differences of cortisol and MT levels between dyslexic and normal children were compared, and the variation trend was also analyzed by dynamic monitoring in 3 time points.The levels of salivary cortisol and MT in children with dyslexia were all lower than those in normal children whether in the morning (7:30-8:30 AM ), at afternoon (15:30-16:30 PM ) or at night (21:30-22:30 PM ) (all P < .001). Compared with normal children, the circadian rhythm variations of salivary cortisol and MT in dyslexic children disappeared and became disordered. The salivary cortisol and MT levels in children with dyslexia were declined throughout the day; and the circadian rhythm was disordered or disappeared.The results suggest that cortisol and MT levels and their circadian rhythm may affect children dyslexia, but the mechanisms need further exploration.

Dyslexia is a common neurodevelopmental disorder caused by a significant genetic component. The KIAA0319 gene is one of the most robust dyslexia susceptibility factors but its function remains poorly understood. Initial RNA-interference studies in rats suggested a role in neuronal migration whereas subsequent work with double knock-out mouse models for both Kiaa0319 and its paralogue Kiaa0319-like reported effects in the auditory system but not in neuronal migration. To further understand the role of KIAA0319 during neurodevelopment, we carried out an expression study of its zebrafish orthologue at different embryonic stages. We used different approaches including RNAscope in situ hybridization combined with light-sheet microscopy. The results show particularly high expression during the first few hours of development. Later, expression becomes localized in well-defined structures. In addition to high expression in the brain, we report for the first time expression in the eyes and the notochord. Surprisingly, kiaa0319-like, which generally shows a similar expression pattern to kiaa0319, was not expressed in the notochord suggesting a distinct role for kiaa0319 in this structure. This observation was supported by the identification of notochord enhancers enriched upstream of the KIAA0319 transcription start site, in both zebrafish and humans. This study supports a developmental role for KIAA0319 in the brain as well as in other developing structures, particularly in the notochord which, is key for establishing body patterning in vertebrates., (© 2019 The Authors. The Journal of Comparative Neurology published by Wiley Periodicals, Inc.)

Genome-wide association studies (GWAS) of developmental dyslexia (DD) often used European samples and identified only a handful associations with moderate or weak effects. This study aims to identify DD functional variants by integrating the GWAS associations with tissue-specific functional data and test the variants in a Chinese DD study cohort named READ. We colocalized associations from nine DD related GWAS with expression quantitative trait loci (eQTL) derived from brain tissues and identified two eSNPs rs349045 and rs201605. Both eSNPs had supportive evidence of chromatin interactions observed in human hippocampus tissues and their respective target genes ZNF45 and DNAH9 both had lower expression in brain tissues in schizophrenia patients than controls. In contrast, an eSNP rs4234898 previously identified based on eQTL from the lymphoblastic cell lines of dyslexic children had no chromatin interaction with its target gene SLC2A3 in hippocampus tissues and SLC2A3 expressed higher in the schizophrenia patients than controls. We genotyped the three eSNPs in the READ cohort of 372 cases and 354 controls and discovered only weak associations in rs201605 and rs4234898 with three DD symptoms (p < .05). The lack of associations could be due to low power in READ but could also implicate different etiology of DD in Chinese., (© 2019 Wiley Periodicals, Inc.)

Ca 2+ release-activated Ca 2+ (CRAC) channels are intimately linked with health and disease. The gene encoding the CRAC channel, ORAI1, was discovered in part by genetic analysis of patients with abolished CRAC channel function. And patients with autosomal recessive loss-of-function (LOF) mutations in ORAI1 and its activator stromal interaction molecule 1 (STIM1) that abolish CRAC channel function and store-operated Ca 2+ entry (SOCE) define essential functions of CRAC channels in health and disease. Conversely, gain-of-function (GOF) mutations in ORAI1 and STIM1 are associated with tubular aggregate myopathy (TAM) and Stormorken syndrome due to constitutive CRAC channel activation. In addition, genetically engineered animal models of ORAI and STIM function have provided important insights into the physiological and pathophysiological roles of CRAC channels in cell types and organs beyond those affected in human patients. The picture emerging from this body of work shows CRAC channels as important regulators of cell function in many tissues, and as potential drug targets for the treatment of autoimmune and inflammatory disorders., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Research on stress and dyslexia has mainly focused on chronic and contextual stress caused by the school environment. Our goal was to test individual differences in the hypothalamic-pituitary-adrenal (HPA) axis reactivity of dyslexic and non-dyslexic children and the related emotional manifestations associated with exposure to a psychosocial stressor., Methods: Eighty-one children (11-14 years old; 38 dyslexic) were exposed to the Trier Social Stress Test adapted to children or to a control condition. The salivary cortisol response, anxiety, and mood were measured before and after the stress., Results: Dyslexic children did not show the expected cortisol response, as the highest percentage of children who were non-reactive to stress was found in this group. Cortisol reactivity to stress was related to higher levels of anxiety and lower positive affect in the non-dyslexic children., Conclusion: These results suggest a pattern of hypo-activation of the HPA axis to psychosocial stress in children with dyslexia., (Copyright © 2019. Published by Elsevier GmbH.)

Several etiological theories, in particular neuronal noise and impaired auditory sampling, predicted neurotransmission deficits in dyslexia. Neurometabolites also affect white matter microstructure, where abnormalities were previously reported in dyslexia. However findings from only few magnetic resonance spectroscopy studies using diverse age groups, different brain regions, data processing and reference scaling are inconsistent. We used MEGA-PRESS single-voxel spectroscopy in two ROIs: left temporo-parietal and occipital cortex in 36 adults and 52 children, where half in each group had dyslexia. Dyslexics, on average, had significantly lower total N-acetylaspartate (tNAA) than controls in the occipital cortex. Adults compared to children were characterized by higher choline and creatine in both areas, higher tNAA in left temporo-parietal and lower glutamate in the visual cortex, reflecting maturational changes in cortical microstructure and metabolism. Although the current findings do not support the proposed etiological theories of dyslexia, they show, for the first time, that tNAA, considered to be a neurochemical correlate of white matter integrity, is deficient in the visual cortex in both children and adults with dyslexia. They also point that several neurotransmitters, including ones previously used as reference, change with age.

