ABSTRACT
BACKGROUND: Loss of the Sortilin-related receptor 1 (SORL1) gene seems to act as a causal event for Alzheimer's disease (AD). Recent studies have established that loss of SORL1, as well as mutations in autosomal dominant AD genes APP and PSEN1/2, pathogenically converge by swelling early endosomes, AD's cytopathological hallmark. Acting together with the retromer trafficking complex, SORL1 has been shown to regulate the recycling of the amyloid precursor protein (APP) out of the endosome, contributing to endosomal swelling and to APP misprocessing. We hypothesized that SORL1 plays a broader role in neuronal endosomal recycling and used human induced pluripotent stem cell-derived neurons (hiPSC-Ns) to test this hypothesis. We examined endosomal recycling of three transmembrane proteins linked to AD pathophysiology: APP, the BDNF receptor Tropomyosin-related kinase B (TRKB), and the glutamate receptor subunit AMPA1 (GLUA1). METHODS: We used isogenic hiPSCs engineered to have SORL1 depleted or to have enhanced SORL1 expression. We differentiated neurons from these cell lines and mapped the trafficking of APP, TRKB and GLUA1 within the endosomal network using confocal microscopy. We also performed cell surface recycling and lysosomal degradation assays to assess the functionality of the endosomal network in both SORL1-depleted and -overexpressing neurons. The functional impact of GLUA1 recycling was determined by measuring synaptic activity. Finally, we analyzed alterations in gene expression in SORL1-depleted neurons using RNA sequencing. RESULTS: We find that as with APP, endosomal trafficking of GLUA1 and TRKB is impaired by loss of SORL1. We show that trafficking of all three cargoes to late endosomes and lysosomes is affected by manipulating SORL1 expression. We also show that depletion of SORL1 significantly impacts the endosomal recycling pathway for APP and GLUA1 at the level of the recycling endosome and trafficking to the cell surface. This has a functional effect on neuronal activity as shown by multi-electrode array (MEA). Conversely, increased SORL1 expression enhances endosomal recycling for APP and GLUA1. Our unbiased transcriptomic data further support SORL1's role in endosomal recycling. We observe altered expression networks that regulate cell surface trafficking and neurotrophic signaling in SORL1-depleted neurons. CONCLUSION: Collectively, and together with other recent observations, these findings suggest that one role for SORL1 is to contribute to endosomal degradation and recycling pathways in neurons, a conclusion that has both pathogenic and therapeutic implications for Alzheimer's disease.
Subject(s)
Alzheimer Disease , Amyloid beta-Protein Precursor , LDL-Receptor Related Proteins , Membrane Glycoproteins , Membrane Transport Proteins , Neurons , Receptor, trkB , Humans , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Amyloid beta-Protein Precursor/metabolism , Endosomes/metabolism , Induced Pluripotent Stem Cells , LDL-Receptor Related Proteins/metabolism , Membrane Glycoproteins/metabolism , Membrane Transport Proteins/metabolism , Neurons/metabolism , Neurons/physiology , Receptor, trkB/metabolismABSTRACT
The ERK5 MAP kinase signalling pathway drives transcription of naïve pluripotency genes in mouse Embryonic Stem Cells (mESCs). However, how ERK5 impacts on other aspects of mESC biology has not been investigated. Here, we employ quantitative proteomic profiling to identify proteins whose expression is regulated by the ERK5 pathway in mESCs. This reveals a function for ERK5 signalling in regulating dynamically expressed early embryonic 2-cell stage (2C) genes including the mESC rejuvenation factor ZSCAN4. ERK5 signalling and ZSCAN4 induction in mESCs increases telomere length, a key rejuvenative process required for prolonged culture. Mechanistically, ERK5 promotes ZSCAN4 and 2C gene expression via transcription of the KLF2 pluripotency transcription factor. Surprisingly, ERK5 also directly phosphorylates KLF2 to drive ubiquitin-dependent degradation, encoding negative feedback regulation of 2C gene expression. In summary, our data identify a regulatory module whereby ERK5 kinase and transcriptional activities bi-directionally control KLF2 levels to pattern 2C gene transcription and a key mESC rejuvenation process.
