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Open Access Publications from the University of California

Scholarly Works (35 results)

  • Article
  • Peer Reviewed
UC San Diego Previously Published Works (2012)
Rett syndrome (RTT, MIM#312750) is a neurodevelopmental disorder that is classified as an autism spectrum disorder. Clinically, RTT is characterized by psychomotor regression with loss of volitional hand use and spoken language, the development of repetitive hand stereotypies, and gait impairment. The majority of people with RTT have mutations in Methyl-CpG-binding Protein 2 (MECP2), a transcriptional regulator. Interestingly, alterations in the function of the protein product produced by MECP2, MeCP2, have been identified in a number of other clinical conditions. The many clinical features found in RTT and the various clinical problems that result from alteration in MeCP2 function have led to the belief that understanding RTT will provide insight into a number of other neurological disorders. Excitingly, RTT is reversible in a mouse model, providing inspiration and hope that such a goal may be achieved for RTT and potentially for many neurodevelopmental disorders.
    Cover page: The relationship of Rett syndrome and MECP2 disorders to autism
    • Thesis
    • Peer Reviewed
    UC San Diego Electronic Theses and Dissertations (2016)

    Rett syndrome is a severe neurodevelopmental disorder predominantly caused by mutations in the Methyl-CpG-binding protein 2 (MECP2). Four out of the eight common mutations in MECP2 account for ~35% of RTT cases. A method for overcoming the phenotypes found in these nonsense mutations is treatment with nonsense suppression therapy. Nonsense suppression therapy are small molecules that suppress premature termination codons that would allow for full length readthrough of MeCP2.However, the ability screen for therapeutics has been limited due to the low throughput of RTT animal disease models. Zebrafish have been shown to be a complementary model translatable for neuroscience research and for high throughput drug screenings. Here, I describe the applications and importance of zebrafish as a preliminary model for MECP2 therapeutics. I re-capitulated the behavioral and molecular phenotypes characterized in zebrafish containing the mecp2Q63x mutation, successfully showing expression of Mecp2 in the brain of 6dpf zebrafish. Using a custom video-based activity capture system, I demonstrated a decrease in total distance travelled, percentage of swimming activity, and decrease in anxiety-like behavior in the mecp2Q63x fish. These findings reproduce previous reports demonstrating dysfunction in motor circuitry seen in RTT patients. I also found increased astrogenesis, as measured by expression of GFAP, in the mecp2Q63x fish. Finally, I generated a novel mecp2 zebrafish mutant with a complete excision of the mecp2 locus using CRISPR/Cas9 system to demonstrate the ability to engineer this locus and paving the way for future generation of fish engineered to contain human disease-causing nonsense mutations. In summary, this works provides the foundation and a platform to use genetically engineered zebrafish to perform high-throughput screening of nonsense suppression therapeutics.

      Cover page: Preliminary development of a zebrafish platform for screening MeCP2 therapeutics
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2015)
        • Thesis
        • Peer Reviewed
        UC San Diego Electronic Theses and Dissertations (2020)

        Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by mutations in Methyl-CpG Binding Protein 2 (MECP2). While defined clinical features are present in all cases, a spectrum of disease severity exists across individuals with RTT. The work presented here seeks to increase understanding of the mechanisms governing phenotypic severity in RTT and the implications these factors hold for potential therapeutic interventions. These efforts are broadly divided between two investigations. The first centers upon a dissection of the underlying causes of variation in phenotypic severity amongst common RTT causing nonsense mutations in MECP2. Included in this investigation is an assessment of nonsense suppression therapy viability in a novel mouse model of the common R294X mutation. The second study explores the contribution of individual genetic variation to clinical severity in people with RTT. To identify genetic modifiers of RTT severity, we performed exome sequencing on affected individuals from both ends of a clinical severity distribution. Subsequent analysis revealed variants in cholesterol and terpenoid synthesis related genes are associated with phenotypic severity in RTT.

