Bilateral Obturator Osteotomy: A Novel Osteotomy for Bladder Exstrophy Closure.

BACKGROUND: Abdominal and pelvic closure remains a challenge during bladder exstrophy initial repair. We aimed to report on the feasibility and results of a novel technique of bilateral obturator osteotomy. METHODS: Retrospective study of prospective collected data of children who underwent single-stage delayed bladder exstrophy closure combined with RSTM (Radical Soft Tissue Mobilization) for BEEC (Bladder Exstrophy Epispadias Complex) by the same team at different institutions between December 2017 and May 2021. When pubic approximation was not feasible at the end of the procedure, bilateral obturator osteotomy was performed through the same approach, consisting in bilateral divisions of the ilio-pubic rami, ischio-pubic rami, obturator membrane, and detachment of the internal obturator muscle. Pubic bone fragments were approximated together on the midline. Immobilization in a thermoformed posterior splint was indicated for 3 weeks. The main outcome criterion was the bladder dehiscence rate at 6 months, assessed by physical inspection. Secondary outcome criteria included neurovascular obturator pedicle injury, analyzed during orthopedic physical examination, wound or bone infections, gait acquisition, reported by parents and evaluated during medical examination, and vascular penile impairment, judged by penile and glans coloration. RESULTS: 17 children (11 males, 6 females) were included, at a median age of 2 months [1-33]; and representing 29% (17/58) of the children with bladder exstrophy who underwent the same surgical approach during the time of study. There was no postoperative bladder dehiscence with a median follow-up of 34 months [6-47]. No complication was observed. Pelvic X-rays showed bilateral normal ossification process. Neither gait abnormality, nor clinical indication of obturator nerve deficiency was observed during follow-up. CONCLUSION: When pubic bones approximation is not possible, bilateral obturator osteotomy is a useful adjunct in bladder exstrophy closure, feasible by the pediatric urologist through the same approach, and not requiring external fixator. LEVEL OF EVIDENCE: IV.

Standardization of a CT Protocol for Imaging Patients with Suspected COVID-19-A RACOON Project.

CT protocols that diagnose COVID-19 vary in regard to the associated radiation exposure and the desired image quality (IQ). This study aims to evaluate CT protocols of hospitals participating in the RACOON (Radiological Cooperative Network) project, consolidating CT protocols to provide recommendations and strategies for future pandemics. In this retrospective study, CT acquisitions of COVID-19 patients scanned between March 2020 and October 2020 (RACOON phase 1) were included, and all non-contrast protocols were evaluated. For this purpose, CT protocol parameters, IQ ratings, radiation exposure (CTDIvol), and central patient diameters were sampled. Eventually, the data from 14 sites and 534 CT acquisitions were analyzed. IQ was rated good for 81% of the evaluated examinations. Motion, beam-hardening artefacts, or image noise were reasons for a suboptimal IQ. The tube potential ranged between 80 and 140 kVp, with the majority between 100 and 120 kVp. CTDIvol was 3.7 ± 3.4 mGy. Most healthcare facilities included did not have a specific non-contrast CT protocol. Furthermore, CT protocols for chest imaging varied in their settings and radiation exposure. In future, it will be necessary to make recommendations regarding the required IQ and protocol parameters for the majority of CT scanners to enable comparable IQ as well as radiation exposure for different sites but identical diagnostic questions.

Insights on the Future of Digital Health: An Analysis of Twitter Posts of IMIA Fellows.

The COVID-19 pandemic has reshaped technology-enhanced services in health and care organizations globally. As the world pivots towards a post-COVID-19 environment, it is essential to examine emerging trends amongst thought leaders in the health information technology sector. This study queried Twitter feeds of IMIA Fellows from 2013 through 2022, utilizing combinations of sentiment analysis, latent dirichlet allocation, and document analysis methods. The results provided a glimpse of positive sentiment year upon year, with the most negative sentiment prevalent in 2020, due to the onset of the pandemic. The findings from this study can be strategically used to analyze emerging trends in digital health, as well as to shape health IT thought leadership in the post-pandemic landscape.

Mutations in FUS lead to synaptic dysregulation in ALS-iPSC derived neurons.

Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset neurodegenerative disorder characterized by progressive muscular weakness due to the selective loss of motor neurons. Mutations in the gene Fused in Sarcoma (FUS) were identified as one cause of ALS. Here, we report that mutations in FUS lead to upregulation of synaptic proteins, increasing synaptic activity and abnormal release of vesicles at the synaptic cleft. Consequently, FUS-ALS neurons showed greater vulnerability to glutamate excitotoxicity, which raised neuronal swellings (varicose neurites) and led to neuronal death. Fragile X mental retardation protein (FMRP) is an RNA-binding protein known to regulate synaptic protein translation, and its expression is reduced in the FUS-ALS lines. Collectively, our data suggest that a reduction of FMRP levels alters the synaptic protein dynamics, leading to synaptic dysfunction and glutamate excitotoxicity. Here, we present a mechanistic hypothesis linking dysregulation of peripheral translation with synaptic vulnerability in the pathogenesis of FUS-ALS.

G-quadruplexes control hepatitis B virus replication by promoting cccDNA transcription and phase separation in hepatocytes.

Phase separation regulates fundamental processes in gene expression and is mediated by the local concentration of proteins and nucleic acids, as well as nucleic acid secondary structures such as G-quadruplexes (G4s). These structures play fundamental roles in both host gene expression and in viral replication due to their peculiar localisation in regulatory sequences. Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is an episomal minichromosome whose persistence is at the basis of chronic infection. Identifying the mechanisms controlling its transcriptional activity is indispensable to develop new therapeutic strategies against chronic hepatitis B. The aim of this study was to determine whether G4s are formed in cccDNA and regulate viral replication. Combining biochemistry and functional studies, we demonstrate that cccDNA indeed contains ten G4s structures. Furthermore, mutations disrupting two G4s located in the enhancer I HBV regulatory region altered cccDNA transcription and viral replication. Finally, we showed for the first time that cccDNA undergoes phase separation in a G4-dependent manner to promote its transcription in infected hepatocytes. Altogether, our data give new insight in the transcriptional regulation of the HBV minichromosome that might pave the way for the identification of novel targets to destabilize or silence cccDNA.

Mimicking hypomethylation of FUS requires liquid-liquid phase separation to induce synaptic dysfunctions.

The hypomethylation of fused in sarcoma (FUS) in frontotemporal lobar degeneration promotes the formation of irreversible condensates of FUS. However, the mechanisms by which these hypomethylated FUS condensates cause neuronal dysfunction are unknown. Here we report that expression of FUS constructs mimicking hypomethylated FUS causes aberrant dendritic FUS condensates in CA1 neurons. These hypomethylated FUS condensates exhibit spontaneous, and activity induced movement within the dendrite. They impair excitatory synaptic transmission, postsynaptic density-95 expression, and dendritic spine plasticity. These neurophysiological defects are dependent upon both the dendritic localisation of the condensates, and their ability to undergo liquid-liquid phase separation. These results indicate that the irreversible liquid-liquid phase separation is a key component of hypomethylated FUS pathophysiology in sporadic FTLD, and this can cause synapse dysfunction in sporadic FTLD.

Combined RNA interference and gene replacement therapy targeting MFN2 as proof of principle for the treatment of Charcot-Marie-Tooth type 2A.

Mitofusin-2 (MFN2) is an outer mitochondrial membrane protein essential for mitochondrial networking in most cells. Autosomal dominant mutations in the MFN2 gene cause Charcot-Marie-Tooth type 2A disease (CMT2A), a severe and disabling sensory-motor neuropathy that impacts the entire nervous system. Here, we propose a novel therapeutic strategy tailored to correcting the root genetic defect of CMT2A. Though mutant and wild-type MFN2 mRNA are inhibited by RNA interference (RNAi), the wild-type protein is restored by overexpressing cDNA encoding functional MFN2 modified to be resistant to RNAi. We tested this strategy in CMT2A patient-specific human induced pluripotent stem cell (iPSC)-differentiated motor neurons (MNs), demonstrating the correct silencing of endogenous MFN2 and replacement with an exogenous copy of the functional wild-type gene. This approach significantly rescues the CMT2A MN phenotype in vitro, stabilizing the altered axonal mitochondrial distribution and correcting abnormal mitophagic processes. The MFN2 molecular correction was also properly confirmed in vivo in the MitoCharc1 CMT2A transgenic mouse model after cerebrospinal fluid (CSF) delivery of the constructs into newborn mice using adeno-associated virus 9 (AAV9). Altogether, our data support the feasibility of a combined RNAi and gene therapy strategy for treating the broad spectrum of human diseases associated with MFN2 mutations.

