• E-cadherin
• Hakai
• Keratinization
• Mir-6766
• Steroid sulfatase

• Cadherins/metabolism
• Cadherins/genetics
• Animals
• Keratinocytes/metabolism
• Keratinocytes/pathology
• Mice
• Steryl-Sulfatase/metabolism
• Steryl-Sulfatase/genetics
• Proteasome Endopeptidase Complex/metabolism
• Mice, Knockout
• Ichthyosis, X-Linked/metabolism
• Ichthyosis, X-Linked/genetics
• Ichthyosis, X-Linked/pathology
• Proteolysis
• Cell Differentiation
• Humans
• Membrane Proteins/metabolism
• Membrane Proteins/genetics
• Keratins/metabolism
• Ubiquitin-Protein Ligases/metabolism
• Ubiquitin-Protein Ligases/genetics
• Cholesterol Esters/metabolism
• Antigens, CD/metabolism
• Protein Precursors

• neuroscience
• human behaviour

• Humans
• Child
• Adolescent
• Animals
• Mice
• Attention Deficit Disorder with Hyperactivity
• Impulsive Behavior
• Disease Models, Animal
• Attention
• Learning

• NRF-2021R1I1A3055750 National Research Foundation of Korea (NRF)

• Animals
• Mice
• Humans
• Ichthyosis, X-Linked/genetics
• Steryl-Sulfatase/genetics
• Reactive Oxygen Species
• Ichthyosis/genetics
• Apoptosis
• RNA, Small Interfering

• ADHD predominantly inattentive (ADHD-PI) presentation
• Spot14
• Thyroid hormone-responsive protein (Thrsp)
• attention-deficit/hyperactivity disorder (ADHD)
• neural stem/progenitor cells (NSPCs)

Background and aims: X-linked ichthyosis (XLI) is a common recessive genetic disease caused by the deletion of steroid sulfatase (STS) in Xp22.31. Maternal copy-number deletions in Xp22.31 (covering STS) can be considered an incidental benefit of genome-wide cell-free DNA profiling. Here, we explored the accuracy and clinical value of maternal deletions in Xp22.31 during non-invasive prenatal screening (NIPS).

Materials and methods: We evaluated 13,156 pregnant women who completed NIPS. The maternal deletions in Xp22.31 revealed by NIPS were confirmed with maternal white blood cells by chromosome microarray analysis (CMA) or copy-number variation sequencing (CNV-seq). Suspected positive women pregnant with male fetuses were informed and provided with prenatal genetic counseling.

Results: Nineteen maternal deletions in Xp22.31 covering STS were detected by NIPS, which were all confirmed, ranging in size from 0.61 to 1.77 Mb. Among them, eleven women with deletions in male fetuses accepted prenatal diagnoses, and finally nine cases of XLI were diagnosed. The nine XLI males had differing degrees of skin abnormalities, and of them, some male members of ten families had symptoms associated with XLI.

Conclusion: NIPS has the potential to detect clinically significant maternal X chromosomal CNVs causing XLI, which can guide the prenatal diagnosis of X-linked ichthyosis and reflect the family history, so as to enhance pregnancy management as well as children and family members’ health management.

• animal models
• attention-deficit hyperactive disorder
• genetic models
• hyperactivity
• neurotransmission
• pathogenesis
• physical trauma models

• Animals
• Attention Deficit Disorder with Hyperactivity/genetics
• Disease Models, Animal
• Mice, Knockout
• Models, Genetic
• Mice

• Atrial fibrillation
• Attention deficit hyperactivity disorder (ADHD)
• Autism
• NLGN4X
• Steroid sulfatase

• concordance correlation coefficient
• data extraction
• meta-analysis
• systematic review

• Calcium signalling
• Cellular Communication Network Factor
• Oestrogen
• Phosphodiesterase 10A
• Psychosis
• Transient Receptor Potential Cation Channel Subfamily M Member 3 (TRPM3)

• arrhythmias
• copy-number
• dermatology
• neurosciences
• psychiatry

• Female
• G-protein coupled receptor
• mice
• postpartum depression
• postpartum psychosis
• steroid sulfatase