          Cover page: On the mechanisms governing Rett syndrome severity
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2020)

          Background

          MECP2 duplication syndrome (MDS) is a rare X-linked genomic disorder primarily affecting males which is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. Core clinical features of MDS include choreiform movements, progressive spasticity, recurrent respiratory infections, developmental delays in the first 6 months of life, hypotonia, vasomotor disturbances, constipation, drooling, and bruxism. Prior studies suggest that HPA axis activity may be altered in MDS and measures of HPA axis activity may offer insight into disease severity.

          Methods

          To ascertain whether cortisol profiles are a potential biomarker of clinical severity, diurnal profiles of cortisol and the cortisol awakening response were examined from saliva samples in 31 participants with MDS (ages 2-24 years), and 27 of these samples were usable. Documentation of a positive diagnostic test for MECP2 duplication was required for entry into the study. Samples were collected on each of two consecutive weekdays at four time points during the day: immediately after waking, 30 min after waking, between 3 and 4 PM, and in the evening before bedtime. Correlations with duplication size, clinical severity, sleep problems, and behavior were also examined.

          Results

          Results revealed that a majority of participants with MDS exhibit a declining cortisol awakening response (n = 17). A declining CAR was significantly associated with increased clinical severity scores (r = - .508; p = .03), larger duplication size, waking later, and an increased number of hospitalizations for infections.

          Conclusions

          Future mechanistic studies will have to determine whether the declining CAR in MDS is attributable to problems with "flip-flop switching" of regional brain activation (involving the suprachiasmatic nucleus and the hippocampus, and the HPA axis) that is responsible for the switch from reduced to increased adrenal sensitivity. Taken together, results suggest the possibility that cortisol profiles could potentially be a biomarker of clinical severity and utilized for the purposes of patient stratification for future clinical trials in MDS.
            Cover page: Cortisol profiles and clinical severity in MECP2 duplication syndrome
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2013)
            Breathing disturbances are a major challenge in Rett Syndrome (RTT). These disturbances are more pronounced during wakefulness; but irregular breathing occurs also during sleep. During the day patients can exhibit alternating bouts of hypoventilation and irregular hyperventilation. But there is significant individual variability in severity, onset, duration and type of breathing disturbances. Research in mouse models of RTT suggests that different areas in the ventrolateral medulla and pons give rise to different aspects of this breathing disorder. Pre-clinical experiments in mouse models that target different neuromodulatory and neurotransmitter receptors and MeCP2 function within glia cells can partly reverse breathing abnormalities. The success in animal models raises optimism that one day it will be possible to control or potentially cure the devastating symptoms also in human patients with RTT.
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2014)
              Mutations in Methyl-CpG-Binding protein 2 (MECP2) are commonly associated with the neurodevelopmental disorder Rett syndrome (RTT). However, some people with RTT do not have mutations in MECP2, and interestingly there have been people identified with MECP2 mutations that do not have the clinical features of RTT. In this report we present four people with neurodevelopmental abnormalities and clear RTT-disease causing MECP2 mutation but lacking the characteristic clinical features of RTT. One patient's symptoms suggest an extension of the known spectrum of MECP2 associated phenotypes to include global developmental delay with obsessive compulsive disorder and attention deficit hyperactivity disorder. These results reemphasize that RTT should remain a clinical diagnosis, based on the recent consensus criteria.
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2016)
                Sudden unexpected death occurs in one quarter of deaths in Rett Syndrome (RTT), a neurodevelopmental disorder caused by mutations in Methyl-CpG-binding protein 2 (MECP2). People with RTT show a variety of autonomic nervous system (ANS) abnormalities and mouse models show similar problems including QTc interval prolongation and hypothermia. To explore the role of cardiac problems in sudden death in RTT, we characterized cardiac rhythm in mice lacking Mecp2 function. Male and female mutant mice exhibited spontaneous cardiac rhythm abnormalities including bradycardic events, sinus pauses, atrioventricular block, premature ventricular contractions, non-sustained ventricular arrhythmias, and increased heart rate variability. Death was associated with spontaneous cardiac arrhythmias and complete conduction block. Atropine treatment reduced cardiac arrhythmias in mutant mice, implicating overactive parasympathetic tone. To explore the role of MeCP2 within the parasympathetic neurons, we selectively removed MeCP2 function from cholinergic neurons (MeCP2 ChAT KO), which recapitulated the cardiac rhythm abnormalities, hypothermia, and early death seen in RTT male mice. Conversely, restoring MeCP2 only in cholinergic neurons rescued these phenotypes. Thus, MeCP2 in cholinergic neurons is necessary and sufficient for autonomic cardiac control, thermoregulation, and survival, and targeting the overactive parasympathetic system may be a useful therapeutic strategy to prevent sudden unexpected death in RTT.
                  Cover page: Methyl-CpG binding-protein 2 function in cholinergic neurons mediates cardiac arrhythmogenesis.
                  • Article
                  • Peer Reviewed
                  UC San Diego Previously Published Works (2014)
                  The aim of the present study was to characterize biomarkers of bone turnover and their relation with bone mineral mass in a cross-sectional cohort of girls with Rett syndrome (RTT) and to examine the role of dietary, biochemical, hormonal, and inflammatory factors on bone mineral mass and bone biomarkers in this disorder.Total body bone mineral content (BMC) and bone mineral density (BMD) were determined by dual-energy x-ray absorptiometry. Dietary nutrient intakes were determined from 3-day food records. Biomarkers of bone turnover, bone metabolites, vitamin D metabolites, hormones, and inflammatory markers were measured by standard clinical laboratory methods.Serum osteocalcin, bone alkaline phosphatase, and C-telopeptide showed significant inverse relations with age in the RTT cohort. Mean osteocalcin concentrations were significantly lower and mean bone alkaline phosphatase concentrations were significantly higher for individual age groups in the RTT cohort than mean values for their respective age ranges in the reference population. Significant inverse associations were identified between urinary calcium losses, expressed as calcium:creatinine ratios, and total body BMC and BMD z scores. Dietary protein, calcium, and phosphorus intakes, expressed as a proportion of Dietary Reference Intakes for age and sex, showed significant positive associations with total body BMD z scores.The present study suggests decreased bone formation instead of increased bone resorption may explain in part the deficits in bone mineral mass in RTT and that attention to the adequacy of dietary protein, calcium, and phosphorus intakes may offer an opportunity to improve bone health in RTT.
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2016)

