Widespread and Functional RNA Circularization in Localized Prostate Cancer.

The cancer transcriptome is remarkably complex, including low-abundance transcripts, many not polyadenylated. To fully characterize the transcriptome of localized prostate cancer, we performed ultra-deep total RNA-seq on 144 tumors with rich clinical annotation. This revealed a linear transcriptomic subtype associated with the aggressive intraductal carcinoma sub-histology and a fusion profile that differentiates localized from metastatic disease. Analysis of back-splicing events showed widespread RNA circularization, with the average tumor expressing 7,232 circular RNAs (circRNAs). The degree of circRNA production was correlated to disease progression in multiple patient cohorts. Loss-of-function screening identified 11.3% of highly abundant circRNAs as essential for cell proliferation; for ∼90% of these, their parental linear transcripts were not essential. Individual circRNAs can have distinct functions, with circCSNK1G3 promoting cell growth by interacting with miR-181. These data advocate for adoption of ultra-deep RNA-seq without poly-A selection to interrogate both linear and circular transcriptomes.

The Evolutionary Landscape of Localized Prostate Cancers Drives Clinical Aggression.

The majority of newly diagnosed prostate cancers are slow growing, with a long natural life history. Yet a subset can metastasize with lethal consequences. We reconstructed the phylogenies of 293 localized prostate tumors linked to clinical outcome data. Multiple subclones were detected in 59% of patients, and specific subclonal architectures associate with adverse clinicopathological features. Early tumor development is characterized by point mutations and deletions followed by later subclonal amplifications and changes in trinucleotide mutational signatures. Specific genes are selectively mutated prior to or following subclonal diversification, including MTOR, NKX3-1, and RB1. Patients with low-risk monoclonal tumors rarely relapse after primary therapy (7%), while those with high-risk polyclonal tumors frequently do (61%). The presence of multiple subclones in an index biopsy may be necessary, but not sufficient, for relapse of localized prostate cancer, suggesting that evolution-aware biomarkers should be studied in prospective studies of low-risk tumors suitable for active surveillance.

Candidate Cancer Driver Mutations in Distal Regulatory Elements and Long-Range Chromatin Interaction Networks.

A comprehensive catalog of cancer driver mutations is essential for understanding tumorigenesis and developing therapies. Exome-sequencing studies have mapped many protein-coding drivers, yet few non-coding drivers are known because genome-wide discovery is challenging. We developed a driver discovery method, ActiveDriverWGS, and analyzed 120,788 cis-regulatory modules (CRMs) across 1,844 whole tumor genomes from the ICGC-TCGA PCAWG project. We found 30 CRMs with enriched SNVs and indels (FDR < 0.05). These frequently mutated regulatory elements (FMREs) were ubiquitously active in human tissues, showed long-range chromatin interactions and mRNA abundance associations with target genes, and were enriched in motif-rewiring mutations and structural variants. Genomic deletion of one FMRE in human cells caused proliferative deficiencies and transcriptional deregulation of cancer genes CCNB1IP1, CDH1, and CDKN2B, validating observations in FMRE-mutated tumors. Pathway analysis revealed further sub-significant FMREs at cancer genes and processes, indicating an unexplored landscape of infrequent driver mutations in the non-coding genome.

An acute immune response underlies the benefit of cardiac stem cell therapy.

Clinical trials using adult stem cells to regenerate damaged heart tissue continue to this day1,2, despite ongoing questions of efficacy and a lack of mechanistic understanding of the underlying biological effect3. The rationale for these cell therapy trials is derived from animal studies that show a modest but reproducible improvement in cardiac function in models of cardiac ischaemic injury4,5. Here we examine the mechanistic basis for cell therapy in mice after ischaemia-reperfusion injury, and find that-although heart function is enhanced-it is not associated with the production of new cardiomyocytes. Cell therapy improved heart function through an acute sterile immune response characterized by the temporal and regional induction of CCR2+ and CX3CR1+ macrophages. Intracardiac injection of two distinct types of adult stem cells, cells killed by freezing and thawing or a chemical inducer of the innate immune response all induced a similar regional accumulation of CCR2+ and CX3CR1+ macrophages, and provided functional rejuvenation to the heart after ischaemia-reperfusion injury. This selective macrophage response altered the activity of cardiac fibroblasts, reduced the extracellular matrix content in the border zone and enhanced the mechanical properties of the injured area. The functional benefit of cardiac cell therapy is thus due to an acute inflammatory-based wound-healing response that rejuvenates the infarcted area of the heart.