Calcium (Ca 2+ ) is a key regulator for a large number of cellular functions in all kinds of cells, and small disturbances of Ca 2+ homeostasis can severely compromise normal physiology in various tissues and organs. A major mechanism controlling Ca 2+ homeostasis is store-operated Ca 2+ entry (SOCE), which relies on the concerted action of the reticular Ca 2+ sensor STIM1 and the plasma membrane Ca 2+ channel ORAI1. Gain-of-function mutations in the respective genes induce excessive Ca 2+ entry, and cause tubular aggregate myopathy (TAM) and Stormorken syndrome. Both disorders are part of a clinical continuum and involve muscle weakness and additional variably pronounced features including miosis, thrombocytopenia, hyposplenism, ichthyosis, dyslexia, and short stature. Mutations in the reticular Ca 2+ buffer calsequestrin (CASQ1) have moreover been associated with the mild end of the TAM/Stormorken syndrome spectrum. Here we review the clinical and histological characteristics of both disorders, provide an overview on the genetic causes, and thereby focus on the pathomechanisms leading to muscle dysfunction and the multi-systemic phenotype of tubular aggregate myopathy and Stormorken syndrome., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

STIM1 and Orai1 are key components of the Ca 2+ -release activated Ca 2+ (CRAC) current. Orai1, which represents the subunit forming the CRAC channel complex, is activated by the ER resident Ca 2+ sensor STIM1. The genetically inherited Stormorken syndrome disease has been associated with the STIM1 single point R304W mutant. The resulting constitutive activation of Orai1 mainly involves the CRAC-activating domain CAD/SOAR of STIM1, the exposure of which is regulated by the molecular interplay between three cytosolic STIM1 coiled-coil (CC) domains. Here we present a dual mechanism by which STIM1 R304W attains the pathophysiological, constitutive activity eliciting the Stormorken syndrome. The R304W mutation induces a helical elongation within the CC1 domain, which together with an increased CC1 homomerization, destabilize the resting state of STIM1. This culminates, even in the absence of store depletion, in structural extension and CAD/SOAR exposure of STIM1 R304W leading to constitutive CRAC channel activation and Stormorken disease.

Reading difficulty (RD; or dyslexia) is a heritable condition characterized by slow, inaccurate reading accompanied by executive dysfunction, specifically with respect to visual attention. The current study was designed to examine the effect of familial history of RD on the relationship between reading and visual attention abilities in children with RD using a functional MRI reading task. Seventy-one children with RD participated in the study. Based on parental reports of the existence of RD in one or both of each child's parents, children with RD were divided into two groups: (1) those with a familial history of RD and (2) those without a familial history of RD. Reading and visual attention measures were collected from all participants. Functional MRI data during word reading was acquired in 30 participants of the entire cohort. Children with or without a familial history of RD demonstrated below-average reading and visual attention scores, with greater interaction between these measures in the group with a familial history of RD. Greater bilateral and diffused activation during word reading also were found in this group. We suggest that a familial history of RD is related to greater association between lower reading abilities and visual attention abilities. Parental history of RD therefore may be an important preschool screener (before reading age) to prompt early intervention focused on executive functions and reading-related skills.

Calcium (Ca 2+ ) is a physiological key factor, and the precise modulation of free cytosolic Ca 2+ levels regulates multiple cellular functions. Store-operated Ca 2+ entry (SOCE) is a major mechanism controlling Ca 2+ homeostasis, and is mediated by the concerted activity of the Ca 2+ sensor STIM1 and the Ca 2+ channel ORAI1. Dominant gain-of-function mutations in STIM1 or ORAI1 cause tubular aggregate myopathy (TAM) or Stormorken syndrome, whereas recessive loss-of-function mutations are associated with immunodeficiency. Here, we report the identification and functional characterization of novel ORAI1 mutations in TAM patients. We assess basal activity and SOCE of the mutant ORAI1 channels, and we demonstrate that the G98S and V107M mutations generate constitutively permeable ORAI1 channels, whereas T184M alters the channel permeability only in the presence of STIM1. These data indicate a mutation-dependent pathomechanism and a genotype/phenotype correlation, as the ORAI1 mutations associated with the most severe symptoms induce the strongest functional cellular effect. Examination of the non-muscle features of our patients strongly suggests that TAM and Stormorken syndrome are spectra of the same disease. Overall, our results emphasize the importance of SOCE in skeletal muscle physiology, and provide new insights in the pathomechanisms involving aberrant Ca 2+ homeostasis and leading to muscle dysfunction., (© 2017 WILEY PERIODICALS, INC.)

DYX1C1, DCDC2, and KIAA0319 are three of the most replicated dyslexia candidate genes (DCGs). Recently, these DCGs were implicated in functions at the cilium. Here, we investigate the regulation of these DCGs by Regulatory Factor X transcription factors (RFX TFs), a gene family known for transcriptionally regulating ciliary genes. We identify conserved X-box motifs in the promoter regions of DYX1C1, DCDC2, and KIAA0319 and demonstrate their functionality, as well as the ability to recruit RFX TFs using reporter gene and electrophoretic mobility shift assays. Furthermore, we uncover a complex regulation pattern between RFX1, RFX2, and RFX3 and their significant effect on modifying the endogenous expression of DYX1C1 and DCDC2 in a human retinal pigmented epithelial cell line immortalized with hTERT (hTERT-RPE1). In addition, induction of ciliogenesis increases the expression of RFX TFs and DCGs. At the protein level, we show that endogenous DYX1C1 localizes to the base of the cilium, whereas DCDC2 localizes along the entire axoneme of the cilium, thereby validating earlier localization studies using overexpression models. Our results corroborate the emerging role of DCGs in ciliary function and characterize functional noncoding elements, X-box promoter motifs, in DCG promoter regions, which thus can be targeted for mutation screening in dyslexia and ciliopathies associated with these genes.-Tammimies, K., Bieder, A., Lauter, G., Sugiaman-Trapman, D., Torchet, R., Hokkanen, M.-E., Burghoorn, J., Castrén, E., Kere, J., Tapia-Páez, I., Swoboda, P. Ciliary dyslexia candidate genes DYX1C1 and DCDC2 are regulated by Regulatory Factor (RF) X transcription factors through X-box promoter motifs., (© The Author(s).)