                    Unlabelled

                    Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Severe breathing abnormalities are common in RTT and are reproduced in mouse models of RTT. Previously, we found that removing MeCP2 from the brainstem and spinal cord in mice caused early lethality and abnormal breathing. To determine whether loss of MeCP2 in functional components of the respiratory network causes specific breathing disorders, we used the Cre/LoxP system to differentially manipulate MeCP2 expression throughout the brainstem respiratory network, specifically within HoxA4-derived tissues, which include breathing control circuitry within the nucleus tractus solitarius and the caudal part of ventral respiratory column but do not include more rostral parts of the breathing control circuitry. To determine whether respiratory phenotypes manifested in animals with MeCP2 removed from specific pons medullary respiratory circuits, we performed whole-body plethysmography and electrophysiological recordings from in vitro brainstem slices from mice lacking MeCP2 in different circuits. Our results indicate that MeCP2 expression in the medullary respiratory network is sufficient for normal respiratory rhythm and preventing apnea. However, MeCP2 expression within components of the breathing circuitry rostral to the HoxA4 domain are neither sufficient to prevent the hyperventilation nor abnormal hypoxic ventilatory response. Surprisingly, we found that MeCP2 expression in the HoxA4 domain alone is critical for survival. Our study reveals that MeCP2 is differentially required in select respiratory components for different aspects of respiratory functions, and collectively for the integrity of this network functions to maintain proper respiration.

                    Significance statement

                    Breathing abnormalities are a significant clinical feature in Rett syndrome and are robustly reproduced in the mouse models of this disease. Previous work has established that alterations in the function of MeCP2, the protein encoded by the gene mutated in Rett syndrome, within the hindbrain are critical for control of normal breathing. Here we show that MeCP2 function plays distinct roles in specific brainstem regions in the genesis of various aspects of abnormal breathing. This provides insight into the pathogenesis of these breathing abnormalities in Rett syndrome, which could be used to target treatments to improve these symptoms. Furthermore, it provides further knowledge about the fundamental neural circuits that control breathing.
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