Genomic hallmarks of localized, non-indolent prostate cancer.

Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.

The role of socioeconomic status on outcomes following cerebellopontine angle tumor resection.

PURPOSE: It is well documented that the interaction between many social factors can affect clinical outcomes. However, the independent effects of economics on outcomes following surgery are not well understood. The goal of this study is to investigate the role socioeconomic status has on postoperative outcomes in a cerebellopontine angle (CPA) tumor resection population. MATERIALS AND METHODS: Over 6 years (07 June 2013 to 24 April 2019), 277 consecutive CPA tumor cases were reviewed at a single, multihospital academic medical center. Patient characteristics obtained included median household income, Charlson Comorbidity Index (CCI), race, BMI, tobacco use, amongst 23 others. Outcomes studied included readmission, ED evaluation, unplanned return to surgery (during and after index admission), return to surgery after index admission, and mortality within 90 days, in addition to reoperation and mortality throughout the entire follow-up period. Univariate analysis was conducted amongst the entire population with significance set at a p value <0.05. The population was divided into quartiles based on median household income and univariate analysis conducted between the lowest (Q1) and highest (Q4) socioeconomic quartiles, with significance set at a p value <0.05. Stepwise regression was conducted to determine the correlations amongst study variables and identify confounding factors. RESULTS: Regression analysis of 273 patients did not find household income to be associated with any of the long-term outcomes assessed. Similarly, a Q1 vs Q4 comparison did not yield significantly different odds of outcomes assessed. CONCLUSION: Although not statistically significant, the odds ratios suggest socioeconomic status may have a clinically significant effect on postsurgical outcomes. Further studies in larger, matched populations are necessary to validate these findings.

Applications of indocyanine green in brain tumor surgery: review of clinical evidence and emerging technologies.

Indocyanine green (ICG) is a water-soluble dye that was approved by the FDA for biomedical purposes in 1956. Initially used to measure cardiocirculatory and hepatic functions, ICG's fluorescent properties in the near-infrared (NIR) spectrum soon led to its application in ophthalmic angiography. In the early 2000s, ICG was formally introduced in neurosurgery as an angiographic tool. In 2016, the authors' group pioneered a novel technique with ICG named second-window ICG (SWIG), which involves infusion of a high dose of ICG (5.0 mg/kg) in patients 24 hours prior to surgery. To date, applications of SWIG have been reported in patients with high-grade gliomas, meningiomas, brain metastases, pituitary adenomas, craniopharyngiomas, chordomas, and pinealomas.The applications of ICG have clearly expanded rapidly across different specialties since its initial development. As an NIR fluorophore, ICG has advantages over other FDA-approved fluorophores, all of which are currently in the visible-light spectrum, because of NIR fluorescence's increased tissue penetration and decreased autofluorescence. Recently, interest in the latest applications of ICG in brain tumor surgery has grown beyond its role as an NIR fluorophore, extending into shortwave infrared imaging and integration into nanotechnology. This review aims to summarize reported clinical studies on ICG fluorescence-guided surgery of intracranial tumors, as well as to provide an overview of the literature on emerging technologies related to the utility of ICG in neuro-oncological surgeries, including the following aspects: 1) ICG fluorescence in the NIR-II window; 2) ICG for photoacoustic imaging; and 3) ICG nanoparticles for combined diagnostic imaging and therapy (theranostic) applications.

Information-Seeking Patterns During the COVID-19 Pandemic Across the United States: Longitudinal Analysis of Google Trends Data.