• MR/L010305/1 Medical Research Council

X-linked ichthyosis (XLI) is a rare X-linked dermatological condition arising from deficiency for the enzyme steroid sulfatase (STS). STS is normally expressed in the brain, and males with XLI exhibit personality differences from males in the general population, and are at increased risk of developmental and mood disorders. As the STS gene escapes X-inactivation, female carriers of XLI-associated genetic mutations have reduced STS expression/activity relative to non-carrier females, and could manifest similar behavioural phenotypes to males with XLI. Additionally, as STS activity normally increases in female tissues towards late pregnancy and into the puerperium, carrier females could theoretically present with increased rates of postpartum psychopathology. Using a worldwide online survey comprising custom-designed demographic questionnaires and multiple validated psychological questionnaires, we collected detailed self-reported information on non-postpartum and postpartum behaviour in confirmed adult (>16yrs) female carriers of genetic mutations associated with XLI (n = 94) for statistical comparison to demographically-matched previously-published normative data from female controls (seven independent studies, 98≤n≤2562), adult males with XLI (n = 58), and to newly-obtained online survey data from a general population sample of mothers from the United Kingdom and United States of America (n = 263). The pattern of results in carrier females relative to controls was remarkably similar to that previously observed in males with XLI, with evidence for increased rates of developmental and mood disorders, and elevated levels of inattention, impulsivity, autism-related traits and general psychological distress. Carrier females exhibited a significantly elevated rate of postpartum mental health conditions (notably mild depression) relative to controls which could not be accounted for by social factors. Our data confirm the psychological profile associated with XLI-associated mutations, and suggest that female carriers may be at increased risk of psychopathology, including in the postpartum period. These findings are relevant to families affected by XLI, to clinicians involved in the care of these families, and to genetic counsellors.

• Adult
• Attention Deficit Disorder with Hyperactivity/pathology
• Case-Control Studies
• Female
• Heterozygote
• Humans
• Ichthyosis, X-Linked/genetics
• Ichthyosis, X-Linked/pathology
• Ichthyosis, X-Linked/psychology
• Male
• Mothers/psychology
• Phenotype
• Polymorphism, Genetic
• Postpartum Period
• Pregnancy
• Psychometrics
• Self Report
• Steryl-Sulfatase/genetics
• Surveys and Questionnaires

• MR/L010305/1 Medical Research Council
• Medical Research Council United Kingdom

• dehydroepiandrosterone sulfate
• postpartum depression
• postpartum psychosis
• steroid sulfatase
• sulfotransferase

• Animals
• Humans
• Maternal Behavior/physiology
• Mental Health
• Postpartum Period
• Psychotic Disorders/metabolism
• Steroids/metabolism
• Sulfates/metabolism
• Sulfotransferases/metabolism

• MR/L010305/1 Medical Research Council

• STS gene
• attention-deficit hyperactivity disorder
• contiguous gene syndrome
• deletion
• point mutation

X-linked ichthyosis is a dermatological condition caused by deficiency for the enzyme steroid sulfatase. Previously, X-linked ichthyosis/steroid sulfatase deficiency has been associated with developmental and neurological phenotypes. Here, we show for the first time, that X-linked ichthyosis may be comorbid with an additional psychiatric phenotype (psychosis).

We report the case of an 11-year-old Saudi Arabian boy with X-linked ichthyosis associated with psychosis, mental retardation, autism spectrum disorder, inattentive attention deficit hyperactivity disorder, and epilepsy. Genetic analysis revealed a 1.68 Mb deletion encompassing STS in 95% of cells while biochemical analysis revealed correspondingly low steroid sulfatase activity consistent with a diagnosis of X-linked ichthyosis. The psychotic symptoms could be reasonably well controlled by administration of an atypical antipsychotic.

This report describes a case of comorbid X-linked ichthyosis and psychosis (most closely corresponding to early-onset schizophrenia) for the first time, and suggests that deficiency for steroid sulfatase and contiguous genes may increase vulnerability to psychosis as well as other psychological disorders.

• Attention deficit hyperactivity disorder
• Autism spectrum disorder
• Case report
• Epilepsy
• Psychosis
• Steroid sulfatase
• X-linked ichthyosis

ADHD (attention deficit hyperactivity disorder) is a common neurodevelopmental disorder. There has been extensive clinical and basic research in the field of ADHD over the past 20 years, but the mechanisms underlying ADHD risk are multifactorial, complex and heterogeneous and, as yet, are poorly defined. In this review, we argue that one approach to address this challenge is to study well-defined disorders to provide insights into potential biological pathways that may be involved in idiopathic ADHD.