The Reading Acceleration Program is a computerized program that improves reading and the activation of the error-detection mechanism in individuals with reading difficulty (RD) and typical readers (TRs). The current study aims to find the neural correlates for this effect in English-speaking 8-12-year-old children with RD and TRs using a functional connectivity analysis. Functional magnetic resonance imaging data were collected during a lexical decision task before and after 4 weeks of training with the program, together with reading and executive functions measures. Results indicated improvement in reading, visual attention, and speed of processing in children with RD. Following training, greater functional connectivity was observed between the left fusiform gyrus and the right anterior cingulate cortex in children with RD and between the left fusiform gyrus and the left anterior cingulate cortex in TRs. The change in functional connectivity after training was correlated with increased behavioral scores for word reading and visual attention in both groups. The results support previous findings of improved monitoring and mental lexicon after training with the Reading Acceleration Program in children with RD and TRs. The differences in laterality of the anterior cingulate cortex in children with RD and the presumable role of the cingulo-opercular control network in language processing are discussed.

Store-operated Ca(2+) entry is the major route of replenishment of intracellular Ca(2+) in animal cells in response to the depletion of Ca(2+) stores in the endoplasmic reticulum. It is primarily mediated by the Ca(2+)-selective release-activated Ca(2+) (CRAC) channel, which consists of the pore-forming subunits ORAI1-3 and the Ca(2+) sensors, STIM1 and STIM2. Recessive loss-of-function mutations in STIM1 or ORAI1 result in immune deficiency and nonprogressive myopathy. Heterozygous gain-of-function mutations in STIM1 cause non-syndromic myopathies as well as syndromic forms of miosis and myopathy with tubular aggregates and Stormorken syndrome; some of these syndromic forms are associated with thrombocytopenia. Increased concentration of Ca(2+) as a result of store-operated Ca(2+) entry is essential for platelet activation. The York Platelet syndrome (YPS) is characterized by thrombocytopenia, striking ultrastructural platelet abnormalities including giant electron-opaque organelles and massive, multilayered target bodies and deficiency of platelet Ca(2+) storage in delta granules. We present clinical and molecular findings in 7 YPS patients from 4 families, demonstrating that YPS patients have a chronic myopathy associated with rimmed vacuoles and heterozygous gain-of-function STIM1 mutations. These findings expand the phenotypic spectrum of STIM1-related human disorders and define the molecular basis of YPS., (Published by Elsevier Inc.)

Stormorken syndrome is a rare autosomal dominant disorder characterized by a phenotype that includes miosis, thrombocytopenia/thrombocytopathy with bleeding time diathesis, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Using targeted sequencing and whole-exome sequencing, we identified the c.910C > T transition in a STIM1 allele (p.R304W) only in patients and not in their unaffected family members. STIM1 encodes stromal interaction molecule 1 protein (STIM1), which is a finely tuned endoplasmic reticulum Ca(2+) sensor. The effect of the mutation on the structure of STIM1 was investigated by molecular modeling, and its effect on function was explored by calcium imaging experiments. Results obtained from calcium imaging experiments using transfected cells together with fibroblasts from one patient are in agreement with impairment of calcium homeostasis. We show that the STIM1 p.R304W variant may affect the conformation of the inhibitory helix and unlock the inhibitory state of STIM1. The p.R304W mutation causes a gain of function effect associated with an increase in both resting Ca(2+) levels and store-operated calcium entry. Our study provides evidence that Stormorken syndrome may result from a single-gene defect, which is consistent with Mendelian-dominant inheritance., (© 2014 The Authors. *Human Mutation published by Wiley Periodicals, Inc.)

Reading disability is a brain-based difficulty in acquiring fluent reading skills that affects significant numbers of children. Although neuroanatomical and neurofunctional networks involved in typical and atypical reading are increasingly well characterized, the underlying neurochemical bases of individual differences in reading development are virtually unknown. The current study is the first to examine neurochemistry in children during the critical period in which the neurocircuits that support skilled reading are still developing. In a longitudinal pediatric sample of emergent readers whose reading indicators range on a continuum from impaired to superior, we examined the relationship between individual differences in reading and reading-related skills and concentrations of neurometabolites measured using magnetic resonance spectroscopy. Both continuous and group analyses revealed that choline and glutamate concentrations were negatively correlated with reading and related linguistic measures in phonology and vocabulary (such that higher concentrations were associated with poorer performance). Correlations with behavioral scores obtained 24 months later reveal stability for the relationship between glutamate and reading performance. Implications for neurodevelopmental models of reading and reading disability are discussed, including possible links of choline and glutamate to white matter anomalies and hyperexcitability. These findings point to new directions for research on gene-brain-behavior pathways in human studies of reading disability.

Handedness and brain asymmetry are widely regarded as unique to humans, and associated with complementary functions such as a left-brain specialization for language and logic and a right-brain specialization for creativity and intuition. In fact, asymmetries are widespread among animals, and support the gradual evolution of asymmetrical functions such as language and tool use. Handedness and brain asymmetry are inborn and under partial genetic control, although the gene or genes responsible are not well established. Cognitive and emotional difficulties are sometimes associated with departures from the "norm" of right-handedness and left-brain language dominance, more often with the absence of these asymmetries than their reversal., Competing Interests: The author has declared that no competing interests exist.

Disorders of human communication abilities can be classified into speech and language disorders. Speech disorders (e.g., dyspraxia) affect the sound generation and sequencing, while language disorders (e.g., dyslexia and specific language impairment, or SLI) are deficits in the encoding and decoding of language according to its rules (reading, spelling, grammar). The diagnosis of such disorders is often complicated, especially when a patient presents more than one disorder at the same time. The present review focuses on these challenges. We have combined data available from the literature with an in silico approach in an attempt to identify putative miRNAs that may have a key role in dyspraxia, dyslexia and SLI. We suggest the use of new miRNAs, which could have an important impact on the three diseases. Further, we relate those miRNAs to the axon guidance pathway and discuss possible interactions and the role of likely deregulated proteins. In addition, we describe potential differences in expressional deregulation and its role in the improvement of diagnosis. We encourage experimental investigations to test the data obtained in silico.

