Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism.

The ubiquitin pathway is an enzymatic cascade including activating E1, conjugating E2, and ligating E3 enzymes, which governs protein degradation and sorting. It is crucial for many physiological processes. Compromised function of members of the ubiquitin pathway leads to a wide range of human diseases, such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. Mutations in the thyroid hormone receptor interactor 12 (TRIP12) gene (OMIM 604506), which encodes an E3 ligase in the ubiquitin pathway, have been associated with autism spectrum disorder (ASD). In addition to autistic features, TRIP12 mutation carriers showed intellectual disability (ID). More recently, TRIP12 was postulated as a novel candidate gene for intellectual disability in a meta-analysis of published ID cohorts. However, detailed clinical information characterizing the phenotype of these individuals was not provided. In this study, we present seven novel individuals with private TRIP12 mutations including two splice site mutations, one nonsense mutation, three missense mutations, and one translocation case with a breakpoint in intron 1 of the TRIP12 gene and clinically review four previously published cases. The TRIP12 mutation-positive individuals presented with mild to moderate ID (10/11) or learning disability [intelligence quotient (IQ) 76 in one individual], ASD (8/11) and some of them with unspecific craniofacial dysmorphism and other anomalies. In this study, we provide detailed clinical information of 11 TRIP12 mutation-positive individuals and thereby expand the clinical spectrum of the TRIP12 gene in non-syndromic intellectual disability with or without ASD.

Mutations in FLVCR2 associated with Fowler syndrome and survival beyond infancy.

Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH, OMIM 225790), also known as Fowler syndrome, is a rare autosomal recessive disorder, caused by mutations in FLVCR2. Hallmarks of the syndrome are glomerular vasculopathy in the central nervous system, severe hydrocephaly, hypokinesia and arthrogryphosis. The disorder is considered prenatally lethal. We report the first patients, a brother and a sister, with Fowler syndrome and survival beyond infancy. The patients present a phenotype of severe intellectual and neurologic disability with seizures, absence of functional movements, and no means of communication. Imaging of the brain showed calcifications, profound ventriculomegaly with only a thin edging of the cerebral cortex and hypoplastic cerebellum. Investigation with whole-exome sequencing (WES) revealed, in both patients, a homozygous pathogenic mutation in FLVCR2, c.1289C>T, compatible with a diagnosis of Fowler syndrome. The results highlight the power of combining WES with a thorough clinical examination in order to identify disease-causing mutations in patients whose clinical presentation differs from previously described cases. Specifically, the findings demonstrate that Fowler syndrome is a diagnosis to consider, not only prenatally but also in severely affected children with gross ventriculomegaly on brain imaging.

Replication of genomewide associations with allergic sensitization and allergic rhinitis.

BACKGROUND: Three genomewide metastudies have recently reported associations with self-reported allergic rhinitis and allergic sensitization. The three studies together identified a set of 37 loci but showed low concordance. This study investigates the reproducibility of the detected single nucleotide polymorphism (SNP) associations in an extensively characterized longitudinal cohort, BAMSE. METHODS: Phenotypic evaluation of allergic rhinitis (AR) and allergic sensitization was performed on 2153 children from BAMSE at 8 and 16 years of age. Allele frequencies of 39 SNPs were investigated for association with the exact allergic phenotypes of the metastudies. Odds ratios and false discovery rates were calculated, and the impact of asthma was evaluated. The cases were also evaluated for age at onset effects (≤ or >8 years of age). RESULTS: Association tests of the 39 SNPs identified 12 SNPs with P-values < 0.05 and Q-values < 0.10. Two of the four loci (TLR6-TLR1 and HLA-DQA1-HLA-DQB1) identified in all three original studies were also identified in this study. Three SNPs located in the TLR6-TLR1 locus had the lowest P-values and Q-values < 0.1 when using a well-defined AR phenotype. Two loci showed significant age at onset effects, but the effect of asthma on the associations was very limited. CONCLUSION: The TLR6-TLR1 locus is likely to have a central role in the development of allergic disease. The association between genetic variation in the SSTR1-MIPOL1 and TSLP-SLC25A46 loci and age at onset is the first report of age at onset effects in allergic rhinitis.

Investigation of disease-associated factors in haemophilia A patients without detectable mutations.