To address this premise, we selected two neurogenetic conditions that are associated with significantly increased ADHD risk: Turner syndrome and the RASopathies (of which Noonan syndrome and neurofibromatosis type 1 are the best-defined with regard to ADHD-related phenotypes). These syndromes were chosen for two main reasons: first, because intellectual functioning is relatively preserved, and second, because they are strikingly phenotypically similar but are etiologically distinct. We review the cognitive, behavioural, neural and cellular phenotypes associated with these conditions and examine their relevance as a model for idiopathic ADHD.

We conclude by discussing current and future opportunities in the clinical and basic research of these conditions, which, in turn, may shed light upon the biological pathways underlying idiopathic ADHD.

• Attention deficit hyperactivity disorder
• Neurofibromatosis type 1
• Noonan syndrome
• RASopathies
• Turner syndrome
• X chromosome

Postpartum psychosis is a severe psychiatric condition which affects 1-2 of every 1000 mothers shortly after childbirth. Whilst there is convincing evidence that the condition is precipitated by a complex combination of biological and environmental factors, as yet the pathophysiological mechanisms remain extremely poorly defined. Here, I critically review approaches that have been, or are being, employed to identify and characterise such mechanisms; I also review a recent animal model approach, and describe a novel biological risk model that it suggests. Clarification of biological risk mechanisms underlying disorder risk should permit the identification of relevant predictive biomarkers which will ensure that “at risk” subjects receive prompt clinical intervention if required.

• CCN3
• Immune system
• Steroid sulfatase
• Nephroblastoma-overexpressed
• Mouse
• Animal model
• Risk factor

• MR/L010305/1 Medical Research Council

• ADHD
• Animal model
• Attention-deficit/hyperactivity disorder
• Transgenic
• Validity

• Animals
• Animals, Genetically Modified
• Attention Deficit Disorder with Hyperactivity
• Behavior, Animal
• Disease Models, Animal
• Impulsive Behavior

• HI12C0011 Korea Health Industry Development Institute

This study examined the relationships among polymorphisms of the STS gene and SULT2A1 gene, dehydroepiandrosterone (DHEA) and its sulfated form (DHEA-S), and characteristics of attention-deficit/hyperactivity disorder (ADHD). We used cheek swabs to obtain the genomic DNA of 200 ADHD male probands (mean age: 8.7 years), 192 patients’ mothers and 157 patients’ fathers. Three SNPs in the STS gene (rs6639786, rs2270112, and rs17268988) and one SNP in the SULT2A1 gene (rs182420) were genotyped. Saliva samples were collected from the ADHD patients to analyze DHEA and DHEA-S levels. The behavioral symptoms were evaluated with the Swanson, Nolan, and Pelham, and Version IV Scale for ADHD (SNAP-IV), and the neuropsychological function was assessed using the Conners’ Continuous Performance Tests (CPT). We found the C allele of rs2270112 within the STS gene to be over-transmitted in males with ADHD. Polymorphisms of rs182420 within the SULT2A1 gene were not associated with ADHD. In addition, the C allele carriers of rs2270112 demonstrated significantly higher DHEA-S levels than the G allele carriers. Levels of DHEA were positively correlated with attention as measured by the CPT. These findings support a potential role in the underlying biological pathogenesis of ADHD with regard to STS polymorphisms and neurosteroid levels.

• Adult
• Autistic Disorder/complications
• Autistic Disorder/diagnosis
• Behavior/physiology
• Child
• Humans
• Ichthyosis, X-Linked/complications
• Ichthyosis, X-Linked/diagnosis
• Ichthyosis, X-Linked/psychology
• Internet
• Male
• Mood Disorders/complications
• Mood Disorders/diagnosis
• Neurodegenerative Diseases/complications
• Neurodegenerative Diseases/diagnosis
• Phenotype
• Psychometrics
• Surveys and Questionnaires
• Young Adult

• MR/L010305/1 Medical Research Council
• Cardiff University

• ADHD
• neurobiology
• phenomenology

• Behavior
• Four core genotypes
• Klinefelter syndrome
• Sex differences
• Sexual differentiation
• Turner syndrome

• Autism
• Basal ganglia
• Imprinted gene
• Mouse
• Rat
• Sex chromosome
• Sry
• Steroid sulfatase
• Testosterone
• Thalamus

• Animals
• Attention Deficit Disorder with Hyperactivity/genetics
• Behavior/physiology
• Endocrine System/physiology
• Genetic Predisposition to Disease
• Humans
• Risk Factors
• Sex Characteristics