BACKGROUND: The COVID-19 pandemic has impacted people's lives at unprecedented speed and scale, including how they eat and work, what they are concerned about, how much they move, and how much they can earn. Traditional surveys in the area of public health can be expensive and time-consuming, and they can rapidly become outdated. The analysis of big data sets (such as electronic patient records and surveillance systems) is very complex. Google Trends is an alternative approach that has been used in the past to analyze health behaviors; however, most existing studies on COVID-19 using these data examine a single issue or a limited geographic area. This paper explores Google Trends as a proxy for what people are thinking, needing, and planning in real time across the United States. OBJECTIVE: We aimed to use Google Trends to provide both insights into and potential indicators of important changes in information-seeking patterns during pandemics such as COVID-19. We asked four questions: (1) How has information seeking changed over time? (2) How does information seeking vary between regions and states? (3) Do states have particular and distinct patterns in information seeking? (4) Do search data correlate with-or precede-real-life events? METHODS: We analyzed searches on 38 terms related to COVID-19, falling into six themes: social and travel; care seeking; government programs; health programs; news and influence; and outlook and concerns. We generated data sets at the national level (covering January 1, 2016, to April 15, 2020) and state level (covering January 1 to April 15, 2020). Methods used include trend analysis of US search data; geographic analyses of the differences in search popularity across US states from March 1 to April 15, 2020; and principal component analysis to extract search patterns across states. RESULTS: The data showed high demand for information, corresponding with increasing searches for coronavirus linked to news sources regardless of the ideological leaning of the news source. Changes in information seeking often occurred well in advance of action by the federal government. The popularity of searches for unemployment claims predicted the actual spike in weekly claims. The increase in searches for information on COVID-19 care was paralleled by a decrease in searches related to other health behaviors, such as urgent care, doctor's appointments, health insurance, Medicare, and Medicaid. Finally, concerns varied across the country; some search terms were more popular in some regions than in others. CONCLUSIONS: COVID-19 is unlikely to be the last pandemic faced by the United States. Our research holds important lessons for both state and federal governments in a fast-evolving situation that requires a finger on the pulse of public sentiment. We suggest strategic shifts for policy makers to improve the precision and effectiveness of non-pharmaceutical interventions and recommend the development of a real-time dashboard as a decision-making tool.

An interview based approach to the anorectal portion of the International Standards of Neurological Classification of Spinal Cord Injury Exam (I-A-ISNCSCI): a pilot study.

STUDY DESIGN: Prospective, single-blinded study. OBJECTIVE: To design and evaluate the use of an interview based version of the anorectal portion of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) exam in the acute inpatient rehabilitation (AIR) setting. SETTING: AIR unit. METHODS: Participants admitted to AIR underwent standard ISNCSCI exams (S-ISNCSCI) as part of routine inpatient care within 3 days of being administered an interview version of the anorectal portion of the ISNCSCI (I-A-ISNCSCI). Agreement between the anorectal portion of the S-ISNCSCI (S-A-ISNCSCI) and the I-A-ISNCSCI was evaluated. RESULTS: Forty of forty-five enrolled participants completed the assessments. Agreement between the I-A-ISNCSCI and S-A-ISNCSCI was substantial for anorectal sensation to light touch (k = 0.71, 95% CI 0.52-0.90, N = 36), pin prick (k = 0.68, 95% CI 0.48-0.87, N = 38), deep anal pressure (k = 0.77, 95% CI 0.53-1.00, N = 37), and completeness of injury based on combined sacral sensory criteria (k = 0.72, 95% CI 0.47-0.97, N = 40); and fair for voluntary anal contraction (k = 0.29, 95% CI -0.01 to 0.59, N = 36). Responses of "I don't know" were excluded from agreement analyses. CONCLUSIONS: This pilot study was a first step in developing interview based tools such as the I-A-ISNCSCI in an AIR setting providing convenient access to individuals with SCI and their direct feedback. The study design introduces potential recall bias and may not match true clinical situations such as remote follow-up of neurological changes for chronic patients. The use of interview based tools for assessing individuals with SCI remains worthy of further study.

Changes in bowel function following exoskeletal-assisted walking in persons with spinal cord injury: an observational pilot study.

STUDY DESIGN: Prospective, observational study. OBJECTIVE: To explore the effects of exoskeletal-assisted walking (EAW) on bowel function in persons with spinal cord injury (SCI). SETTING: Ambulatory research facility located in a tertiary care hospital. METHODS: Individuals 18-65 years of age, with thoracic vertebrae one (T1) to T11 motor-complete paraplegia of at least 12 months duration were enrolled. Pre- and post-EAW training, participants were asked to report on various aspects of their bowel function as well as on their overall quality of life (QOL) as related to their bowel function. RESULTS: Ten participants completed 25-63 sessions of EAW over a period of 12-14 weeks, one participant was lost to follow up due to early withdrawal after ten sessions. Due to the small sample size, each participant's results were presented descriptively in a case series format. At least 5/10 participants reported improvements with frequency of bowel evacuations, less time spent on bowel management per bowel day, fewer bowel accidents per month, reduced laxative and/or stool softener use, and improved overall satisfaction with their bowel program post-EAW training. Furthermore, 8/10 reported improved stool consistency and 7/10 reported improved bowel function related QOL. One participant reported worsening of bowel function post-EAW. CONCLUSION: Between 50 and 80% of the participants studied reported improvements in bowel function and/or management post-EAW training. EAW training appeared to mitigate SCI-related bowel dysfunction and the potential benefits of EAW on bowel function after SCI is worthy or further study.

