Lawrence T Reiter

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Lawrence verified their affiliation via an institutional email.

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• Ph.D.
• Professor at Tulane University

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by a spectrum of symptoms, including developmental delay, intellectual disability, and increased risk of autism. PWS is an imprinting disorder caused by the loss of paternal expression of critical genes in the 15q11.2-q13 region, including MAGEL2, SNRPN/SNURF, and SNORD116....

The neurogenetic disorder duplication 15q syndrome (Dup15q) is characterized by a high incidence of autism spectrum disorder (ASD) and pharmacoresistant epilepsy. Standard-of-care broad-spectrum anti-seizure medications (ASM) often fail to control seizures in Dup15q, emphasizing the need for the identification of new therapeutic compounds. Previous...

Misexpression of the E3 ubiquitin ligase UBE3A is thought to contribute to a range of neurological disorders. In the context of Dup15q syndrome, excess genomic copies of UBE3A is thought to contribute to the autism, muscle tone and spontaneous seizures characteristic of the disorder. In a Drosophila model of Dup 15q syndrome, it was recently shown...

Angelman syndrome (AS) is a rare neurogenetic disorder characterized by developmental delays, speech impairments, ataxic movements, and in some cases, hyperphagic feeding behavior. Loss of function mutations, loss of expression from the maternal allele or absence of maternal UBE3A result in AS. Recent studies have established a connection between U...

Background Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome is an ultra-rare neurocristopathy with no known genetic or environmental etiology. Rapid-onset obesity over a 3–12 month period with onset between ages 1.5–7 years of age is followed by an unfolding constellation of symptoms...

Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability and atypical behaviors. AS results from loss of expression of the E3 ubiquitin-protein ligase UBE3A from the maternal allele in neurons. Individuals with AS display impaired coordination, poor balance, and gait ataxia. PIEZO2 is a mechanosensitive ion channel...

An approach called antisense oligonucleotide (ASO) therapy has ushered in a new age in genetic medicine. ASO therapy works by introducing a short strand of RNA that binds to specific messenger RNA (mRNA) molecules in the host, and thus prevents the mRNA from being translated. Clinical trials are currently under way to see if ASO therapy will work f...

IntroductionPrader–Willi syndrome is a complex neurodevelopmental genetic disorder due to lack of paternal expression of critical imprinted genes in the 15q11.2-q13.1 chromosomal region, generally from a paternal deletion. Predominant features include infantile hypotonia, a poor suck with failure to thrive, craniofacial features, and developmental...

A major issue in studying human neurogenetic disorders, especially rare syndromes affecting the nervous system, is the ability to grow neuronal cultures that accurately represent these disorders for analysis. Although there has been some success in generating induced pluripotent stem cells (iPSC) from both skin and blood, there are still limitation...

Background: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hormonal dysregulation, obesity, intellectual disability, and behavioral problems. Most PWS cases are caused by paternal interstitial deletions of 15q11.2-q13.1, while a smaller number of cases are caused by chromosome 15 maternal uniparental disomy (PW-UPD)....

Background Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hormonal dysregulation, obesity, intellectual disability, and behavioral problems. Most PWS cases are caused by paternal interstitial deletions of 15q11.2-q13.1, while a smaller number of cases are caused by chromosome 15 maternal uniparental disomy (PW-UPD). C...

Background Duplication 15q syndrome (Dup15q) is a rare neurogenetic disorder characterized by autism and pharmacoresistant epilepsy. Most individuals with isodicentric (idic15) have been on multiple medications to control seizures. We recently developed a model of Dup15q in Drosophila by elevating levels of fly Dube3a in glial cells using repo-GAL4...

Epilepsy affects millions of individuals worldwide and many cases are pharmacoresistant. Duplication 15q syndrome (Dup15q) is a genetic disorder caused by duplications of the 15q11.2-q13.1 region. Phenotypes include in a high rate of pharmacoresistant epilepsy. We developed a Dup15q model in Drosophila melanogaster that recapitulates seizures in Du...

Duplication 15q syndrome (Dup15q) is a rare neurogenetic disorder characterized by autistic features and difficult to control (pharmacoresistant) epileptic seizures. Most individuals with isodicentric (idic15) have been on multiple medications to control their seizures and some are still seizing after years of treatment. We recently developed a mod...

The chromosome 15q11-q13 locus is a highly unstable genomic region prone to recurrent duplications and deletions and governed by complex gene regulation mechanisms that include imprinting, chromatin conformational changes, and antisense regulatory transcripts. As a consequence of this complexity, the genes in the 15q region are frequently subjected...