Subject(s)
Kruppel-Like Transcription Factors/metabolism , Mitogen-Activated Protein Kinase 7/metabolism , Mouse Embryonic Stem Cells , Animals , Mice , Mouse Embryonic Stem Cells/cytology , Mouse Embryonic Stem Cells/metabolismABSTRACT
Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single-cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signaling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of Lrig1 in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence.
Subject(s)
Adult Stem Cells/metabolism , Lateral Ventricles/metabolism , MAP Kinase Signaling System/genetics , Membrane Glycoproteins/metabolism , Nerve Tissue Proteins/metabolism , Neural Stem Cells/metabolism , Neurogenesis/genetics , Adult Stem Cells/cytology , Adult Stem Cells/drug effects , Animals , Bone Morphogenetic Protein 4/pharmacology , Cell Cycle/genetics , Cell Cycle Proteins/metabolism , Cell Proliferation/genetics , DNA-Binding Proteins/metabolism , ErbB Receptors/pharmacology , Fibroblast Growth Factor 2/pharmacology , Gene Ontology , Immunohistochemistry , Interferons/pharmacology , Lateral Ventricles/cytology , MAP Kinase Signaling System/drug effects , Membrane Glycoproteins/genetics , Mice , Nerve Tissue Proteins/genetics , Neural Stem Cells/cytology , Neural Stem Cells/drug effects , Proteomics , RNA-Seq , Regeneration/drug effects , Tetraspanin 29/metabolism , Up-RegulationABSTRACT
Point mutations within the histone H3.3 are frequent in aggressive childhood brain tumors known as pediatric high-grade gliomas (pHGGs). Intriguingly, distinct mutations arise in discrete anatomical regions: H3.3-G34R within the forebrain and H3.3-K27M preferentially within the hindbrain. The reasons for this contrasting etiology are unknown. By engineering human fetal neural stem cell cultures from distinct brain regions, we demonstrate here that cell-intrinsic regional identity provides differential responsiveness to each mutant that mirrors the origins of pHGGs. Focusing on H3.3-G34R, we find that the oncohistone supports proliferation of forebrain cells while inducing a cytostatic response in the hindbrain. Mechanistically, H3.3-G34R does not impose widespread transcriptional or epigenetic changes but instead impairs recruitment of ZMYND11, a transcriptional repressor of highly expressed genes. We therefore propose that H3.3-G34R promotes tumorigenesis by focally stabilizing the expression of key progenitor genes, thereby locking initiating forebrain cells into their pre-existing immature state.
Subject(s)
Brain Neoplasms , Glioma , Neural Stem Cells , Brain Neoplasms/genetics , Carcinogenesis/genetics , Glioma/genetics , Histones/genetics , Humans , Mutation/geneticsABSTRACT
Adrenergic receptors are mediators of adrenergic and noradrenergic modulation throughout the brain. Previous studies have provided evidence for the expression of adrenergic receptors in the midbrain auditory nucleus, the inferior colliculus (IC), but have not examined the cellular patterns of expression in detail. Here, we utilize multichannel fluorescent in situ hybridization to detect the expression of adrenergic receptor-encoding mRNA in the inferior colliculus of male and female mice. We found expression of α1 , α2A , and ß2 receptor-encoding mRNA throughout all areas of the IC. While we observed similar levels of expression of α1 receptor-encoding mRNA across the subregions of the IC, α2A and ß2 receptor-encoding mRNA was expressed differentially. To account for developmental changes in noradrenergic receptor expression, we measured expression levels in mice aged P15, P20, and P60. We observed little change in levels of expression across these ages. To ascertain the modulatory potential of multiple adrenergic receptor subtypes in a single IC cell, we measured co-expression of α1 , α2A , and ß2 receptor-encoding mRNA. We found greater proportions of cells in the IC that expressed no adrenergic receptor-encoding mRNA, α1 and α2A adrenergic receptor-encoding mRNA, and α1, α2A, and ß2 receptor-encoding mRNA than would be predicted by independent expression of each receptor subtype. These data suggest a coordinated pattern of adrenergic receptor expression in the IC and provide the first evidence for adrenergic receptor expression and co-expression in the subregions of the mouse auditory midbrain.