Precise regulation of neurite growth and differentiation determines accurate formation of synaptic connections, whose disruptions are frequently associated with neurological disorders. Dedicator of cytokinesis 4 (Dock4), an atypical guanine nucleotide exchange factor for Rac1, is found to be associated with neuropsychiatric diseases, including autism and schizophrenia. Nonetheless, the neuronal function of Dock4 is only beginning to be understood. Using mouse neuroblastoma (Neuro-2a) cells as a model, this study identifies that Dock4 is critical for neurite differentiation and extension. This regulation is through activation of Rac1 and modulation of the dynamics of actin-enriched protrusions on the neurites. In cultured hippocampal neurons, Dock4 regulates the establishment of the axon-dendrite polarity and the arborization of dendrites, two critical processes during neural differentiation. Importantly, a microdeletion Dock4 mutant linked to autism and dyslexia that lacks the GEF domain leads to defective neurite outgrowth and neuronal polarization. Further analysis reveals that the SH3 domain-mediated interaction of Dock4 is required for its activity toward neurite differentiation, whereas its proline-rich C terminus is not essential for this regulation. Together, our findings reveal an important role of Dock4 for neurite differentiation during early neuronal development.

Inspired by the localization, on 15q21.2 of the CYP19A1 gene in the linkage region of speech and language disorders, and a rare translocation in a dyslexic individual that was brought to our attention, we conducted a series of studies on the properties of CYP19A1 as a candidate gene for dyslexia and related conditions. The aromatase enzyme is a member of the cytochrome P450 super family, and it serves several key functions: it catalyzes the conversion of androgens into estrogens; during early mammalian development it controls the differentiation of specific brain areas (e.g. local estrogen synthesis in the hippocampus regulates synaptic plasticity and axonal growth); it is involved in sexual differentiation of the brain; and in songbirds and teleost fishes, it regulates vocalization. Our results suggest that variations in CYP19A1 are associated with dyslexia as a categorical trait and with quantitative measures of language and speech, such as reading, vocabulary, phonological processing and oral motor skills. Variations near the vicinity of its brain promoter region altered transcription factor binding, suggesting a regulatory role in CYP19A1 expression. CYP19A1 expression in human brain correlated with the expression of dyslexia susceptibility genes such as DYX1C1 and ROBO1. Aromatase-deficient mice displayed increased cortical neuronal density and occasional cortical heterotopias, also observed in Robo1-/- mice and human dyslexic brains, respectively. An aromatase inhibitor reduced dendritic growth in cultured rat neurons. From this broad set of evidence, we propose CYP19A1 as a candidate gene for human cognitive functions implicated in reading, speech and language.

Estrogen is involved in numerous physiological processes such as growth, differentiation, and function of the male and female reproductive tissues. In the developing brain, estrogen signaling has been linked to cognitive functions, such as learning and memory; however, the molecular mechanisms underlying this phenomenon are poorly understood. We have previously shown a link between developmental dyslexia and estrogen signaling, when we studied the functional interactions between the dyslexia candidate protein DYX1C1 and the estrogen receptors α (ERα) and β (ERβ). Here, we investigate the 17β-estradiol (E2)-dependent regulation of dyslexia susceptibility 1 candidate 1 (DYX1C1) expression. We demonstrate that ERβ, not ERα, binds to a transcriptionally active cis-regulatory region upstream of DYX1C1 transcriptional start site and that DYX1C1 expression is enhanced by E2 in a neuroblastoma cell line. This regulation is dependent on transcription factor II-I and liganded ERβ recruitment to this region. In addition, we describe that a single nucleotide polymorphism previously shown to be associated with dyslexia and located in the cis-regulatory region of DYX1C1 may alter the epigenetic and endocrine regulation of this gene. Our data provide important molecular insights into the relationship between developmental dyslexia susceptibility and estrogen signaling.

Reading coherence, defined as the ability to create appropriate, meaningful connections between the elements within a specific text itself and between elements within a text and the reader's prior knowledge, is one of the key processes involved in reading comprehension. This article describes reading coherence within the context of a neuropsychological model combining recent research in motivation, attention, and working memory. Specifically, a unique neuropsychologically identifiable form of reading coherence failure arising from the attentional and motivational deficiencies, based in altered frontoventral striatal reward circuits associated with noradrenaline (NA) circuitry, consistent with the delay-aversion model (dual-pathway model) of Sonuga-Barke ( 2003 ) is postulated. This article provides a model for this subset of reading disorders of which etiology is based on the executive support processes for reading and not in the mechanics of actual reading such as decoding and phonetics.

This article reviews and synthesizes recent research regarding auditory processing, attention, and their roles in generating both adaptive and maladaptive behavioral responses. Research in these areas is beginning to converge on the role of polymorphisms associated with catecholamine metabolism and transport, particularly the neurotransmitter dopamine. The synthesis offered in this article appears to be the first to argue that genetic differences in dopamine metabolism may be the common factor in four disparate disorders that are often observed to be comorbid, i.e., attention-deficit hyperactivity disorder, auditory processing disorders, developmental language disorders, and reading disorders.

Kiaa0319L is a novel protein encoded by a recently discovered gene KIAA0319-like(L) that may be associated with reading disability. Little is known about the characteristics of this protein and its distribution in the brain. We investigated here expression of this protein in adult mice, using an antibody specific for human and rodent Kiaa0319L. In the brain, Kiaa0319L was localized strongly in the olfactory bulb, and strong expression was found in other regions, including hippocampus, cerebellum, diencephalon and the cerebral cortex. Immunohistochemistry confirmed expression in these brain regions, and showed further that the protein was expressed preferentially in neurons in layer IV and VI of the neocortex, CA1 and CA2 subfields of the hippocampus and a subpopulation of neurons in CA3 and dentate gyrus. Furthermore, the protein was confined to dendrites of CA1 neurons in the stratum radiatum, but not those in the stratum oriens, and in astrocytes within the hippocampus. In the cerebellum, the protein was observed in the molecular layer and a fraction of Purkinje neurons. These findings confirmed expression of Kiaa0319L in brain regions that are involved in reading performance, supporting its possible involvement in reading disability. The specific patterns of localization in the neocortex, hippocampus and cerebellum suggest further that this protein may be related to other biological processes in a subpopulation of neurons within these regions, eg. formation and maintenance of polarity in the neuron.