To investigate disease causing mechanism in haemophilia A patients without detectable mutation. Screening for F8 mutations in 307 haemophilia A patients using: re-sequencing and inversion PCR, reverse transcription (RT-PCR) of mRNA, MLPA analysis, haplotyping using SNP and microsatellite markers. No F8 mutations were detected in 9 of the 307 patients (2.9%) using re-sequencing and inversion PCR. MLPA analysis detected duplication in exon 6 in one patient and RT-PCR showed no products for different regions of mRNA in four other patients, indicating failed transcription. No obvious associations were observed between the phenotypes of the nine patients, their F8 haplotypes and the putative mutations detected. The mutation-positive patients carrying the same haplotypes as the mutation-negative patients show a multitude of different mutations, emphasizing the lack of associations at the haplotype level. VWF mutation screening and factor V measurements ruled out type 2N VWD and combined factor V and VIII deficiency respectively. To further investigate a possible role for FVIII interacting factors the haplotypes/diplotypes of F2, F9, F10 and VWF were compared. The nine patients had no specific haplotype/diplotype combination in common that can explain disease. Duplications and faulty transcription contribute to the mutational spectrum of haemophilia A patients where conventional mutation screening fail to identify mutations.

Self-reported attachment style, trauma exposure and dissociative symptoms among adolescents.

The aim of this study was to analyze whether self-reported attachment style (measuring avoidance and anxiety) among adolescents was associated with dissociative symptoms, in addition to self-reported potentially traumatic experiences. A group consisting of 462 adolescents completed three self-assessment questionnaires: Linkoping Youth Life Experience Scale (LYLES), Experiences in Close Relationships, modified version (ECR) and Dissociation Questionnaire Sweden (Dis-Q-Sweden). Self-reported attachment style had a stronger association with dissociative symptoms than self reported traumas. It was also found that scores on a dissociation questionnaire correlated strongly with scores on self-reported attachment style in adolescence. Discussion concerns reasons why self-reported attachment style is an important factor that may influence dissociative symptoms during adolescence.

Effects of gradient encoding and number of signal averages on fractional anisotropy and fiber density index in vivo at 1.5 tesla.

BACKGROUND: Tensor estimation can be improved by increasing the number of gradient directions (NGD) or increasing the number of signal averages (NSA), but at a cost of increased scan time. PURPOSE: To evaluate the effects of NGD and NSA on fractional anisotropy (FA) and fiber density index (FDI) in vivo. MATERIAL AND METHODS: Ten healthy adults were scanned on a 1.5T system using nine different diffusion tensor sequences. Combinations of 7 NGD, 15 NGD, and 25 NGD with 1 NSA, 2 NSA, and 3 NSA were used, with scan times varying from 2 to 18 min. Regions of interest (ROIs) were placed in the internal capsules, middle cerebellar peduncles, and splenium of the corpus callosum, and FA and FDI were calculated. Analysis of variance was used to assess whether there was a difference in FA and FDI of different combinations of NGD and NSA. RESULTS: There was no significant difference in FA of different combinations of NGD and NSA of the ROIs (P>0.005). There was a significant difference in FDI between 7 NGD/1 NSA and 25 NGD/3 NSA in all three ROIs (P<0.005). There were no significant differences in FDI between 15 NGD/3 NSA, 25 NGD/1 NSA, and 25 NGD/2 NSA and 25 NGD/3 NSA in all ROIs (P>0.005). CONCLUSION: We have not found any significant difference in FA with varying NGD and NSA in vivo in areas with relatively high anisotropy. However, lower NGD resulted in reduced FDI in vivo. With larger NGD, NSA has less influence on FDI. The optimal sequence among the nine sequences tested with the shortest scan time was 25 NGD/1 NSA.

Photoreceptor evolution: ancient siblings serve different tasks.

Photoreceptor cells of vertebrate eyes are fundamentally different from those of invertebrate eyes. New work on the brain of a ragworm now suggests that ancestral bilaterians possessed both types of photoreceptor cell.

White matter abnormalities in children with idiopathic developmental delay.