A comparative study of survival models for breast cancer prognostication revisited: the benefits of multi-gene models.

BACKGROUND: The development of clinical -omic biomarkers for predicting patient prognosis has mostly focused on multi-gene models. However, several studies have described significant weaknesses of multi-gene biomarkers. Indeed, some high-profile reports have even indicated that multi-gene biomarkers fail to consistently outperform simple single-gene ones. Given the continual improvements in -omics technologies and the availability of larger, better-powered datasets, we revisited this "single-gene hypothesis" using new techniques and datasets. RESULTS: By deeply sampling the population of available gene sets, we compare the intrinsic properties of single-gene biomarkers to multi-gene biomarkers in twelve different partitions of a large breast cancer meta-dataset. We show that simple multi-gene models consistently outperformed single-gene biomarkers in all twelve partitions. We found 270 multi-gene biomarkers (one per ~11,111 sampled) that always made better predictions than the best single-gene model. CONCLUSIONS: The single-gene hypothesis for breast cancer does not appear to retain its validity in the face of improved statistical models, lower-noise genomic technology and better-powered patient cohorts. These results highlight that it is critical to revisit older hypotheses in the light of newer techniques and datasets.

Cribriform and intraductal prostate cancer are associated with increased genomic instability and distinct genomic alterations.

BACKGROUND: Invasive cribriform and intraductal carcinoma (CR/IDC) is associated with adverse outcome of prostate cancer patients. The aim of this study was to determine the molecular aberrations associated with CR/IDC in primary prostate cancer, focusing on genomic instability and somatic copy number alterations (CNA). METHODS: Whole-slide images of The Cancer Genome Atlas Project (TCGA, N = 260) and the Canadian Prostate Cancer Genome Network (CPC-GENE, N = 199) radical prostatectomy datasets were reviewed for Gleason score (GS) and presence of CR/IDC. Genomic instability was assessed by calculating the percentage of genome altered (PGA). Somatic copy number alterations (CNA) were determined using Fisher-Boschloo tests and logistic regression. Primary analysis were performed on TCGA (N = 260) as discovery and CPC-GENE (N = 199) as validation set. RESULTS: CR/IDC growth was present in 80/260 (31%) TCGA and 76/199 (38%) CPC-GENE cases. Patients with CR/IDC and ≥ GS 7 had significantly higher PGA than men without this pattern in both TCGA (2.2 fold; p = 0.0003) and CPC-GENE (1.7 fold; p = 0.004) cohorts. CR/IDC growth was associated with deletions of 8p, 16q, 10q23, 13q22, 17p13, 21q22, and amplification of 8q24. CNAs comprised a total of 1299 gene deletions and 369 amplifications in the TCGA dataset, of which 474 and 328 events were independently validated, respectively. Several of the affected genes were known to be associated with aggressive prostate cancer such as loss of PTEN, CDH1, BCAR1 and gain of MYC. Point mutations in TP53, SPOP and FOXA1were also associated with CR/IDC, but occurred less frequently than CNAs. CONCLUSIONS: CR/IDC growth is associated with increased genomic instability clustering to genetic regions involved in aggressive prostate cancer. Therefore, CR/IDC is a pathologic substrate for progressive molecular tumour derangement.

Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome.

Here we demonstrate association of variants in the mitochondrial asparaginyl-tRNA synthetase NARS2 with human hearing loss and Leigh syndrome. A homozygous missense mutation ([c.637G>T; p.Val213Phe]) is the underlying cause of nonsyndromic hearing loss (DFNB94) and compound heterozygous mutations ([c.969T>A; p.Tyr323*] + [c.1142A>G; p.Asn381Ser]) result in mitochondrial respiratory chain deficiency and Leigh syndrome, which is a neurodegenerative disease characterized by symmetric, bilateral lesions in the basal ganglia, thalamus, and brain stem. The severity of the genetic lesions and their effects on NARS2 protein structure cosegregate with the phenotype. A hypothetical truncated NARS2 protein, secondary to the Leigh syndrome mutation p.Tyr323* is not detectable and p.Asn381Ser further decreases NARS2 protein levels in patient fibroblasts. p.Asn381Ser also disrupts dimerization of NARS2, while the hearing loss p.Val213Phe variant has no effect on NARS2 oligomerization. Additionally we demonstrate decreased steady-state levels of mt-tRNAAsn in fibroblasts from the Leigh syndrome patients. In these cells we show that a decrease in oxygen consumption rates (OCR) and electron transport chain (ETC) activity can be rescued by overexpression of wild type NARS2. However, overexpression of the hearing loss associated p.Val213Phe mutant protein in these fibroblasts cannot complement the OCR and ETC defects. Our findings establish lesions in NARS2 as a new cause for nonsyndromic hearing loss and Leigh syndrome.