To identify the putative interacting partners for Kiaa0319-like protein. KIAA0319-like, located near the dyslexia susceptibility locus, DYX8 in chromosome 1p34.3, has been suggested as a positional candidate for developmental dyslexia due to its homology with another gene, KIAA0319 which has been strongly established as a candidate gene for developmental dyslexia. Previous research has shown that a single marker, rs7523017 (P = 0.042) has been associated with developmental dyslexia by a Canadian group. There is little functional information about this gene and protein. In this article, we put forward further evidence that support Kiaa0319-like is a candidate for this disorder. A yeast-2-hybrid screen and co-immunopreciptiation assays were performed to find protein interacting partners of KIAA0319L. A human cortex immunohistochemistry assay was performed to show the colocalization of Kiaa0319-like and its specific interacting partner in cells. Nogo Receptor 1 (NgR1), an axon guidance receptor, was identified to have physical interactions with Kiaa0319-like protein. These two proteins interact predominantly in the cytoplasmic granules of cortical neurons in the human brain cortex. Based on this data, it can be concluded that Kiaa0319-like protein interacts with Nogo Receptor 1, supporting the idea that Kiaa0319-like protein participates in axon guidance.

The KIAA0319 gene has been associated with reading disability in several studies. It encodes a plasma membrane protein with a large, highly glycosylated, extracellular domain. This protein is proposed to function in adhesion and attachment and thought to play an important role during neuronal migration in the developing brain. We have previously proposed that endocytosis of this protein could constitute an important mechanism to regulate its function. Here we show that KIAA0319 undergoes ectodomain shedding and intramembrane cleavage. At least five different cleavage events occur, four in the extracellular domain and one within the transmembrane domain. The ectodomain shedding processing cleaves the extracellular domain, generating several small fragments, including the N-terminal region with the Cys-rich MANEC domain. It is possible that these fragments are released to the extracellular medium and trigger cellular responses. The intramembrane cleavage releases the intracellular domain from its membrane attachment. Our results suggest that this cleavage event is not carried out by γ-secretase, the enzyme complex involved in similar processing in many other type I proteins. The soluble cytoplasmic domain of KIAA0319 is able to translocate to the nucleus, accumulating in nucleoli after overexpression. This fragment has an unknown role, although it could be involved in regulation of gene expression. The absence of DNA-interacting motifs indicates that such a function would most probably be mediated through interaction with other proteins, not by direct DNA binding. These results suggest that KIAA0319 not only has a direct role in neuronal migration but may also have additional signaling functions.

Background: Functional Magnetic Resonance Imaging (fMRI) has been proven to be useful for studying brain functions. However, due to the existence of noise and distortion, mapping between the fMRI signal and the actual neural activity is difficult. Because of the difficulty, differential pattern analysis of fMRI brain images for healthy and diseased cases is regarded as an important research topic. From fMRI scans, increased blood ows can be identified as activated brain regions. Also, based on the multi-sliced images of the volume data, fMRI provides the functional information for detecting and analyzing different parts of the brain., Methods: In this paper, the capability of a hierarchical method that performed an optimization algorithm based on modified maximum model (MCM) in our previous study is evaluated. The optimization algorithm is designed by adopting modified maximum correlation model (MCM) to detect active regions that contain significant responses. Specifically, in the study, the optimization algorithm is examined based on two groups of datasets, dyslexia and healthy subjects to verify the ability of the algorithm that enhances the quality of signal activities in the interested regions of the brain. After verifying the algorithm, discrete wavelet transform (DWT) is applied to identify the difference between healthy and dyslexia subjects., Results: We successfully showed that our optimization algorithm improves the fMRI signal activity for both healthy and dyslexia subjects. In addition, we found that DWT based features can identify the difference between healthy and dyslexia subjects., Conclusion: The results of this study provide insights of associations of functional abnormalities in dyslexic subjects that may be helpful for neurobiological identification from healthy subject.

Mechanosensory hair cells of the organ of Corti transmit information regarding sound to the central nervous system by way of peripheral afferent neurons. In return, the central nervous system provides feedback and modulates the afferent stream of information through efferent neurons. The medial olivocochlear efferent system makes direct synaptic contacts with outer hair cells and inhibits amplification brought about by the active mechanical process inherent to these cells. This feedback system offers the potential to improve the detection of signals in background noise, to selectively attend to particular signals, and to protect the periphery from damage caused by overly loud sounds. Acetylcholine released at the synapse between efferent terminals and outer hair cells activates a peculiar nicotinic cholinergic receptor subtype, the alpha9alpha10 receptor. At present no pharmacotherapeutic approaches have been designed that target this cholinergic receptor to treat pathologies of the auditory system. The potential use of alpha9alpha10 selective drugs in conditions such as noise-induced hearing loss, tinnitus and auditory processing disorders is discussed.