• MR/L010305/1 Medical Research Council

• Administration, Oral
• Attention Deficit Disorder with Hyperactivity/drug therapy
• Central Nervous System Agents/administration & dosage
• Central Nervous System Agents/pharmacology
• Central Nervous System Agents/therapeutic use
• Child
• Dehydroepiandrosterone/metabolism
• Dose-Response Relationship, Drug
• Female
• Follow-Up Studies
• Humans
• Hydrocortisone/metabolism
• Male
• Methylphenidate/administration & dosage
• Methylphenidate/pharmacology
• Methylphenidate/therapeutic use
• Prospective Studies
• Saliva/metabolism

The 39,X^Y*O mouse, which lacks the orthologues of the ADHD and autism candidate genes STS (steroid sulphatase) and ASMT (acetylserotonin O-methyltransferase), exhibits behavioural phenotypes relevant to developmental disorders. The neurobiology underlying these phenotypes is unclear, although there is evidence for serotonergic abnormalities in the striatum and hippocampus.

Using microarray and quantitative gene expression analyses, and gas chromatography–mass spectrometry, we compared brain gene expression and steroid biochemistry in wildtype (40,XY) and 39,X^Y*O adult mice to identify non-obvious genetic and endocrine candidates for between-group differences in behaviour and neurochemistry. We also tested whether acute STS inhibition by COUMATE in wildtype (40,XY) adult male mice recapitulated any significant gene expression or biochemical findings from the genetic comparison. Data were analysed by unpaired t-test or Mann Whitney U-test depending on normality, with a single factor of KARYOTYPE.

Microarray analysis indicated seven robust gene expression differences between the two groups (Vmn2r86, Sfi1, Pisd-ps1, Tagap1, C1qc, Metap1d, Erdr1); Erdr1 and C1qc expression was significantly reduced in the 39,X^Y*O striatum and hippocampus, whilst the expression of Dhcr7 (encoding 7-dehydrocholesterol reductase, a modulator of serotonin system development), was only reduced in the 39,X^Y*O hippocampus. None of the confirmed gene expression changes could be recapitulated by COUMATE administration. We detected ten free, and two sulphated steroids in 40,XY and 39,X^Y*O brain; surprisingly, the concentrations of all of these were equivalent between groups.

Our data demonstrate that the mutation in 39,X^Y*O mice: i) directly disrupts expression of the adjacent Erdr1 gene, ii) induces a remarkably limited suite of downstream gene expression changes developmentally, with several of relevance to associated neurobehavioural phenotypes and iii) does not elicit large changes in brain steroid biochemistry. It is possible that individuals with STS/ASMT deficiency exhibit a similarly specific pattern of gene expression changes to the 39,X^Y*O mouse, and that these contribute towards their abnormal neurobiology. Future work may focus on whether complement pathway function, mitochondrial metabolism and cholesterol biosynthesis pathways are perturbed in such subjects.

• Cholesterol sulfate
• Corneodesmosomes
• Epidermal barrier function
• Epidermal lipid metabolism
• Steroid sulfatase
• X-linked ichthyosis

Whilst gonadal hormones can substantially influence sexual differentiation of the brain, recent findings have suggested that sex-linked genes may also directly influence neurodevelopment. Here we used the well-established murine ‘four core genotype’ (FCG) model on a gonadally-intact, outbred genetic background to characterise the contribution of Sry-dependent effects (i.e. those arising from the expression of the Y-linked Sry gene in the brain, or from hormonal sequelae of gonadal Sry expression) and direct effects of sex-linked genes other than Sry (‘sex chromosome complement’ effects) to sexually dimorphic mouse behavioural phenotypes. Over a 24 hour period, XX and XY gonadally female mice (lacking Sry) exhibited greater horizontal locomotor activity and reduced food consumption per unit bodyweight than XX and XY gonadally male mice (possessing Sry); in two behavioural tests (the elevated plus and zero mazes) XX and XY gonadally female mice showed evidence for increased anxiety-related behaviours relative to XX and XY gonadally male mice. Exploratory correlational analyses indicated that these Sry-dependent effects could not be simply explained by brain expression of the gene, nor by circulating testosterone levels. We also noted a sex chromosome complement effect on food (but not water) consumption whereby XY mice consumed more over a 24hr period than XX mice, and a sex chromosome complement effect in a third test of anxiety-related behaviour, the light-dark box. The present data suggest that: i) the male-specific factor Sry may influence activity and feeding behaviours in mice, and ii) dissociable feeding and anxiety-related murine phenotypes may be differentially modulated by Sry and by other sex-linked genes. Our results may have relevance for understanding the molecular underpinnings of sexually dimorphic behavioural phenotypes in healthy men and women, and in individuals with abnormal sex chromosome constitutions.