Persistent residual errors in motor adaptation tasks: reversion to baseline and exploratory escape.

When movements are perturbed in adaptation tasks, humans and other animals show incomplete compensation, tolerating small but sustained residual errors that persist despite repeated trials. State-space models explain this residual asymptotic error as interplay between learning from error and reversion to baseline, a form of forgetting. Previous work using zero-error-clamp trials has shown that reversion to baseline is not obligatory and can be overcome by manipulating feedback. We posited that novel error-clamp trials, in which feedback is constrained but has nonzero error and variance, might serve as a contextual cue for recruitment of other learning mechanisms that would then close the residual error. When error clamps were nonzero and had zero variance, human subjects changed their learning policy, using exploration in response to the residual error, despite their willingness to sustain such an error during the training block. In contrast, when the distribution of feedback in clamp trials was naturalistic, with persistent mean error but also with variance, a state-space model accounted for behavior in clamps, even in the absence of task success. Therefore, when the distribution of errors matched those during training, state-space models captured behavior during both adaptation and error-clamp trials because error-based learning dominated; when the distribution of feedback was altered, other forms of learning were triggered that did not follow the state-space model dynamics exhibited during training. The residual error during adaptation appears attributable to an error-dependent learning process that has the property of reversion toward baseline and that can suppress other forms of learning.

Beyond cones: an improved model of whisker bending based on measured mechanics and tapering.

The sense of touch is represented by neural activity patterns evoked by mechanosensory input forces. The rodent whisker system is exceptional for studying the neurophysiology of touch in part because these forces can be precisely computed from video of whisker deformation. We evaluate the accuracy of a standard model of whisker bending, which assumes quasi-static dynamics and a linearly tapered conical profile, using controlled whisker deflections. We find significant discrepancies between model and experiment: real whiskers bend more than predicted upon contact at locations in the middle of the whisker and less at distal locations. Thus whiskers behave as if their stiffness near the base and near the tip is larger than expected for a homogeneous cone. We assess whether contact direction, friction, inhomogeneous elasticity, whisker orientation, or nonconical shape could explain these deviations. We show that a thin-middle taper of mouse whisker shape accounts for the majority of this behavior. This taper is conserved across rows and columns of the whisker array. The taper has a large effect on the touch-evoked forces and the ease with which whiskers slip past objects, which are key drivers of neural activity in tactile object localization and identification. This holds for orientations with intrinsic whisker curvature pointed toward, away from, or down from objects, validating two-dimensional models of simple whisker-object interactions. The precision of computational models relating sensory input forces to neural activity patterns can be quantitatively enhanced by taking thin-middle taper into account with a simple corrective function that we provide.

Withaferin A suppresses the up-regulation of acetyl-coA carboxylase 1 and skin tumor formation in a skin carcinogenesis mouse model.

Withaferin A (WA), a natural product derived from Withania somnifera, has been used in traditional oriental medicines to treat neurological disorders. Recent studies have demonstrated that this compound may have a potential for cancer treatment and a clinical trial has been launched to test WA in treating melanoma. Herein, WA's chemopreventive potential was tested in a chemically-induced skin carcinogenesis mouse model. Pathological examinations revealed that WA significantly suppressed skin tumor formation. Morphological observations of the skin tissues suggest that WA suppressed cell proliferation rather than inducing apoptosis during skin carcinogenesis. Antibody Micro array analysis demonstrated that WA blocked carcinogen-induced up-regulation of acetyl-CoA carboxylase 1 (ACC1), which was further confirmed in a skin cell transformation model. Overexpression of ACC1 promoted whereas knockdown of ACC1 suppressed anchorage-independent growth and oncogene activation of transformable skin cells. Further studies demonstrated that WA inhibited tumor promotor-induced ACC1 gene transcription by suppressing the activation of activator protein 1. In melanoma cells, WA was also able to suppress the expression levels of ACC1. Finally, results using human skin cancer tissues confirmed the up-regulation of ACC1 in tumors than adjacent normal tissues. In summary, our results suggest that withaferin A may have a potential in chemoprevention and ACC1 may serve as a critical target of WA. © 2015 Wiley Periodicals, Inc.