Molecular basis of RNA-binding and autoregulation by the cancer-associated splicing factor RBM39.

Pharmacologic depletion of RNA-binding motif 39 (RBM39) using aryl sulfonamides represents a promising anti-cancer therapy but requires high levels of the adaptor protein DCAF15. Consequently, novel approaches to deplete RBM39 in an DCAF15-independent manner are required. Here, we uncover that RBM39 autoregulates via the inclusion of a poison exon into its own pre-mRNA and identify the cis-acting elements that govern this regulation. We also determine the NMR solution structures of RBM39's tandem RNA recognition motifs (RRM1 and RRM2) bound to their respective RNA targets, revealing how RRM1 recognises RNA stem loops whereas RRM2 binds specifically to single-stranded N(G/U)NUUUG. Our results support a model where RRM2 selects the 3'-splice site of a poison exon and the RRM3 and RS domain stabilise the U2 snRNP at the branchpoint. Our work provides molecular insights into RBM39-dependent 3'-splice site selection and constitutes a solid basis to design alternative anti-cancer therapies.

P2X7R influences tau aggregate burden in human tauopathies and shows distinct signalling in microglia and astrocytes.

The purinoceptor P2X7R is a promising therapeutic target for tauopathies, including Alzheimer's disease (AD). Pharmacological inhibition or genetic knockdown of P2X7R ameliorates cognitive deficits and reduces pathological tau burden in mice that model aspects of tauopathy, including mice expressing mutant human frontotemporal dementia (FTD)-causing forms of tau. However, disagreements remain over which glial cell types express P2X7R and therefore the mechanism of action is unresolved. Here, we show that P2X7R protein levels increase in human AD post-mortem brain, in agreement with an upregulation of P2RX7 mRNA observed in transcriptome profiles from the AMP-AD consortium. P2X7R protein increases mirror advancing Braak stage and coincide with synapse loss. Using RNAScope we detect P2RX7 mRNA in microglia and astrocytes in human AD brain, including in the vicinity of senile plaques. In cultured microglia, P2X7R activation modulates the NLRP3 inflammasome pathway by promoting the formation of active complexes and release of IL-1ß. In astrocytes, P2X7R activates NFκB signalling and increases production of the cytokines CCL2, CXCL1 and IL-6 together with the acute phase protein Lcn2. To further explore the role of P2X7R in a disease-relevant context, we expressed wild-type or FTD-causing mutant forms of tau in mouse organotypic brain slice cultures. Inhibition of P2X7R reduces insoluble tau levels without altering soluble tau phosphorylation or synaptic localisation, suggesting a non-cell autonomous role of glial P2X7R on pathological tau aggregation. These findings support further investigations into the cell-type specific effects of P2X7R-targeting therapies in tauopathies.

Financial and relational impact of having a boy with posterior urethral valves.

Introduction: Childhood chronic diseases affect family functioning and well-being. The aim of this study was to measure the impact of caring for a child with PUV, and the factors that most impact the burden of care. Patients and method: We gave a questionnaire on the familial impact of having a child with posterior urethral valves to all parents of a child included in the CIRCUP trial from 2015 onwards. The questionnaire included questions about the parents' demographics, health, professional, financial and marital status and how these evolved since the child's birth as well as the "impact on family scale" (IOFS), which gives a total score ranging from 15 (no impact) to 60 (maximum impact). We then analyzed both the results of the specific demographic questions as well as the factors which influenced the IOFS score. Results: We retrieved answers for 38/51 families (74.5% response rate). The average IOFS score was 23.7 (15-51). We observed that the child's creatinine level had an effect on the IOFS score (p = 0.02), as did the parent's gender (p = 0.008), health status (p = 0.015), being limited in activity since the birth of the child (p = 0.020), being penalized in one's job (p = 0.009), being supported in one's job (p = 0.002), and decreased income (p = 0.004). Out of 38 mother/father binomials, 8/33 (24.2%) declared that they were no longer in the same relationship afterwards. Conclusion: In conclusion, having a boy with PUV significantly impacts families. The risk of parental separation and decrease in revenue is significant. Strategies aiming to decrease these factors should be put in place as soon as possible.

Indocyanine Green (ICG)-Guided One-Stage Delayed Bladder Closure and Radical Soft-Tissue Mobilization (Kelly Procedure) For Bladder Exstrophy Repair: The First Experience.

