ABSTRACT
Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Autism Spectrum Disorder/genetics , Autistic Disorder/genetics , DNA Copy Number Variations/genetics , Genetic Predisposition to Disease , Humans , MutationABSTRACT
Gaucher disease type 1 (GD1) is the most common lysosomal storage disease and affects nearly 1 in 40,000 live births. In addition, it is the most common genetic disorder in the Ashkenazi Jewish population with phenotypic variation presenting in early childhood to asymptomatic nonagenarians. There have been a number of studies showing an increased risk of certain malignancies in patients, especially non- Hodgkin's lymphoma (NHL) and multiple myeloma. We describe a 66-year-old Ashkenazi Jewish male with GD1 who was first started on enzyme replacement therapy (ERT) with imiglucerase for GD1 at age 57 years, followed a year later by the diagnosis of diffuse large b-cell non-Hodgkin's lymphoma (DLBCL). He was treated with R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone, plus the monoclonal antibody rituximab), however relapsed and developed myelodysplasia necessitating an allo-stem-cell transplantation but succumbed to severe graft vs. host disease. In addition, we also describe a 38-year-old Ashkenazi Jewish male with GD1 who was diagnosed with DLBCL at age 22 years with Gaucher disease diagnosed on pre-treatment bone marrow biopsy which was confirmed by enzyme assay and genotyping. At age 24 years, he was started on ERT with imiglucerase and at age 35 years, he switched to eliglustat. He has remained in remission from the lymphoma. A meta-analysis of the literature will be elaborated upon and we will discuss the relationship of GD1 to NHL and discuss more recent information regarding lyso-GL1 and the development of NHL and multiple myeloma.
ABSTRACT
Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders without any defined uniting pathophysiology. Ca2+ signaling is emerging as a potential node in the genetic architecture of the disorder. We previously reported decreased inositol trisphosphate (IP3)-mediated Ca2+ release from the endoplasmic reticulum in several rare monogenic syndromes highly comorbid with autism - fragile X and tuberous sclerosis types 1 and 2 syndromes. We now extend those findings to a cohort of subjects with sporadic ASD without any known mutations. We developed and applied a high throughput Fluorometric Imaging Plate Reader (FLIPR) assay to monitor agonist-evoked Ca2+ signals in human primary skin fibroblasts. Our results indicate that IP3 -mediated Ca2+ release from the endoplasmic reticulum in response to activation of purinergic receptors is significantly depressed in subjects with sporadic as well as rare syndromic forms of ASD. We propose that deficits in IP3-mediated Ca2+ signaling represent a convergent hub function shared across the spectrum of autistic disorders - whether caused by rare highly penetrant mutations or sporadic forms - and holds promise as a biomarker for diagnosis and novel drug discovery.
Subject(s)
Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/metabolism , Calcium Signaling , Transcriptome , Adenosine Triphosphate/metabolism , Adolescent , Adult , Autism Spectrum Disorder/psychology , Calcium/metabolism , Case-Control Studies , Child , Child, Preschool , Female , Fibroblasts/metabolism , Gene Expression Profiling , High-Throughput Screening Assays , Humans , Male , Molecular Imaging , ROC Curve , Young AdultABSTRACT
BACKGROUND: Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life; the only available potential treatment has been hematopoietic stem cell transplantation, which is associated with high morbidity and mortality in this population. The study objective was to evaluate safety and efficacy (including survival) of enzyme replacement with sebelipase alfa in infants with lysosomal acid lipase deficiency. This is an ongoing multicenter, open-label, phase 2/3 study conducted in nine countries. The study enrolled infants with growth failure prior to 6 months of age with rapidly progressive lysosomal acid lipase deficiency; they received once-weekly doses of sebelipase alfa initiated at 0.35 mg/kg with intrapatient dose escalation up to 5 mg/kg. The main outcome of interest is survival to 12 months and survival beyond 24 months of age. RESULTS: Nine patients were enrolled; median