Dyslexia, or specific reading disability, is the unexpected failure in learning to read and write when intelligence and senses are normal. One of the susceptibility genes, DYX1C1, has been implicated in neuronal migration, but little is known about its interactions and functions. As DYX1C1 was suggested to interact with the U-box protein CHIP (carboxy terminus of Hsc70-interacting protein), which also participates in the degradation of estrogen receptors alpha (ERalpha) and beta (ERbeta), we hypothesized that the effects of DYX1C1 might be at least in part mediated through the regulation of ERs. ERs have shown to be important in brain development and cognitive functions. Indeed, we show that DYX1C1 interacts with both ERs in the presence of 17beta-estradiol, as determined by co-localization, co-immunoprecipitation and proximity ligation assays. Protein levels of endogenous ERalpha or exogenous ERbeta were reduced upon over-expression of DYX1C1, resulting in decreased transcriptional responses to 17beta-estradiol. Furthermore, we detected in vivo complexes of DYX1C1 with ERalpha or ERbeta at endogenous levels along neurites of primary rat hippocampal neurons. Taken together, our data suggest that DYX1C1 is involved in the regulation of ERalpha and ERbeta, and may thus affect the brain development and regulate cognitive functions. These findings provide novel insights into the function of DYX1C1 and link neuronal migration and developmental dyslexia to the estrogen-signaling effects in the brain.

Recently, genetic studies have implicated KIAA0319 in developmental dyslexia, the most common of the childhood learning disorders. The first functional data indicated that the KIAA0319 protein is expressed on the plasma membrane and may be involved in neuronal migration. Further analysis of the subcellular distribution of the overexpressed protein in mammalian cells indicates that KIAA0319 can colocalize with the early endosomal marker early endosome antigen 1 (EEA1) in large intracellular vesicles, suggesting that it is endocytosed. Antibody internalization assays with full-length KIAA0319 and deletion constructs confirmed that KIAA0319 is internalized and showed the importance of the cytoplasmic juxtamembranal region in this process. The present study has identified the medium subunit (mu2) of adaptor protein 2 (AP-2) as a binding partner of KIAA0319 in a yeast two-hybrid screen. Using Rab5 mutants or depletion of the mu-subunit of AP-2 or clathrin heavy chain by RNA interference, we demonstrate that KIAA0319 follows a clathrin-mediated endocytic pathway. We also identify tyrosine-995 of KIAA0319 as a critical amino acid required for the interaction with AP-2 and subsequent internalization. These results suggest the surface expression of KIAA0319 is regulated by endocytosis, supporting the idea that the internalization and recycling of the protein may be involved in fine tuning its role in neuronal migration.

Background: Developmental dyslexia is a specific cognitive disorder in reading acquisition that has genetic and neurological origins. Despite histological evidence for brain differences in dyslexia, we recently demonstrated that in large cohort of subjects, no differences between control and dyslexic readers can be found at the macroscopic level (MRI voxel), because of large variances in brain local volumes. In the present study, we aimed at finding brain areas that most discriminate dyslexic from control normal readers despite the large variance across subjects. After segmenting brain grey matter, normalizing brain size and shape and modulating the voxels' content, normal readers' brains were used to build a 'typical' brain via bootstrapped confidence intervals. Each dyslexic reader's brain was then classified independently at each voxel as being within or outside the normal range. We used this simple strategy to build a brain map showing regional percentages of differences between groups. The significance of this map was then assessed using a randomization technique., Results: The right cerebellar declive and the right lentiform nucleus were the two areas that significantly differed the most between groups with 100% of the dyslexic subjects (N = 38) falling outside of the control group (N = 39) 95% confidence interval boundaries. The clinical relevance of this result was assessed by inquiring cognitive brain-based differences among dyslexic brain subgroups in comparison to normal readers' performances. The strongest difference between dyslexic subgroups was observed between subjects with lower cerebellar declive (LCD) grey matter volumes than controls and subjects with higher cerebellar declive (HCD) grey matter volumes than controls. Dyslexic subjects with LCD volumes performed worse than subjects with HCD volumes in phonologically and lexicon related tasks. Furthermore, cerebellar and lentiform grey matter volumes interacted in dyslexic subjects, so that lower and higher lentiform grey matter volumes compared to controls differently modulated the phonological and lexical performances. Best performances (observed in controls) corresponded to an optimal value of grey matter and they dropped for higher or lower volumes., Conclusion: These results provide evidence for the existence of various subtypes of dyslexia characterized by different brain phenotypes. In addition, behavioural analyses suggest that these brain phenotypes relate to different deficits of automatization of language-based processes such as grapheme/phoneme correspondence and/or rapid access to lexicon entries.

Developmental dyslexia is associated with problems in a range of linguistic and non-linguistic skills. Some of those problems have been attributed to dysfunction of the cerebellum and its associated neural systems. Two studies of cerebellar structure were undertaken by our group. In Study 1, white and grey matter volumes in the cerebellum were investigated in 10 dyslexic and 11 control adult male, right-handed participants using whole-brain volumetric MRI (3D-T1-weighted data sets with a spatial resolution of 0.8 x 0.8 x 0.8 mm(3)). The key finding was that the dyslexic group had a larger volume of white matter in both cerebellar hemispheres, differences that remained significant even when adjusting for total cerebellar volume. In Study 2, with the same participants, long-echo-time proton spectroscopy was used to investigate the ratios of the metabolites choline (Cho), N-acetylaspartate (NAA), and creatine (Cr) in the cerebellar hemispheres and vermis. Two significant differences were found: The dyslexic group had a lower ratio of NAA/Cho in the right cerebellar hemisphere together with a higher ratio of Cho/Cr in the left cerebellar hemisphere. Although it is difficult to interpret the volumetric and spectroscopic results unambiguously, taken together they suggest two possible interpretations: excessive connectivity or abnormal myelination.

Twin studies indicate genetic overlap between symptoms of attention deficit hyperactivity disorder (ADHD) and reading disabilities (RD), and linkage studies identify several chromosomal regions possibly containing common susceptibility genes, including the 15q region. Based on a translocation finding and association to two specific alleles, the candidate gene, DYX1C1, has been proposed as the susceptibility gene for RD in 15q. Previously, we tested markers in DYX1C1 for association with ADHD. Although we identified association for haplotypes across the gene, we were unable to replicate the association to the specific alleles reported. Thus, the risk alleles for ADHD are yet to be identified. The susceptibility alleles may be in a remote regulatory element, or DYX1C1 may not be the risk gene. To continue study of 15q, we tested a coding region change in DYX1C1, followed by markers across the gene Protogenin (PRTG) in 253 ADHD nuclear families. PRTG was chosen based on its location and because it is closely related to DCC and Neogenin, two genes known to guide migratory cells and axons during development. The markers in DYX1C1 were not associated to ADHD when analyzed individually; however, six markers in PRTG showed significant association with ADHD as a categorical trait (P = 0.025-0.005). Haplotypes in both genes showed evidence for association. We identified association with ADHD symptoms measured as quantitative traits in PRTG, but no evidence for association with two key components of reading, word identification and decoding was observed. These findings, while preliminary, identify association of ADHD to a gene that potentially plays a role in cell migration and axon growth.