Duplication of 15q11.2‐q13.1 (dup15q syndrome) is one of the most common copy number variations associated with autism spectrum disorders (ASD) and intellectual disability (ID). As with many neurogenetic conditions, accurate behavioral assessment is challenging due to the level of impairment and heterogeneity across individuals. Large‐scale phenoty...

Background: Duplications of 15q11.2-q13.1 (Dup15q syndrome), including the paternally imprinted gene UBE3A and three nonimprinted gamma-aminobutyric acid type-A (GABAA) receptor genes, are highly penetrant for neurodevelopmental disorders such as autism spectrum disorder (ASD). To guide targeted treatments of Dup15q syndrome and other forms of ASD...

Major challenges to identifying genes that contribute to autism spectrum disorder (ASD) risk include the availability of large ASD cohorts, the contribution of many genes overall, and small effect sizes attributable to common gene variants. An alternative approach is to use a model organism to detect alleles that impact ASD-relevant behaviors and a...

The genetics underlying autism spectrum disorder (ASD) are complex. Approximately 3–5% of ASD cases arise from maternally inherited duplications of 15q11.2-q13.1, termed Duplication 15q syndrome (Dup15q). 15q11.2-q13.1 includes the gene UBE3A which is believed to underlie ASD observed in Dup15q syndrome. UBE3A is an E3 ubiquitin ligase that targets...

Major challenges to identifying genes that contribute to autism spectrum disorder (ASD) risk include the availability of large ASD cohorts, the contribution of many genes overall, and small effect sizes attributable to common gene variants. An alternative approach is to use a model organism to detect alleles that impact ASD-relevant behaviors and a...

Background: The inability to analyze gene expression in living neurons from Angelman (AS) and Duplication 15q (Dup15q) syndrome subjects has limited our understanding of these disorders at the molecular level. Method: Here, we use dental pulp stem cells (DPSC) from AS deletion, 15q Duplication, and neurotypical control subjects for whole transcr...

UBTF (upstream binding transcription factor) exists as two isoforms; UBTF1 regulates rRNA transcription by RNA polymerase 1, whereas UBTF2 regulates mRNA transcription by RNA polymerase 2. Herein, we describe 4 patients with very similar patterns of neuroregression due to recurrent de novo mutations in UBTF (GRCh37/hg19, NC_000017.10:g.42290219C>T,...

Background: Chromosome 15q11.2-q13.1 duplication syndrome (Dup15q syndrome) is a rare disorder caused by duplications of chromosome 15q11.2-q13.1, resulting in a wide range of developmental disabilities in affected individuals. The Dup15q Alliance is an organization that provides family support and promotes research to improve the quality of life...

Maternally derived copy number gains of human chromosome 15q11.2-q13.3 (Dup15q syndrome or Dup15q) cause intellectual disability, epilepsy, developmental delay, hypotonia, speech impairments, and minor dysmorphic features. Dup15q syndrome is one of the most common and penetrant chromosomal abnormalities observed in individuals with autism spectrum...

Duplication 15q syndrome (Dup15q) is an autism-associated disorder co-incident with high rates of pediatric epilepsy. Additional copies of the E3 ubiquitin ligase UBE3A are thought to cause Dup15q phenotypes, yet models overexpressing UBE3A in neurons have not recapitulated the epilepsy phenotype. We show that Drosophila endogenously expresses Dube...

Dental pulp stem cells (DPSC) are a relatively new alternative stem cell source for the study of neurogenetic disorders. DPSC can be obtained non-invasively and collected from long-distances remaining viable during transportation. These highly proliferative cells express stem cell markers and retain the ability to differentiate down multiple cell l...

BACKGROUND Chromosome 15q11.2-q13.1 duplication syndrome (Dup15q syndrome) is a rare disorder caused by duplications of chromosome 15q11.2-q13.1, resulting in a wide range of developmental disabilities in affected individuals. The Dup15q Alliance is an organization that provides family support and promotes research to improve the quality of life of...

The model organism Drosophila melanogaster has been at the forefront of genetic studies since before the discovery of DNA. Although human disease modeling in flies may still be rather novel, recent advances in genetic tool design and genome sequencing now confer huge advantages in the fly system when modeling human disease. In this review, we focus...

A major issue in studying human neurogenetic disorders, especially rare syndromes affecting the nervous system, is the ability to grow neuronal cultures that accurately represent these disorders for analysis. Although there has been some success in generating induced pluripotent stem (iPS) cells from both skin and blood, there are still limitations...

Background Duplications of 15q11.2-q13.1 (Dup15q syndrome) are highly penetrant for autism spectrum disorder (ASD). A distinct electrophysiological (EEG) pattern characterized by excessive activity in the beta band has been noted in clinical reports. We asked whether EEG power in the beta band, as well as in other frequency bands, distinguished chi...