Subject(s)
Inferior Colliculi/metabolism , RNA, Messenger/analysis , Receptors, Adrenergic/metabolism , Animals , Female , Male , Mice , Receptors, Adrenergic/analysisABSTRACT
Sox proteins are a family of lineage-associated transcription factors. They regulate expression of genes involved in control of self-renewal and multipotency in both developmental and adult stem cells. Overexpression of Sox proteins is frequently observed in many different human cancers. Despite their importance as therapeutic targets, Sox proteins are difficult to 'drug' using structure-based design. However, Sox protein localisation, activity and interaction partners are regulated by a plethora of post-translational modifications (PTMs), such as: phosphorylation, acetylation, sumoylation, methylation, and ubiquitylation. Here we review the various reported post-translational modifications of Sox proteins and their potential functional importance in guiding cell fate processes. The enzymes that regulate these PTMs could be useful targets for anti-cancer drug discovery.
Subject(s)
Antineoplastic Agents/therapeutic use , Molecular Targeted Therapy , Neoplasms/drug therapy , Neoplasms/pathology , Protein Processing, Post-Translational , SOX Transcription Factors/antagonists & inhibitors , Animals , Humans , Neoplasms/genetics , Neoplasms/metabolism , SOX Transcription Factors/chemistry , SOX Transcription Factors/genetics , Signal TransductionABSTRACT
PURPOSE: Beckwith-Wiedemann syndrome (BWS) is a developmental disorder caused by dysregulation of the imprinted gene cluster of chromosome 11p15.5 and often associated with loss of methylation (LOM) of the imprinting center 2 (IC2) located in KCNQ1 intron 10. To unravel the etiological mechanisms underlying these epimutations, we searched for genetic variants associated with IC2 LOM. METHODS: We looked for cases showing the clinical features of both BWS and long QT syndrome (LQTS), which is often associated with KCNQ1 variants. Pathogenic variants were identified by genomic analysis and targeted sequencing. Functional experiments were performed to link these pathogenic variants to the imprinting defect. RESULTS: We found three rare cases in which complete IC2 LOM is associated with maternal transmission of KCNQ1 variants, two of which were demonstrated to affect KCNQ1 transcription upstream of IC2. As a consequence of KCNQ1 haploinsufficiency, these variants also cause LQTS on both maternal and paternal transmission. CONCLUSION: These results are consistent with the hypothesis that, similar to what has been demonstrated in mouse, lack of transcription across IC2 results in failure of methylation establishment in the female germline and BWS later in development, and also suggest a new link between LQTS and BWS that is important for genetic counseling.
Subject(s)
Beckwith-Wiedemann Syndrome/genetics , DNA Methylation/genetics , KCNQ1 Potassium Channel/genetics , Adolescent , Adult , Animals , Beckwith-Wiedemann Syndrome/epidemiology , Beckwith-Wiedemann Syndrome/pathology , Child , Child, Preschool , Chromosomes, Human, Pair 11/genetics , Female , Genomic Imprinting/genetics , Humans , Infant , Introns/genetics , Male , Maternal Inheritance/genetics , Mice , Pedigree , Young AdultABSTRACT
BACKGROUND: Transport protein particle (TRAPP) is a supramolecular protein complex that functions in localizing proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in muscle disease by virtue of homozygous and compound heterozygous deleterious mutations being identified in individuals with limb girdle muscular dystrophy and congenital muscular dystrophy. It remains unclear how this protein leads to muscle disease. Furthermore, a role for this protein, or any other membrane trafficking protein, in the etiology of the dystroglycanopathy group of muscular dystrophies has yet to be found. Here, using a multidisciplinary approach including genetics, immunofluorescence, western blotting, and live cell analysis, we implicate both TRAPPC11 and another membrane trafficking protein, GOSR2, in α-dystroglycan hypoglycosylation. CASE PRESENTATION: Subject 1 presented with severe epileptic episodes and subsequent developmental deterioration. Upon clinical evaluation she was found to have brain, eye, and liver abnormalities. Her serum aminotransferases and creatine kinase were abnormally high. Subjects 2 and 3 are siblings from a family unrelated to subject 1. Both siblings displayed hypotonia, muscle weakness, low muscle bulk, and elevated creatine kinase levels. Subject 3 also developed a seizure disorder. Muscle biopsies from subjects 1 and 3 were severely dystrophic with abnormal immunofluorescence and western blotting indicative of α-dystroglycan hypoglycosylation. Compound heterozygous mutations in TRAPPC11 were identified in subject 1: c.851A>C and c.965+5G>T. Cellular biological analyses on fibroblasts confirmed abnormal membrane trafficking. Subject 3 was found to have compound heterozygous mutations in GOSR2: c.430G>T and c.2T>G. Cellular biological analyses on fibroblasts from subject 3 using two different model cargo proteins did not reveal defects in protein transport. No mutations were found in any of the genes currently known to cause dystroglycanopathy in either individual. CONCLUSION: Recessive mutations in TRAPPC11 and GOSR2 are associated with congenital muscular dystrophy and hypoglycosylation of α-dystroglycan. This is the first report linking membrane trafficking proteins to dystroglycanopathy and suggests that these genes should be considered in the diagnostic evaluation of patients with congenital muscular dystrophy and dystroglycanopathy.