The vascular supply of the pelvic structures and the external genitalia can be easily injured during the one-stage delayed bladder closure and radical soft-tissue mobilization (Kelly procedure) for bladder exstrophy surgical repair. Aiming to help surgeons assessing and confirming tissue perfusion and viability, indocyanine green (ICG)-based laser angiography was incorporated into the operative approach to reduce the risk of ischemic injuries. The EleVision IR system (Medtronic Ltd) was adopted to confirm the identification of the vascular pedicles and assess the tissue perfusion in real-time in a 5-month-old with bladder exstrophy undergoing the one-stage delayed bladder closure and radical soft-tissue mobilization (Kelly procedure). ICG (0.15 mg/kg) was intravenously administered at 6 key steps during surgery with the ability to be re-dosed every 15 minutes. ICG-based laser angiography helped to confirm the correct identification of the vascular structures during surgery and to assess tissue perfusion in real-time. Blood flow did not change considerably after initial dissection or upon approximating the pubis symphysis. At the end of the procedure, good penile perfusion was shown, proving that no direct injury or substantial compression of the pudendal vessels had occurred following the mobilization and the reconstructive phase. ICG-based laser angiography proved to be safe, effective, and easy to employ and should be considered as a reasonable adjunct for tissue perfusion assessment and operative decision-making in patients undergoing bladder exstrophy Kelly repair.

Assessment of Anorectal Function and Related Quality of Life of 27 Patients with Bladder Exstrophy or Epispadias After Kelly Radical Soft Tissue Mobilisation.

INTRODUCTION: The Radical soft-tissue mobilisation (RSTM) described by J.H. Kelly for bladder exstrophy repair implies a detachment of levator ani muscle insertions from the pelvic wall. The aim of this controlled study was to evaluate the impact of this procedure on subsequent anorectal function. METHODS: Monocentric controlled study of prospectively collected data of children who underwent RSTM for BEEC from 2010 to 2017. Patients born after 2017 were not included, as they were below the theoretical age of continence acquisition at the time of the study. Anorectal function was assessed using the Childhood Bladder and Bowel Dysfunction Questionnaire, and quality of life (QoL) related to fecal continence using the CINCY FIS questionnaire. The control group was paired on age and sex with a 1:3 patient/control ratio. Answers to questionnaires were collected from September 2021 to January 2022. Univariate statistical analysis comparing two groups and subgroup analysis following age were also performed. RESULTS: During the period of study, 55 children with BEEC underwent Kelly RSTM. Twenty-seven (49%) were included and paired with 81 healthy children on age and sex. Median age at surgery was 15 months [0.5-93] and median follow-up was 10 years [4-13]. Patient's group median age at evaluation was 11 years [5-19]. There was no difference between patients and control group in anorectal function for both incontinence and constipation items. No significant difference was found in QoL related to fecal incontinence assessment. Subgroup analysis did not show difference. CONCLUSION: This study suggests that the levator ani detachment during Kelly procedure, realised in a paediatric population under the age of 8, did not impact anorectal function with a mid-term follow-up. LEVEL OF EVIDENCE: III.

HNRNPH1 regulates the neuroprotective cold-shock protein RBM3 expression through poison exon exclusion.

Enhanced expression of the cold-shock protein RNA binding motif 3 (RBM3) is highly neuroprotective both in vitro and in vivo. Whilst upstream signalling pathways leading to RBM3 expression have been described, the precise molecular mechanism of RBM3 cold induction remains elusive. To identify temperature-dependent modulators of RBM3, we performed a genome-wide CRISPR-Cas9 knockout screen using RBM3-reporter human iPSC-derived neurons. We found that RBM3 mRNA and protein levels are robustly regulated by several splicing factors, with heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) being the strongest positive regulator. Splicing analysis revealed that moderate hypothermia significantly represses the inclusion of a poison exon, which, when retained, targets the mRNA for nonsense-mediated decay. Importantly, we show that HNRNPH1 mediates this cold-dependent exon skipping via its thermosensitive interaction with a G-rich motif within the poison exon. Our study provides novel mechanistic insights into the regulation of RBM3 and provides further targets for neuroprotective therapeutic strategies.

Outcome of long gap esophageal atresia at 6 years: A prospective case control cohort study.