Early embryonic stages of pluripotency are modeled for epigenomic studies primarily with human embryonic stem cells (ESC) or induced pluripotent stem cells (iPSCs). For analysis of DNA methylation, however, ESCs and iPSCs do not accurately reflect the DNA methylation levels found in preimplantation embryos. Whole genome bisulfite sequencing (WGBS)...

Chromosome 15q11-q13.1 duplication is a common copy number variant associated with autism spectrum disorder (ASD). Most cases are de novo, maternal in origin and fully penetrant for ASD. Here, we describe a unique family with an interstitial 15q11.2-q13.1 maternal duplication and the presence of somatic mosaicism in the mother. She is typically fun...

In mammals, expression of UBE3A is epigenetically regulated in neurons and expression is restricted to the maternal copy of UBE3A. A recent report claimed that Drosophila melanogaster UBE3A homolog (Dube3a) is preferentially expressed from the maternal allele in fly brain, inferring an imprinting mechanism. However, complex epigenetic regulatory fe...

In mammals, expression of UBE3A is epigenetically regulated in neurons and expression is restricted to the maternal copy of UBE3A. A recent report claimed that Drosophila melanogaster UBE3A homolog (Dube3a) is preferentially expressed from the maternal allele in fly brain, inferring an imprinting mechanism. However, complex epigenetic regulatory...

15q duplication syndrome and related disorders (dup15q) are caused by presence of at least one extra maternally-derived copy of the Prader-Willi/Angelman critical region (PWACR) within chromosome 15q11.2-q13.1. The extra copy or copies most commonly arise by one of two mechanisms: A maternal isodicentric 15q11.2-q13.1 supernumerary chromosome – idi...

Background: One of the most common genetic variants associated with autism spectrum disorder (ASD) are duplications of chromosome 15q11.2-q13.1 (Dup15q syndrome). To identify distinctive developmental and behavioral features in Dup15q syndrome, we examined the social communication, adaptive, and cognitive skills in clinic-referred subjects and com...

Fig. 1. Non-immortalized DPSC (NI-DPSC) and Immortalized DPSC (I-DPSC) were used at passage 5. A) Cells were stained with Alizarin Red after 21 days of differentiation and pictures show staining at 4x and 10x magnification. B) Cells were stained with Oil Red O after 21 days of differentiation. Pictures show no difference between undifferentiated NI...

The fruit fly, Drosophila melanogaster, has been the focus of genetics research for over a century. One consequence of this long history as a genetic model is a remarkably robust and diverse set of genetic tools, including loss of function mutations in most genes, a powerful transgenesis system, whole-genome RNA interference libraries, and expressi...

A major challenge to the study and treatment of neurogenetic syndromes is accessing live neurons for study from affected individuals. Although several sources of stem cells are currently available, acquiring these involve invasive procedures, may be difficult or expensive to generate and are limited in number. Dental pulp stem cells (DPSCs) are mul...

The E3 ubiquitin ligase UBE3A, also known as E6-AP, has a multitude of ascribed functions and targets relevant to human health and disease. Epigenetic regulation of the UBE3A gene by parentally imprinted noncoding transcription within human chromosome 15q11.2-q13.3 is responsible for the maternal-specific effects of 15q11.2-q13.3 deletion or duplic...

12 a b s t r a c t A major challenge to the study and treatment of neurogenetic syndromes is accessing live neurons for study from 21 affected individuals. Although several sources of stem cells are currently available, acquiring these involve inva-22 sive procedures, may be difficult or expensive to generate and are limited in number. Dental pulp...

Dental pulp stem cells (DPSCs) provide an exciting new avenue to study neurogenetic disorders. DPSCs are neural crest-derived cells with the ability to differentiate into numerous tissues including neurons. The therapeutic potential of stem cell-derived lines exposed to culturing ex vivo before reintroduction into patients could be limited if the c...

Dental pulp stem cells (DPSCs) provide an exciting new avenue to study neurogenetic disorders. DPSCs are neural crest-derived cells with the ability to differentiate into numerous tissues including neurons. The therapeutic potential of stem cell-derived lines exposed to culturing ex vivo before rein-troduction into patients could be limited if the...

Changes in UBE3A expression levels in neurons can cause neurogenetic disorders ranging from Angelman syndrome (AS) (decreased levels) to autism (increased levels). Here we investigated the effects on neuronal function of varying UBE3A levels using the Drosophila neuromuscular junction as a model for both of these neurogenetic disorders. Stimulation...