Embryonic knockdown of candidate dyslexia susceptibility gene (CDSG) homologs in cerebral cortical progenitor cells in the rat results in acute disturbances of neocortical migration. In the current report we investigated the effects of embryonic knockdown and overexpression of the homolog of DCDC2, one of the CDSGs, on the postnatal organization of the cerebral cortex. Using a within-litter design, we transfected cells in rat embryo neocortical ventricular zone around embryonic day (E) 15 with either 1) small hairpin RNA (shRNA) vectors targeting Dcdc2, 2) a DCDC2 overexpression construct, 3) Dcdc2 shRNA along with DCDC2 overexpression construct, 4) an overexpression construct composed of the C terminal domain of DCDC2, or 5) an overexpression construct composed of the DCX terminal domain of DCDC2. RNAi of Dcdc2 resulted in pockets of heterotopic neurons in the periventricular region. Approximately 25% of the transfected brains had hippocampal pyramidal cell migration anomalies. Dcdc2 shRNA-transfected neurons migrated in a bimodal pattern, with approximately 7% of the neurons migrating a short distance from the ventricular zone, and another 30% migrating past their expected lamina. Rats transfected with Dcdc2 shRNA along with the DCDC2 overexpression construct rescued the periventricular heterotopia phenotype, but did not affect the percentage of transfected neurons that migrate past their expected laminar location. There were no malformations associated with any of the overexpression constructs, nor was there a significant laminar disruption of migration. These results support the claim that knockdown of Dcdc2 expression results in neuronal migration disorders similar to those seen in the brains of dyslexics.

The niacin skin test reflects a flush and oedema owing to the production of prostaglandin D2 from arachidonic acid. A diminished response may indicate abnormalities in the phospholipid metabolism, which has been shown in schizophrenia. There is evidence that dyslexia might also involve phospholipid abnormalities, therefore we examined the skin response in 51 dyslexics and 45 controls. Four concentrations of aqueous methyl nicotinate were applied topically to the forearm. Flushing was rated using a seven-point scale at 3 min intervals over 21 min. Repeated measures ANOVA for the four concentrations across all seven time-points showed no significant effect of subject group, but when analyses were confined to the first 9 min, flushing was reduced in dyslexics. Significant group differences were also found for the lowest niacin concentration (0.0001M) across six out of seven time-points. The results indicate a slightly reduced and delayed response to niacin in dyslexia.

The DYX2 locus on chromosome 6p22.2 is the most replicated region of linkage to developmental dyslexia (DD). Two candidate genes within this region have recently been implicated in the disorder: KIAA0319 and DCDC2. Variants within DCDC2 have shown association with DD in a US and a German sample. However, when we genotyped these specific variants in two large, independent UK samples, we obtained only weak, inconsistent evidence for their involvement in DD. Having previously found evidence that variation in the KIAA0319 gene confers susceptibility to DD, we sought to refine this genetic association by genotyping 36 additional SNPs in the gene. Nine SNPs, predominantly clustered around the first exon, showed the most significant association with DD in one or both UK samples, including rs3212236 in the 5' flanking region (P = 0.00003) and rs761100 in intron 1 (P = 0.0004). We have thus refined the region of association with developmental dyslexia to putative regulatory sequences around the first exon of the KIAA0319 gene, supporting the presence of functional mutations that could affect gene expression. Our data also suggests a possible interaction between KIAA0319 and DCDC2, which requires further testing.

Background: The current study examined the neuro-cognitive network of visual word rhyming judgment in 14 children with dyslexia and 14 age-matched control children (8- to 14-year-olds) using functional magnetic resonance imaging (fMRI)., Methods: In order to manipulate the difficulty of mapping orthography to phonology, we used conflicting and non-conflicting trials. The words in conflicting trials either had similar orthography but different phonology (e.g., pint-mint) or similar phonology but different orthography (e.g., jazz-has). The words in non-conflicting trials had similar orthography and phonology (e.g., gate-hate) or different orthography and phonology (e.g., press-list)., Results: There were no differences in brain activation between the controls and children with dyslexia in the easier non-conflicting trials. However, the children with dyslexia showed less activation than the controls in left inferior frontal gyrus (BA 45/44/47/9), left inferior parietal lobule (BA 40), left inferior temporal gyrus/fusiform gyrus (BA 20/37) and left middle temporal gyrus (BA 21) for the more difficult conflicting trials. For the direct comparison of conflicting minus non-conflicting trials, controls showed greater activation than children with dyslexia in left inferior frontal gyrus (BA 9/45/46) and medial frontal gyrus (BA 8). Children with dyslexia did not show greater activation than controls for any comparison., Conclusions: Reduced activation in these regions suggests that children with dyslexia have deficient orthographic representations in ventral temporal cortex as well as deficits in mapping between orthographic and phonological representations in inferior parietal cortex. The greater activation for the controls in inferior frontal gyrus could reflect more effective top-down modulation of posterior representations.

Dyslexia, or specific reading disability, is the most common learning disorder with a complex, partially genetic basis, but its biochemical mechanisms remain poorly understood. A locus on Chromosome 3, DYX5, has been linked to dyslexia in one large family and speech-sound disorder in a subset of small families. We found that the axon guidance receptor gene ROBO1, orthologous to the Drosophila roundabout gene, is disrupted by a chromosome translocation in a dyslexic individual. In a large pedigree with 21 dyslexic individuals genetically linked to a specific haplotype of ROBO1 (not found in any other chromosomes in our samples), the expression of ROBO1 from this haplotype was absent or attenuated in affected individuals. Sequencing of ROBO1 in apes revealed multiple coding differences, and the selection pressure was significantly different between the human, chimpanzee, and gorilla branch as compared to orangutan. We also identified novel exons and splice variants of ROBO1 that may explain the apparent phenotypic differences between human and mouse in heterozygous loss of ROBO1. We conclude that dyslexia may be caused by partial haplo-insufficiency for ROBO1 in rare families. Thus, our data suggest that a slight disturbance in neuronal axon crossing across the midline between brain hemispheres, dendrite guidance, or another function of ROBO1 may manifest as a specific reading disability in humans., Competing Interests: Competing interests. The authors have declared that no competing interests exist.