BACKGROUND DATA: EA is the most frequent congenital esophageal malformation. Long gap EA remains a therapeutic challenge for pediatric surgeons. A case case-control prospective study from a multi-institutional national French data base was performed to assess the outcome, at age of 1 and 6 years, of long gap esophageal atresia (EA) compared with non-long gap EA/tracheo-esophageal fistula (TEF). The secondary aim was to assess whether initial treatment (delayed primary anastomosis of native esophagus vs. esophageal replacement) influenced mortality and morbidity at ages 1 and 6 years. METHODS: A multicentric population-based prospective study was performed and included all patients who underwent EA surgery in France from January 1, 2008 to December 31, 2010. A comparative study was performed with non-long gap EA/TEF patients. Morbidity at birth, 1 year, and 6 years was assessed. RESULTS: Thirty-one patients with long gap EA were compared with 62 non-long gap EA/TEF patients. At age 1 year, the long gap EA group had longer parenteral nutrition support and longer hospital stay and were significantly more likely to have complications both early post-operatively and before age 1 year compared with the non-long gap EA/TEF group. At 6 years, digestive complications were more frequent in long gap compared to non-long gap EA/TEF patients. Tracheomalacia was the only respiratory complication that differed between the groups. Spine deformation was less frequent in the long gap group. There were no differences between conservative and replacement groups at ages 1 and 6 years except feeding difficulties that were more common in the native esophagus group. CONCLUSIONS: Long gap strongly influenced digestive morbidity at age 6 years.

Long-term results of artificial urinary sphincter implantation for urinary incontinence due to intrinsic sphincter deficiency in children.

PURPOSE: To report long-term results of artificial urinary sphincter implantation for urinary incontinence due to intrinsic sphincter deficiency in children. MATERIALS AND METHODS: This retrospective monocentric study included all patients who underwent artificial urinary sphincter (AMS 800) implantation before 18 years of age between 1986 and October 2018 for intrinsic sphincter deficiency. The primary outcome was the continence rate at the last follow-up, defined by the daily use of 0 pads. The secondary outcome was the overall survival of the device, defined as the absence of any repeated surgery (revision or explantation) during follow-up. Reoperation-free, revision-free, and explantation-free device survival rates were estimated using the Kaplan-Meier method. RESULTS: Thirty-six patients with a median age of 12 years (interquartile range [IQR]: 10-14) were included (15 females, 21 males). The median follow-up was 18.7 years (IQR: 9-26). The main underlying condition was spinal dysraphism (n = 24; 67%). The median time to the first reoperation was 9 years (IQR: 3.75-14.7). At the last follow-up, survival rates without revision were 84%, 71%, 55%, and 33% at 5, 10, 15, and 20 years, respectively. Survival rates without explantation were 91%, 84%, 80%, and 72% at 5, 10, 15, and 20 years, respectively. At the last follow-up, 29 patients had a functional device. The overall continence rate was 88%. All patients who had their device still in place were continent at the last follow-up. CONCLUSION: The artificial urinary sphincter is an effective long-term treatment for urinary incontinence related to intrinsic sphincter deficiency in children, providing a high rate of continence, even if associated with a high rate of reoperation.

Latitudes and attitudes: A multinational study of laparoscopic pyeloplasty in children.

PURPOSE: The Anderson-Hynes technique has been the treatment of choice for primary ureteropelvic junction obstruction in children. Laparoscopic approach has shown similar outcomes to open, with advantages of shorter hospital stay and less pain. We reviewed the experience of 11 geographically diverse, tertiary pediatric urology institutions focusing on the outcomes and complications of laparoscopic pyeloplasty. MATERIALS AND METHODS: A descriptive, retrospective study was conducted evaluating patients undergoing Anderson-Hynes dismembered laparoscopic pyeloplasty. Centers from four different continents participated. Demographic data, perioperative management, results, and complications are described. RESULTS: Over a 9-year period, 744 laparoscopic pyeloplasties were performed in 743 patients. Mean follow-up was 31 months (6-120m). Mean age at surgery was 82 months (1 w-19 y). Median operative time was 177 min. An internal stent was placed in 648 patients (87%). A catheter was placed for bladder drainage in 702 patients (94%). Conversion to open pyeloplasty was necessary in seven patients. Average length of hospital stay was 2.8 days. Mean time of analgesic requirement was 3.2 days. Complications, according to Clavien-Dindo classification, were observed in 56 patients (7.5%); 10 (1%) were Clavien-Dindo IIIb. Treatment failure occurred in 35 cases with 30 requiring redo pyeloplasty (4%) and 5 cases requiring nephrectomy (0.6%). CONCLUSION: We have described the laparoscopic pyeloplasty experience of institutions with diverse cultural and economic backgrounds. They had very similar outcomes, in agreement with previously published data. Based on these findings, we conclude that laparoscopic pyeloplasty is safe and successful in diverse geographics areas of the world.