Subject(s)
Dystroglycans/metabolism , Muscular Dystrophies/genetics , Mutation , Qb-SNARE Proteins/genetics , Vesicular Transport Proteins/genetics , Abnormalities, Multiple/diagnostic imaging , Abnormalities, Multiple/genetics , Abnormalities, Multiple/metabolism , Brain/diagnostic imaging , Diffusion Magnetic Resonance Imaging/methods , Female , Glycosylation , Humans , Infant , Muscle, Skeletal/metabolism , Muscular Dystrophies/congenital , Muscular Dystrophies/diagnostic imaging , Muscular Dystrophies/metabolismABSTRACT
Embryonic stem cells (ESCs) can self-renew or differentiate into all cell types, a phenomenon known as pluripotency. Distinct pluripotent states have been described, termed "naïve" and "primed" pluripotency. The mechanisms that control naïve-primed transition are poorly understood. In particular, we remain poorly informed about protein kinases that specify naïve and primed pluripotent states, despite increasing availability of high-quality tool compounds to probe kinase function. Here, we describe a scalable platform to perform targeted small molecule screens for kinase regulators of the naïve-primed pluripotent transition in mouse ESCs. This approach utilizes simple cell culture conditions and standard reagents, materials and equipment to uncover and validate kinase inhibitors with hitherto unappreciated effects on pluripotency. We discuss potential applications for this technology, including screening of other small molecule collections such as increasingly sophisticated kinase inhibitors and emerging libraries of epigenetic tool compounds.
Subject(s)
High-Throughput Screening Assays , Mouse Embryonic Stem Cells/drug effects , Protein Kinase Inhibitors/pharmacology , Animals , Cell Differentiation , Cells, Cultured , Mice , Mouse Embryonic Stem Cells/cytology , Mouse Embryonic Stem Cells/enzymologyABSTRACT
Post-translational modification of proteins by phosphorylation plays a key role in regulating all aspects of eukaryotic biology. Embryonic stem cell (ESC) pluripotency, defined as the ability to differentiate into all cell types in the adult body, is no exception. Maintenance and dissolution of pluripotency are tightly controlled by phosphorylation. As a result, key signalling pathways that regulate pluripotency have been identified and their functions well characterised. Amongst the best studied are the fibroblast growth factor (FGF)-ERK1/2 pathway, PI3K-AKT, the leukemia inhibitory factor (LIF)-JAK-STAT3 axis, Wnt-GSK3 signalling, and the transforming growth factor (TGF)ß family. However, these kinase pathways constitute only a small proportion of the protein kinase complement of pluripotent cells, and there is accumulating evidence that diverse phosphorylation systems modulate ESC pluripotency. Here, we review recent progress in understanding the overarching role of phosphorylation in mediating communication from the cellular environment, metabolism, and cell cycle to the core pluripotency machinery.