BACKGROUND: The underlying cause of developmental delay (DD) often remains unclear despite extensive clinical examination and investigations. Interference in normal development of the brain may result in DD. PURPOSE: To identify the prevalence of abnormalities on magnetic resonance (MR) imaging in idiopathic developmental delay. MATERIAL AND METHODS: Of the 124 children referred for MR imaging with DD, 34 were excluded due to known history of progressive neurodevelopmental disorders, birth asphyxia, congenital CNS infections, metabolic disorder, chromosomal anomalies, and severe epileptic syndromes. The following structures were systematically reviewed: ventricles, corpus callosum, gray and white matter, limbic system, basal ganglia, brainstem, and cerebellum. RESULTS: Ten out of 90 (11%) were referred with DD only, whilst 80/90 (89%) were referred with DD and additional clinical findings, such as seizures, neurological deficit, and abnormal head size. Of the 90 patients, 14 (16%) had normal MR and 76 (84%) had abnormal MR findings. Abnormal ventricles were seen in 43/90 (48%); abnormal corpus callosum was identified in 40/90 (44%). Other MR findings included abnormalities in the white matter (23/90, 26%), hippocampi (5/90, 6%), cerebellum (5/90, 6%), and brainstem (4/90, 4%). CONCLUSION: Abnormalities of the ventricles and corpus callosum were identified in a large proportion of patients with idiopathic DD, indicative of changes in the white matter. Further studies using quantitative methods and diffusion tensor imaging are required to evaluate the white matter in these children.

Long-term follow-up of a patient with traumatic brain injury using diffusion tensor imaging.

This case report describes a patient who sustained severe head trauma with diffuse axonal injury (DAI). Examination with magnetic resonance diffusion tensor imaging (MRDTI), 6 days post-injury, showed a severe reduction in fractional anisotropy (FA) in the rostral pons containing the corticospinal tract, which correlated to the patient's severe hemiparesis. By 18 months post-accident, the patient had recovered completely and conventional MRI showed no pathology. However, although her FA values in the rostral pons had increased, they were still not normalized. It seems that a complete normalization of the FA values is not required to achieve clinical recovery, and that MR-DTI seems to be more sensitive to DAI compared to conventional MRI.

Eye ancestry: old genes for new eyes.

The vast differences between vertebrate and arthropod eyes suggest that the recently discovered homologous master control genes for eye development had another function before eyes evolved in the early Cambrian.

Visual pigments: trading noise for fast recovery.

Spontaneous activation of rhodopsin without light absorption occurs at a much lower rate in rod photoreceptors and insect rhabdoms than in cones. The difference lies in the pigment molecules themselves, and has implications for the design of visual photoreceptors.

Visual discrimination: Seeing the third quality of light.

Objects can differ in brightness and colour. At least that is what our own visual system tells us. It now seems that stomatopod shrimps, and possibly also cephalopod molluscs, can see the direction of the electric vector of light, in much the same way we see colour.

Child physical abuse - High school students' mental health and parental relations depending on who perpetrated the abuse.

The aim of this study was to contribute to the research of child physical abuse (CPA) by examining if there were any differences in high school students' mental health (in this study symptoms of depression and anxiety, self-esteem and sense of coherence) and/or, in how they perceive their parents, depending on whether or not they had been subjected to CPA during childhood. In addition, if high school students reported different mental health and/or, relationships with their parents, depending on if their mother, father or both parents were the perpetrators of CPA. A representative national sample of high school students (N=3288, data collected 2009) participated in the study. Participants completed the following: questions about CPA and alleged perpetrators, the Hopkins Symptom Checklist, Rosenberg Self-Esteem Scale, the Sense of Coherence Scale and Parental Bonding Instrument. The results showed students who reported experiences of CPA were more likely to report symptoms of mental illness and negative perceptions of their parents' parenting. However, there were no mental health differences depending on whether their mother, father or both parents were the perpetrators of CPA. Still, there were differences in perceived parenting indicating that mothers' parenting was perceived as more negative when mothers only or both parents were perpetrators of the abuse than when only fathers were perpetrators.

From cornea to retinal image in invertebrate eyes.

The optical information processing that takes place in an eye involves a large variety of very different optical components that are put together to solve a task which, in its basic nature, does not differ much from one species to another. The principal task of an eye is to sort the incoming photons so that they excite specific sensory neurons depending on angle of incidence, wavelength and plane of polarization. Despite the apparent simplicity of the task, the solutions to it are often complex and the variation between species is enormous. The pinhole camera, the Keplerian and Galilean telescopes, the corner reflector, optical fibres, and interference filters, are all names of optical devices invented by man. It now appears that all of these devices, and many more, exist in various combinations in the optics of invertebrate eyes. The similarity between man's and nature's optical engineering has been useful in many ways. For the study of eyes, it has helped to understand biological design principles in unparalleled detail.