Myogenesis is an important process during both development and muscle repair. Previous studies suggest that mTORC1 plays a role in the formation of mature muscle from immature muscle precursor cells. Here we show that gene expression for several myogenic transcription factors including Myf5, Myog and Mef2c but not MyoD and myosin heavy chain isofor...

Myogenesis is an important process during both development and muscle repair. Previous studies suggest that mTORC1 plays a role in the formation of mature muscle from immature muscle precursor cells. Here we show that gene expression for several myogenic transcription factors including Myf5, Myog and Mef2c but not MyoD and myosin heavy chain isofor...

Duplications of the chromosome 15q11-q13.1 region are associated with an estimated 1 to 3% of all autism cases, making this copy number variation (CNV) one of the most frequent chromosome abnormalities associated with autism spectrum disorder (ASD). Several genes located within the 15q11-q13.1 duplication region including ubiquitin protein ligase E...

Background / Purpose: The TORC1 signaling pathway is critical for cell growth and proliferation. It has been implicated in disorders ranging from diabetes and obesity to depression and cancer. Previous work has implicated the TORC1 pathway in the regulation of longevity and muscle function in a variety of model systems. In this study, we manipula...

Seizures are common in individuals with duplications of chromosome 15q11.2-q13 (Dup15q). The goal of this study was to examine the phenotypes and treatments of seizures in Dup15q in a large population. A detailed electronic survey was conducted through the Dup15q Alliance containing comprehensive questions regarding seizures and their treatments in...

Chromosomal copy number variants (CNV) are the most common genetic lesion found in autism. Many autism-associated CNVs are duplications of chromosome 15q. Although most cases of interstitial (int) dup(15) that present clinically are de novo and maternally derived or inherited, both pathogenic and unaffected paternal duplications of 15q have been id...

The molecular defects associated with Angelman syndrome (AS) and 15q duplication autism are directly correlated to expression levels of the E3 ubiquitin ligase protein UBE3A. Here we used Drosophila melanogaster to screen for the targets of this ubiquitin ligase under conditions of both decreased (as in AS) or increased (as in dup(15)) levels of th...

This Microsoft PowerPoint file contains images of gels used for either direct comparison of experimental and control lanes or to excise a previously identified band for proteomic identification. The band numbers and gel numbers can be found in Table S1. (PPTX)

Complete list of proteins identified in our screen, fraction where they were identified, molecular weight of the protein excised from the gel, pH, fold change, CG identifying number and FBgn identifying number. (PDF)

Complete qRT-PCR data with error calculations from triplicate replicates for all genes identified in our screen. Genes with an asterisk (*) were used for transcription factor binding site analysis. (PDF)

DAVID analysis of proteins identified in the screen. Clusters of proteins that act in similar pathways or biological processes are listed along with an enrichment score for the cluster as well as a pvalue and fold enrichment for a given group in the cluster as compared to the entire set of proteins. (PDF)

Online resource. (A) Proximal and (B) distal breakpoints for int dup (15) subjects. University California Santa Cruz tracks being used are chromosome band, segmental duplications, mapability, HapMap single nucleotide polymorphisms (SNPs) and RefSeq Genes. Note the decrease in both mapability and the number of SNPs in regions covered by the segmenta...

Childhood neurodevelopmental disorders like Angelman syndrome and autism may be the result of underlying defects in neuronal plasticity and ongoing problems with synaptic signaling. Some of these defects may be due to abnormal monoamine levels in different regions of the brain. Ube3a, a gene that causes Angelman syndrome (AS) when maternally delete...

Monoamine and BH4 levels in different tissue. 5HT-5-hydroxytryptamine (serotonin), DA -dopamine, DOPAC-3,4-dihydroxyphenylacetic acid, E-epinephrine, HIAA-5-hydroxyindoleacetic acid, HVA -homovanillic acid, NE-norepinephrine, BH4-tetrahydrobiopterin. Values are means (n = 6). (PDF)

Correlation analyses of imprinting center of the Prader-Willi locus (PWS-IC) methylation and ubiquitin ligase 3A (UBE3A) transcript levels. This analysis was performed as explained in Figures 6a and 6b, except that only the controls or autism samples were correlated with PWS-IC methylation.

Correlation analyses of imprinting center of the Prader-Willi locus (PWS-IC) and GABAA receptor β3 (GABRB3) transcript levels. This analysis was performed as explained in Figure 6c, except that only the duplication of 15q11-q13 (dup15q), controls or autism samples were correlated with PWS-IC methylation.

GABAA receptor β3 (GABRB3) protein levels did not correlate with imprinting center of the Prader-Willi locus (PWS-IC) methylation. When all three groups were analyzed together or separately, there was no correlation between percentage PWS-IC methylation and GABRB3 protein levels.