Subject(s)
Embryonic Stem Cells/enzymology , Embryonic Stem Cells/physiology , Pluripotent Stem Cells/enzymology , Pluripotent Stem Cells/physiology , Protein Kinases/metabolism , Signal Transduction , Animals , Gene Expression Regulation , Humans , Mice , Phosphorylation , Protein Processing, Post-TranslationalABSTRACT
We present the case of a newborn with co-occurrence of Marfan syndrome and aplasia cutis congenita (ACC) and a family history significant for Marfan syndrome and ACC in the father. This case details a previously unreported mutation in Marfan syndrome and describes a novel coinheritance of Marfan syndrome and ACC.
ABSTRACT
Lipoprotein lipase (LPL) deficiency is an autosomal recessive condition due to absent or decreased activity of LPL enzyme. The LPL deficiency is a rare condition that is mainly diagnosed in children, but there is no standard screening method at this time. In our report, we describe a 6-day-old male infant who was found to have hypertriglyceridemia after lipemia retinalis was diagnosed from a fundoscopic examination for nonaccidental trauma work-up. After dietary modification was done, his triglyceride levels decreased significantly, and there were no complications. When diagnosed later in life, recurrent pancreatitis can be a significant complication.
Subject(s)
Hyperlipidemias/diagnosis , Hyperlipoproteinemia Type I/diagnosis , Retina/pathology , Retinal Diseases/pathology , Battered Child Syndrome , Fundus Oculi , Humans , Hyperlipidemias/diet therapy , Hyperlipidemias/enzymology , Hyperlipoproteinemia Type I/diet therapy , Hypertriglyceridemia/blood , Hypertriglyceridemia/enzymology , Hypertriglyceridemia/etiology , Hypertriglyceridemia/genetics , Infant, Newborn , Male , Retina/diagnostic imaging , Retinal Diseases/complications , Tomography Scanners, X-Ray ComputedABSTRACT
Embryonic stem cells (ESCs) can self-renew or differentiate into any cell type, a phenomenon known as pluripotency. Distinct pluripotent states, termed naive and primed pluripotency, have been described. However, the mechanisms that control naive-primed pluripotent transition are poorly understood. Here, we perform a targeted screen for kinase inhibitors, which modulate the naive-primed pluripotent transition. We find that XMD compounds, which selectively inhibit Erk5 kinase and BET bromodomain family proteins, drive ESCs toward primed pluripotency. Using compound selectivity engineering and CRISPR/Cas9 genome editing, we reveal distinct functions for Erk5 and Brd4 in pluripotency regulation. We show that Erk5 signaling maintains ESCs in the naive state and suppresses progression toward primed pluripotency and neuroectoderm differentiation. Additionally, we identify a specialized role for Erk5 in defining ESC lineage selection, whereby Erk5 inhibits a cardiomyocyte-specific differentiation program. Our data therefore reveal multiple critical functions for Erk5 in controlling ESC identity.
Subject(s)
Mitogen-Activated Protein Kinase 7/genetics , Mouse Embryonic Stem Cells/metabolism , Nuclear Proteins/genetics , Pluripotent Stem Cells/metabolism , Transcription Factors/genetics , Animals , Benzodiazepinones/pharmacology , CRISPR-Cas Systems , Cell Differentiation , Cells, Cultured , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA (Cytosine-5-)-Methyltransferases/metabolism , Embryoid Bodies/cytology , Embryoid Bodies/metabolism , Gene Editing , Gene Expression Regulation , Mice , Mitogen-Activated Protein Kinase 7/antagonists & inhibitors , Mitogen-Activated Protein Kinase 7/metabolism , Mouse Embryonic Stem Cells/cytology , Mouse Embryonic Stem Cells/drug effects , Myocytes, Cardiac/cytology , Myocytes, Cardiac/metabolism , Nanog Homeobox Protein/genetics , Nanog Homeobox Protein/metabolism , Neural Plate/cytology , Neural Plate/metabolism , Nuclear Proteins/metabolism , Pluripotent Stem Cells/cytology , Pluripotent Stem Cells/drug effects , Protein Kinase Inhibitors/pharmacology , Signal Transduction , Transcription Factors/metabolism , DNA Methyltransferase 3BABSTRACT
Goldenhar Syndrome is characterized by craniofacial, ocular and vertebral defects secondary to abnormal development of the 1st and 2nd branchial arches and vertebrae. Other findings include cardiac and vascular abnormalities. Though these associations are known, the specific anomalies are not well defined. We present a 7-month-old infant with intermittent respiratory distress that did not improve with respiratory interventions. Echocardiogram suggested a double aortic arch. Cardiac CT angiogram confirmed a right arch and aberrant, stenotic left subclavian artery, dilation of the main pulmonary artery, and agenesis of the left thyroid lobe. Repeat echocardiograms were concerning for severely dilated coronary arteries. Given dilation, a rheumatologic workup ensued, only identifying few weakly positive autoantibodies. Further imaging demonstrated narrowing of the aorta below the renal arteries and extending into the common iliac arteries and proximal femoral arteries. Given a physical exam devoid of rheumatologic findings, only weakly positive autoantibodies, normal inflammatory markers, and presence of the coronary artery dilation, the peripheral artery narrowings were not thought to be vasculitic. This case illustrates the need to identify definitive anomalies related to Goldenhar Syndrome. Although this infant's presentation is rare, recognition of specific vascular findings will help differentiate Goldenhar Syndrome from other disease processes.