Risk factors for febrile urinary tract infection in boys with posterior urethral valves.

Objective: Boys with posterior urethral valves (PUV) present an increased risk of febrile urinary tract infection (fUTI). Identifying specific risk factors could allow for tailoring UTI prevention. The aim of this study was to use the data from the CIRCUP randomized controlled trial data to identify patient characteristics associated with a higher risk of fUTI. Patients and methods: We performed a secondary analysis of the data from the CIRCUP randomized trial which included boys with PUV, randomized to circumcision and antibiotic prophylaxis vs. antibiotic prophylaxis alone and followed for 2 years. There was only 1 episode of fUTI in the circumcision group vs. 17 in the uncircumcised group. We therefore only studied the antibiotic prophylaxis alone group and compared age at prenatal diagnosis, size and weight at birth, presence of dilating VUR at diagnosis, abnormal DMSA scan at 2 months, and nadir creatinine between children who presented a fUTI and those who did not, as well as age at first episode of fUTI. Results: The study group consisted of 42 patients of which 17 presented at least on fUTI. Presence of dilating VUR was significantly associated with risk of fUTI (p = 0.03), OR: 6 [CI 95% = (1.13-27.52)]. None of the other parameters were associated with increased risk of fUTI. We observed three distinct time periods for presenting a fUTI with a decrease in infection rate after the first 40 days of life, then at 240 days of life. Conclusion: In boys with PUV, presence of high-grade VUR is associated with a higher risk of presenting a fUTI. The rate of febrile UTIs seems to decrease after 9 months.

Heterozygous expression of the Alzheimer's disease-protective PLCγ2 P522R variant enhances Aß clearance while preserving synapses.

BACKGROUND: A rare coding variant, P522R, in the phospholipase C gamma 2 (PLCG2) gene has been identified as protective against late-onset Alzheimer's disease (AD), but the mechanism is unknown. PLCG2 is exclusively expressed in microglia within the central nervous system, and altered microglial function has been implicated in the progression of AD. METHODS: Healthy control hiPSCs were CRISPR edited to generate cells heterozygous and homozygous for the PLCG2P522R variant. Microglia derived from these hiPSC's were used to investigate the impact of PLCγ2P522R on disease relevant processes, specifically microglial capacity to take up amyloid beta (Aß) and synapses. Targeted qPCR assessment was conducted to explore expression changes in core AD linked and microglial genes, and mitochondrial function was assessed using an Agilent Seahorse assay. RESULTS: Heterozygous expression of the P522R variant resulted in increased microglial clearance of Aß, while preserving synapses. This was associated with the upregulation of a number of genes, including the anti-inflammatory cytokine Il-10, and the synapse-linked CX3CR1, as well as alterations in mitochondrial function, and increased cellular motility. The protective capacity of PLCγ2P522R appeared crucially dependent on (gene) 'dose', as cells homozygous for the variant showed reduced synapse preservation, and a differential gene expression profile relative to heterozygous cells. CONCLUSION: These findings suggest that PLCγ2P522R may result in increased surveillance by microglia, and prime them towards an anti-inflammatory state, with an increased capacity to respond to increasing energy demands, but highlights the delicate balance of this system, with increasing PLCγ2P522R 'dose' resulting in reduced beneficial impacts.

Alternative Splicing in Human Biology and Disease.

Alternative pre-mRNA splicing allows for the production of multiple mRNAs from an individual gene, which not only expands the protein-coding potential of the genome but also enables complex mechanisms for the post-transcriptional control of gene expression. Regulation of alternative splicing entails a combinatorial interplay between an abundance of trans-acting splicing factors, cis-acting regulatory sequence elements and their concerted effects on the core splicing machinery. Given the extent and biological significance of alternative splicing in humans, it is not surprising that aberrant splicing patterns can cause or contribute to a wide range of diseases. In this introductory chapter, we outline the mechanisms that govern alternative pre-mRNA splicing and its regulation and discuss how dysregulated splicing contributes to human diseases affecting the motor system and the brain.