Correlation analyses of 15q11-q13 copy number and transcript levels. This analysis was performed as explained in Figure 5, except that only the duplication of 15q11-q13 (dup15q) samples were correlated with copy number.

Distribution of ubiquitin ligase 3A (UBE3A) and GABAA receptor β3 (GABRB3) protein levels in individual brain samples by condition. Western blot analyses of protein levels were performed as described in Figure 7 for UBE3A or GABRB3.

Protein levels showed no significant association with copy number. We found no significant relationship between UBE3A or GABRB3 protein levels and copy number in all cases or in duplication of 15q11-q13 (dup15q) only.

Primers used in this study. Primer sequences used for quantitative RT-PCR and copy number analyses are provided.

Ubiquitin ligase 3A (UBE3A) transcript levels are significantly higher in duplication of 15q11-q13 (dup15q) copy number samples than in control and autism brain tissues. Fold change vs genotype for UBE3A levels in brain tissue.

Correlation analyses of imprinting center of the Prader-Willi locus (PWS-IC) methylation and SNRPN transcript levels. This analysis was performed as explained in Figure 6d, except that only the duplication of 15q11-q13 (dup15q), controls or autism samples were correlated with PWS-IC methylation.

Ubiquitin ligase 3A (UBE3A) protein levels did not correlate with imprinting center of the Prader-Willi locus (PWS-IC) methylation. In all cases, the positive trend between UBE3A protein level and methylation was similar to transcript level and methylation; however, it did not reach significance, nor did the other groups when analyzed separately.

Duplication of chromosome 15q11-q13 (dup15q) accounts for approximately 3% of autism cases. Chromosome 15q11-q13 contains imprinted genes necessary for normal mammalian neurodevelopment controlled by a differentially methylated imprinting center (imprinting center of the Prader-Willi locus, PWS-IC). Maternal dup15q occurs as both interstitial dupli...

Fragile X syndrome (FXS; MIM #300624), a well-recognized form of inherited human mental retardation is caused, in most cases, by a CGG trinucleotide repeat expansion in the 5'-untranslated region of FMR1, resulting in reduced expression of the fragile X mental retardation protein (FMRP). Clinical features include macroorchidism, anxiety, mental ret...

Alzheimer's disease (AD) pathogenesis is characterized by senile plaques in the brain and evidence of oxidative damage. Oxidative stress may precede plaque formation in AD; however, the link between oxidative damage and plaque formation remains unknown. Presenilins are transmembrane proteins in which mutations lead to accelerated plaque formation a...

Background: It has been estimated that as many as ~3-5% of all autism cases may be the result of maternal duplications of the 15q11-q13 region. A key structural feature of chromosome 15 is the high number of low copy repeats (LCRs), which predispose to both deletion and duplication events mediated by non-allelic homologous recombination (NAHR). The...

Angelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay with mental retardation, a generally happy disposition, ataxia and characteristic behaviors such as inappropriate laughter, social-seeking behavior and hyperactivity. The majority of AS cases are due to loss of the maternal copy of the UBE3A gene. Maternal...

The most common chromosomal abnormalities associated with autism are 15q11-q13 duplications. Maternally derived or inherited duplications of 15q pose a substantial risk for an autism phenotype, while paternally derived duplications may be incompletely penetrant or result in other neurodevelopmental problems. Therefore, the determination of maternal...

Background: It has been estimated that as many as ~3-5% of all autism cases may be the result of duplications of the 15q11-q13 region. Unfortunately, genotype-phenotype correlations have not consistently demonstrated that these duplications are the sole cause of ASD in these cases. Maternally transmitted 15q duplications consistently show autistic...

The role of the hypoxic response during metastasis was analysed in migrating border cells of the Drosophila ovary. Acute exposure to 1% O(2) delayed or blocked border cell migration (BCM), whereas prolonged exposure resulted in the first documented accelerated BCM phenotype. Similarly, manipulating the expression levels of sima, the Drosophila hypo...

Angelman syndrome (AS) is a childhood-onset neurogenetic disorder characterized by functionally severe developmental delay with mental retardation, deficits in expressive language, ataxia, appendicular action tremors and unique behaviors such as inappropriate laughter and stimulus-sensitive hyperexcitibility. Most cases of AS are caused by mutation...

Upon completion of sequencing the Drosophila genome, it was estimated that 61% of human disease-associated genes had sequence homologs in flies, and in some diseases such as cancer, the number was as high as 68%. We now know that as many as 75% of the genes associated with genetic disease have counterparts in Drosophila. Using better tools for muta...