ABSTRACT
We provide an insight into the role Drosophila has played in elucidating neurophysiological perturbations associated with Parkinson's disease- (PD-) related genes. Synaptic signalling deficits are observed in motor, central, and sensory systems. Given the neurological impact of disease causing mutations within these same genes in humans the phenotypes observed in fly are of significant interest. As such we observe four unique opportunities provided by fly nervous system models of Parkinson's disease. Firstly, Drosophila models are instrumental in exploring the mechanisms of neurodegeneration, with several PD-related mutations eliciting related phenotypes including sensitivity to energy supply and vesicular deformities. These are leading to the identification of plausible cellular mechanisms, which may be specific to (dopaminergic) neurons and synapses rather than general cellular phenotypes. Secondly, models show noncell autonomous signalling within the nervous system, offering the opportunity to develop our understanding of the way pathogenic signalling propagates, resembling Braak's scheme of spreading pathology in PD. Thirdly, the models link physiological deficits to changes in synaptic structure. While the structure-function relationship is complex, the genetic tractability of Drosophila offers the chance to separate fundamental changes from downstream consequences. Finally, the strong neuronal phenotypes permit relevant first in vivo drug testing.
ABSTRACT
Noonan syndrome (NS; MIM 163950) is an autosomal dominant syndrome which is clinically diagnosed by the distinct facial features, short stature, cardiac anomalies and developmental delay. About 50% of cases are associated with gain of function mutations in PTPN11 gene which leads to activation of the RAS/mitogen-activated protein kinase signaling pathway. This is known to have a role in tumorigenesis. Despite this, only limited reports of solid tumors (Fryssira H, Leventopoulos G, Psoni S, et al. Tumor development in three patients with Noonan syndrome. Eur J Pediatr 2008;167:1025-1031; Schuettpelz LG, McDonald S, Whitesell K et al. Pilocytic astrocytoma in a child with Noonan syndrome. Pediatr Blood Cancer 2009;53:1147-1149; Sherman CB, Ali-Nazir A, Gonzales-Gomez I, et al. Primary mixed glioneuronal tumor of the central nervous system in a patient with Noonan syndrome. J Pediatr Hematol Oncol 2009;31:61-64; Sanford RA, Bowman R, Tomita T, et al. A 16 year old male with Noonan's syndrome develops progressive scoliosis and deteriorating gait. Pediatr Neurosurg 1999;30:47-52) and no prior reports of optic gliomas have been described in patients with NS. We present here a patient with NS with a PTPN11 mutation and an optic pathway pilomyxoid astrocytoma.
Subject(s)
Astrocytoma/etiology , Noonan Syndrome/complications , Optic Nerve Neoplasms/etiology , Adolescent , Humans , Male , Mutation , Noonan Syndrome/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/geneticsABSTRACT
A 14-year-old boy presented with a chronic history of atypical papular mucinosis consisting of multiple subcutaneous nodules and confluent papular skin lesions. He initially presented at age 2 years with the rapid onset of numerous subcutaneous nodular lesions that completely resolved over a period of years. Clinical and histologic evidence, together with his clinical course, were suggestive of self-healing juvenile cutaneous mucinosis (SHJCM), but a few years later, during childhood, he experienced a recurrence of the subcutaneous nodules involving the limbs, trunk, and face, in addition to new findings of multiple flesh-colored papules coalescing into plaques on his neck and back. Although his early childhood course and histologic picture were suggestive of SHJCM, the progressive nature of his disorder is not like that seen in SHJCM and appears different from other reported disorders involving cutaneous mucinosis.