Hematopoietic progenitors are required for proper development of coronary vasculature.

RATIONALE: During embryogenesis, hematopoietic cells appear in the myocardium prior to the initiation of coronary formation. However, their role is unknown. OBJECTIVE: Here we investigate whether pre-existing hematopoietic cells are required for the formation of coronary vasculature. METHODS AND RESULTS: As a model of for hematopoietic cell deficient animals, we used Runx1 knockout embryos and Vav1-cre; R26-DTA embryos, latter of which genetically ablates 2/3 of CD45(+) hematopoietic cells. Both Runx1 knockout embryos and Vav1-cre; R26-DTA embryos revealed disorganized, hypoplastic microvasculature of coronary vessels on section and whole-mount stainings. Furthermore, coronary explant experiments showed that the mouse heart explants from Runx1 and Vav1-cre; R26-DTA embryos exhibited impaired coronary formation ex vivo. Interestingly, in both models it appears that epicardial to mesenchymal transition is adversely affected in the absence of hematopoietic progenitors. CONCLUSION: Hematopoietic cells are not merely passively transported via coronary vessel, but substantially involved in the induction of the coronary growth. Our findings suggest a novel mechanism of coronary growth.

Robotic therapy for chronic stroke: general recovery of impairment or improved task-specific skill?

There is a great need to develop new approaches for rehabilitation of the upper limb after stroke. Robotic therapy is a promising form of neurorehabilitation that can be delivered in higher doses than conventional therapy. Here we sought to determine whether the reported effects of robotic therapy, which have been based on clinical measures of impairment and function, are accompanied by improved motor control. Patients with chronic hemiparesis were trained for 3 wk, 3 days a week, with titrated assistive robotic therapy in two and three dimensions. Motor control improvements (i.e., skill) in both arms were assessed with a separate untrained visually guided reaching task. We devised a novel PCA-based analysis of arm trajectories that is sensitive to changes in the quality of entire movement trajectories without needing to prespecify particular kinematic features. Robotic therapy led to skill improvements in the contralesional arm. These changes were not accompanied by changes in clinical measures of impairment or function. There are two possible interpretations of these results. One is that robotic therapy only leads to small task-specific improvements in motor control via normal skill-learning mechanisms. The other is that kinematic assays are more sensitive than clinical measures to a small general improvement in motor control.

A splice donor mutation in NAA10 results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome.

INTRODUCTION: Lenz microphthalmia syndrome (LMS) is a genetically heterogeneous X-linked disorder characterised by microphthalmia/anophthalmia, skeletal abnormalities, genitourinary malformations, and anomalies of the digits, ears, and teeth. Intellectual disability and seizure disorders are seen in about 60% of affected males. To date, no gene has been identified for LMS in the microphthalmia syndrome 1 locus (MCOPS1). In this study, we aim to find the disease-causing gene for this condition. METHODS AND RESULTS: Using exome sequencing in a family with three affected brothers, we identified a mutation in the intron 7 splice donor site (c.471+2T→A) of the N-acetyltransferase NAA10 gene. NAA10 has been previously shown to be mutated in patients with Ogden syndrome, which is clinically distinct from LMS. Linkage studies for this family mapped the disease locus to Xq27-Xq28, which was consistent with the locus of NAA10. The mutation co-segregated with the phenotype and cDNA analysis showed aberrant transcripts. Patient fibroblasts lacked expression of full length NAA10 protein and displayed cell proliferation defects. Expression array studies showed significant dysregulation of genes associated with genetic forms of anophthalmia such as BMP4, STRA6, and downstream targets of BCOR and the canonical WNT pathway. In particular, STRA6 is a retinol binding protein receptor that mediates cellular uptake of retinol/vitamin A and plays a major role in regulating the retinoic acid signalling pathway. A retinol uptake assay showed that retinol uptake was decreased in patient cells. CONCLUSIONS: We conclude that the NAA10 mutation is the cause of LMS in this family, likely through the dysregulation of the retinoic acid signalling pathway.