Prior research with rodent models, performed predominantly in males, has demonstrated a significant association between focal neocortical malformations (e.g. ectopias and microgyria) and rate-specific auditory processing deficits. In the current study and consistent with prior findings, we report that ectopic male BXSB/MpJ mice exhibit impairments in detecting a two-tone oddball stimulus at short but not long inter-stimulus interval durations when compared to non-ectopic male littermates. However, ectopic female littermates showed no rapid auditory processing deficit when compared to non-ectopic females on this same task. Current results add growing support to: (1) an association between focal cortical malformations and impaired auditory processing in males; and (2) the existence of sex differences in the behavioral consequences of focal cortical malformations.

A functional magnetic resonance imaging (fMRI) study during Japanese 'kana' readings was performed on Japanese dyslexic children. Five dyslexic children (aged 9-12 years) and five healthy children (aged 9-11 years) were investigated. The fMRI examination was performed by getting these children to read sentences constructed from Japanese phonograms, 'kana', compared with staring at meaningless figures as a control task. All control subjects showed activation of the left middle temporal gyrus. In the dyslexic children, the activation of the middle temporal gyrus was rather vague. However, other distinctively activated regions were detected as follows: the bilateral occipital cortex in two dyslexics, the inferior part of the frontal regions in two other dyslexics, and both the bilateral occipital cortex and the inferior part of precentral gyrus in the remaining one. These results indicate compensatory management processes for the unskilled reading ability of dyslexic children. The present results were similar to previous ones for adult dyslexia with the Roman alphabet, and suggest that brain malfunction in dyslexia during the task of reading must be common despite differences in languages.

Disorders of neurodevelopment include attention deficit hyperactivity disorder, dyspraxia, dyslexia and autism. There is considerable co-morbidity of these disorders and their identification often presents difficulties to those making a diagnosis. This is especially difficult when a multidisciplinary approach is not adopted. All of these disorders have been reported as associated with fatty acid abnormalities ranging from genetic abnormalities in the enzymes involved in phospholipid metabolism to symptoms reportedly improved following dietary supplementation with long chain fatty acids. If definitive disorders of lipid metabolism could be defined then the diagnosis and subsequent management of neurodevelopmental disorders might be transformed. In the identification of those disorders of development which involve lipid metabolism, there are now several tests, measures of lipid metabolism, which could be useful., (Copyright 2000 Harcourt Publishers Ltd.)

There is mounting evidence that developmental dyslexia is a neurodevelopmental disorder which involves abnormalities of fatty acid metabolism, particularly with respect to certain long-chain highly unsaturated fatty acids (HUFAs). Psychophysical evidence also strongly suggests that dyslexics may have visual deficits as well as phonological problems. Specifically, these visual deficits appear to be related to the magnocellular pathway, which is specialized for processing fast, rapidly-changing information about the visual scene. It remains unclear how these two aspects of dyslexia - fatty acid processing and visual magnocellular function - could be related. We propose some hypotheses - necessarily speculative, given the paucity of biochemical research in this field to date - which address this question., (Copyright 2000 Harcourt Publishers Ltd.)

Developmental dyslexia is a complex syndrome whose exact cause remains unknown. It has been suggested that a problem with fatty acid metabolism may play a role, particularly in relation to the visual symptoms exhibited by many dyslexics. We explored this possibility using two self-report questionnaires, designed on the basis of clinical experience, to assess (1) clinical signs of fatty acid deficiency; and (2) symptoms associated with dyslexia in known dyslexic and non-dyslexic subjects. Dyslexic signs and symptoms included the auditory-linguistic and spoken language difficulties traditionally associated with the disorder, as well as visual problems (both with reading and more generally) and motor problems. Fatty acid deficiency signs were significantly elevated in dyslexic subjects relative to controls, particularly within males (P<0.001). In addition, the severity of these clinical signs of fatty acid deficiency was strongly correlated with the severity of dyslexic signs and symptoms not only in the visual domain, but also with respect to auditory, linguistic and motor problems. The pattern of relationships differed somewhat between dyslexic and control groups, and sex differences were also observed. Our findings support the hypothesis that fatty acid metabolism may be abnormal in developmental dyslexia, and indicate the need for further studies using more objective measures., (Copyright 2000 Harcourt Publishers Ltd.)

There is increasing evidence that abnormalities of fatty acid and membrane phospholipid metabolism play a part in a wide range of neurodevelopmental and psychiatric disorders. This proposal is discussed here in relation to attention-deficit/hyperactivity disorder (ADHD), dyslexia, developmental coordination disorder (dyspraxia) and the autistic spectrum. These are among the most common neurodevelopmental disorders of childhood, with significant implications for society as well as for those directly affected. However, controversy still surrounds both the identification and management of these conditions, and while their aetiology is recognized as being complex and multifactorial, little progress has yet been made in elucidating predisposing factors at the biological level. An overview is provided here of the contents of this Special Issue, which contains a selection of reports from a unique multidisciplinary workshop involving both researchers and clinicians. Its purpose was to explore the possibility that ADHD, dyslexia, dyspraxia and autism fall within a phospholipid spectrum of disorders. This proposal could explain the high degree of co-morbidity between these conditions, their aggregation within families and relation to other psychiatric disorders, and a range of associated features that are already well known at a clinical level. The existing evidence for fatty acid abnormalities in these disorders is summarized, and new approaches are outlined that have the potential to improve both the identification and the management of these and related neurodevelopmental and psychiatric conditions., (Copyright 2000 Harcourt Publishers Ltd.)