Bilaterally symmetrical rhopalial nervous system of the box jellyfish Tripedalia cystophora.

Cubomedusae, or box jellyfish, have the most elaborate visual system of all cnidarians. They have 24 eyes of four morphological types, distributed on four sensory structures called rhopalia. Box jellyfish also display complex, probably visually guided behaviors such as obstacle avoidance and fast directional swimming. Here we describe the strikingly complex and partially bilaterally symmetrical nervous system found in each rhopalium of the box jellyfish, Tripedalia cystophora, and present the rhopalial neuroanatomy in an atlas-like series of drawings. Discrete populations of neurons and commissures connecting the left and the right side along with two populations of nonneuronal cells were visualized using several different histochemical staining techniques and electron microscopy. The number of rhopalial nerve cells and their overall arrangement indicates that visual processing and integration at least partly happen within the rhopalia. The larger of the two nonneuronal cell populations comprises approximately 2,000 likely undifferentiated cells and may support a rapid cell turnover in the rhopalial nervous system.

A conserved sequence in tRNA and rRNA promoters of Lactococcus lactis.

A tRNA operon (trnA) from Lactococcus lactis consisting of seven tRNA genes and a 5S rRNA gene was cloned and sequenced. Promoter-fusion of the trnA promoter to a promoter-less beta-galactosidase gene of Leuconostoc mesenteroides resulted in high levels of beta-galactosidase activity in L. lactis. Searching for sequences with similarity to the sequence of the promoter region revealed a consensus sequence of promoters preceeding rRNA operons and tRNA operons from Lactococcus species including a not previously described conserved sequence (AGTT).

Phosphoribosylpyrophosphate synthetase of Bacillus subtilis. Cloning, characterization and chromosomal mapping of the prs gene.

The gene (prs) encoding phosphoribosylpyrophosphate (PRPP) synthetase has been cloned from a library of Bacillus subtilis DNA by complementation of an Escherichia coli prs mutation. Flanking DNA sequences were pruned away by restriction endonuclease and exonuclease BAL 31 digestions, resulting in a DNA fragment of approx. 1.8 kb complementing the E. coli prs mutation. Minicell experiments revealed that this DNA fragment coded for a polypeptide, shown to be the PRPP synthetase subunit, with an Mr of approx. 40,000. B. subtilis strains harbouring the prs gene in a multicopy plasmid contained up to nine-fold increased PRPP synthetase activity. The prs gene was cloned in an integration vector and the resulting hybrid plasmid inserted into the B. subtilis chromosome by homologous recombination. The integration site was mapped by transduction and the gene order established as purA-guaA-prs-cysA.

A pessimistic estimate of the time required for an eye to evolve.

Theoretical considerations of eye design allow us to find routes along which the optical structures of eyes may have evolved. If selection constantly favours an increase in the amount of detectable spatial information, a light-sensitive patch will gradually turn into a focused lens eye through continuous small improvements of design. An upper limit for the number of generations required for the complete transformation can be calculated with a minimum of assumptions. Even with a consistently pessimistic approach the time required becomes amazingly short: only a few hundred thousand years.

Absorption of white light in photoreceptors.

The fraction F of incident light absorbed by a photoreceptor of length l has traditionally been given by F = 1 - e-kl, where k is the absorption coefficient of the photoreceptor. Unfortunately, this widely-used expression is incorrect for absorption of the type of light most common in natural scenes--broad spectrum "white" light--and significantly over-estimates absorption. This is because the measured values of k are only valid at the absorbance peak wavelength of rhodopsin, whereas at other wavelengths (which the eye may also see) k is lower. We have accounted for the wavelength dependence of k and calculated the absorption of white light from four different natural radiant sources: the quantal irradiances of natural daylight and a patch of very blue sky, and the quantal reflections of soil and green foliage irradiated by natural daylight. Based on these results, a simple averaged correction for white light stimulation is derived, F = kl/(2.3 + kl), which is valid for a wide range of k and l, and therefore applicable to both vertebrate and invertebrate photoreceptors.