Subject(s)
Scleromyxedema/diagnosis , Adolescent , Humans , Male , Remission, Spontaneous , Scleromyxedema/physiopathologyABSTRACT
Angelman syndrome (AS) is caused by a lack of expression of the maternally inherited UBE3A gene in the brain. However, about 10% of individuals with a clinical diagnosis of AS do not have an identifiable molecular defect. It is likely that most of those individuals have an AS-like syndrome that is clinically and molecularly distinct from AS. These AS-like syndromes can be broadly classified into chromosomal microdeletion and microduplication syndromes, and single-gene disorders. The microdeletion/microduplication syndromes are now easily identified by chromosomal microarray analysis and include PhelanMcDermid syndrome (chromosome 22q13.3 deletion), MBD5 haploinsufficiency syndrome (chromosome 2q23.1 deletion), and KANSL1 haploinsufficiency syndrome (chromosome 17q21.31 deletion). The single-gene disorders include PittHopkins syndrome (TCF4), Christianson syndrome (SLC9A6), MowatWilson syndrome (ZEB2), Kleefstra syndrome (EHMT1), and Rett (MECP2) syndrome. They also include disorders due to mutations in HERC2, adenylosuccinase lyase (ADSL), CDKL5, FOXG1, MECP2 (duplications), MEF2C, and ATRX. Although many of these single-gene disorders can be caused by chromosomal microdeletions resulting in haploinsufficiency of the critical gene, the individual disorders are often caused by intragenic mutations that cannot be detected by chromosomal microarray analysis. We provide an overview of the clinical features of these syndromes, comparing and contrasting them with AS, in the hope that it will help guide clinicians in the diagnostic work-up of individuals with AS-like syndromes.
Subject(s)
Angelman Syndrome/genetics , Ataxia/genetics , Epilepsy/genetics , Genetic Diseases, X-Linked/genetics , Intellectual Disability/genetics , Microcephaly/genetics , Ocular Motility Disorders/genetics , Chromosome Deletion , Humans , Ubiquitin-Protein Ligases/geneticsABSTRACT
Multifactorial inheritance is the most important model accounting for the genetic behavior of the common epilepsies. Important to this model is the concept that many cumulative or synergistic risk genes ultimately lead to a threshold effect. Sophisticated molecular testing indicates that the common epilepsies are very polygenic without evidence of any single gene having even a mild-to-modest risk effect. However, enrichment of copy number variants in cohorts of individuals with epilepsy indicates that certain structural changes in the genome can confer significant risk for epilepsy. The mechanisms whereby copy number variants confer this effect are not yet known. The study of epilepsy due to single gene defects however has helped clarify certain seizure mechanisms. For example, discoveries using animal models of SCN1A or ARX mutations implicate a predominant role for interneurons due to disturbed GABAergic function. It is hoped that future genetic and neurobiological studies will provide better insight into how multiple genes contribute to the common epilepsies.
Subject(s)
Epilepsy/genetics , Genetic Predisposition to Disease/genetics , Molecular Biology , Multifactorial Inheritance/genetics , Genetic Association Studies , Homeodomain Proteins/genetics , Humans , Mutation/genetics , NAV1.1 Voltage-Gated Sodium Channel/genetics , Transcription Factors/geneticsABSTRACT
Neonatal diabetes mellitus (NDM) is a rare metabolic disorder, affecting approximately 1 in 500,000 live births. The management of NDM is challenging, as the benefits of controlling hyperglycemia must be balanced with the risks of iatrogenic hypoglycemia. NDM occurs in both permanent and transient forms, which have been genetically and phenotypically well characterized. Herein, we present the previously unreported combination of transient NDM (TNDM) and congenital diaphragmatic hernia (CDH). In addition to reviewing the management and genetics of NDM we discuss the potential for overlapping genetic or embryologic abnormalities to explain the concurrence of CDH and NDM.