• Animals
• Anxiety/genetics
• Behavior, Animal
• Body Weight
• Brain/metabolism
• Feeding Behavior
• Female
• Genes, sry
• Genetic Association Studies
• Male
• Mice
• Motor Activity/genetics
• Phenotype
• Sex Chromosomes
• Sex Factors
• Testosterone/blood

• Biotechnology and Biological Sciences Research Council
• Medical Research Council

• acetylserotonin o-methyltransferase
• attention deficit hyperactivity disorder
• autism
• dehydroepiandrosterone
• hippocampus
• locomotor activity
• serotonin
• spatial working memory
• steroid sulfatase
• xp22.3

Attention-deficit hyperactivity disorder (ADHD) is a developmental disorder characterized by symptoms of inattention, impulsivity and hyperactivity that adversely affect many aspects of life. Whereas the etiology of ADHD remains unknown, growing evidence indicates a genetic involvement in the development of this disorder. The brain circuits associated with ADHD are rich in monoamines, which are involved in the mechanism of action of psychostimulants and other medications used to treat this disorder. Dopamine (DA) is believed to play a major role in ADHD but other neurotransmitters are certainly also involved. Genetically modified mice have become an indispensable tool used to analyze the contribution of genetic factors in the pathogenesis of human disorders. Although rodent models cannot fully recapitulate complex human psychiatric disorders such as ADHD, transgenic mice offer an opportunity to directly investigate in vivo the specific roles of novel candidate genes identified in ADHD patients. Several knock-out and transgenic mouse models have been proposed as ADHD models, mostly based on targeting genes involved in DA transmission, including the gene encoding the dopamine transporter (DAT1). These mutant models provided an opportunity to evaluate the contribution of dopamine-related processes to brain pathology, to dissect the neuronal circuitry and molecular mechanisms involved in the antihyperkinetic action of psychostimulants and to evaluate novel treatments for ADHD. New transgenic models mouse models targeting other genes have recently been proposed for ADHD. Here, we discuss the recent advances and pitfalls in modeling ADHD endophenotypes in genetically altered animals.

The enzyme steroid sulfatase (STS) desulfates a variety of steroid compounds thereby altering their activity. STS is expressed in the skin, and its deficiency in this tissue has been linked to the dermatological condition X-linked ichthyosis. STS is also highly expressed in the developing and adult human brain, and in a variety of steroidogenic organs (including the placenta and gonads); therefore it has the potential to influence brain development and function directly and/or indirectly (through influencing the hormonal milieu). In this review, we first discuss evidence from human and animal model studies suggesting that STS deficiency might predispose to neurobehavioural abnormalities and certain psychiatric disorders. We subsequently discuss potential mechanisms that may underlie these vulnerabilities. The data described herein have potential implications for understanding the complete spectrum of clinical phenotypes associated with X-linked ichthyosis, and may indicate novel pathogenic mechanisms underlying psychological dysfunction in developmental disorders such as attention deficit hyperactivity disorder and Turner syndrome.

• Acetylcholine
• Aggression
• Attention
• Attention deficit hyperactivity disorder
• Dehydroepiandrosterone sulfate
• Impulsivity
• Hippocampus
• Postpartum psychosis
• Serotonin

• attention deficit hyperactivity disorder
• dehydroepiandrosterone sulfate
• hippocampus
• obsessive–compulsive disorder
• progressive ratio
• striatum
• animal models
• behavioral science
• biological psychiatry
• neurochemistry

• behavior
• copy number variant
• mouse
• rat
• single nucleotide polymorphism

• G0900636 Medical Research Council

It is now generally agreed that there are inherent sex differences in healthy individuals across a number of neurobiological domains (including brain structure, neurochemistry, and cognition). Moreover, there is a burgeoning body of evidence highlighting sex differences within neuropsychiatric populations (in terms of the rates of incidence, clinical features/progression, neurobiology and pathology). Here, we consider the extent to which attention and impulsivity are sexually dimorphic in healthy populations and the extent to which sex might modulate the expression of disorders characterised by abnormalities in attention and/or impulsivity such as attention deficit hyperactivity disorder (ADHD), autism and addiction. We then discuss general genetic mechanisms that might underlie sex differences in attention and impulsivity before focussing on specific positional and functional candidate sex-linked genes that are likely to influence these cognitive processes. Identifying novel sex-modulated molecular targets should ultimately enable us to develop more effective therapies in disorders associated with attentional/impulsive dysfunction.