age at baseline was 3.0 months (range 1.1-5.8 months). Sixty-seven percent (exact 95% CI 30%-93%) of sebelipase alfa-treated infants survived to 12 months of age compared with 0% (exact 95% CI 0%-16%) for a historical control group (n = 21). Patients who survived to age 12 months exhibited improvements in weight-for-age, reductions in markers of liver dysfunction and hepatosplenomegaly, and improvements in anemia and gastrointestinal symptoms. Three deaths occurred early (first few months of life), two patients died because of advanced disease, and a third patient died following complications of non-protocol-specified abdominal paracentesis. A fourth death occurred at 15 months of age and was related to other clinical conditions. The five surviving patients have survived to age ≥24 months with continued sebelipase alfa treatment; all have displayed marked improvement in growth parameters and liver function. Serious adverse events considered related to sebelipase alfa were reported in one of the nine infants (infusion reaction: tachycardia, pallor, chills, and pyrexia). Most infusion-associated reactions were mild and non-serious. CONCLUSION: Sebelipase alfa markedly improved survival with substantial clinically meaningful improvements in growth and other key disease manifestations in infants with rapidly progressive lysosomal acid lipase deficiency TRIAL REGISTRATION: Clinicaltrials.gov NCT01371825 . Registered 9 June 2011.
Subject(s)
Sterol Esterase/therapeutic use , Wolman Disease/drug therapy , Female , Humans , Infant , Male , Survival Analysis , Wolman Disease/mortality , Wolman DiseaseABSTRACT
PURPOSE: The purpose of this study was to enhance understanding of lysosomal acid lipase deficiency (LALD) in infancy. METHODS: Investigators reviewed medical records of infants with LALD and summarized data for the overall population and for patients with and without early growth failure (GF). Kaplan-Meier survival analyses were conducted for the overall population and for treated and untreated patients. RESULTS: Records for 35 patients, 26 with early GF, were analyzed. Prominent symptom manifestations included vomiting, diarrhea, and steatorrhea. Median age at death was 3.7 months; estimated probability of survival past age 12 months was 0.114 (95% confidence interval (CI): 0.009-0.220). Among patients with early GF, median age at death was 3.5 months; estimated probability of survival past age 12 months was 0.038 (95% CI: 0.000-0.112). Treated patients (hematopoietic stem cell transplant (HSCT), n = 9; HSCT and liver transplant, n = 1) in the overall population and the early GF subset survived longer than untreated patients, but survival was still poor (median age at death, 8.6 months). CONCLUSIONS: These data confirm and expand earlier insights on the progression and course of LALD presenting in infancy. Despite variations in the nature, onset, and severity of clinical manifestations, and treatment attempts, clinical outcome was poor.Genet Med 18 5, 452-458.
Subject(s)
Hematopoietic Stem Cell Transplantation , Sterol Esterase/genetics , Wolman Disease/genetics , Wolman Disease/therapy , Disease Progression , Female , Humans , Infant , Infant, Newborn , Kaplan-Meier Estimate , Male , Treatment Outcome , Wolman Disease/mortality , Wolman Disease/pathology , Wolman DiseaseABSTRACT
Polymorphisms that alter serotonin transporter SERT expression and functionality increase the risks for autism and psychiatric traits. Here, we investigate how SERT controls serotonin signaling in developing CNS in mice. SERT is transiently expressed in specific sets of glutamatergic neurons and uptakes extrasynaptic serotonin during perinatal CNS development. We show that SERT expression in glutamatergic thalamocortical axons (TCAs) dictates sensory map architecture. Knockout of SERT in TCAs causes lasting alterations in TCA patterning, spatial organizations of cortical neurons, and dendritic arborization in sensory cortex. Pharmacological reduction of serotonin synthesis during the first postnatal week rescues sensory maps in SERTGluΔ mice. Furthermore, knockdown of SERT expression in serotonin-producing neurons does not impair barrel maps. We propose that spatiotemporal SERT expression in non-serotonin-producing neurons represents a determinant in early life genetic programming of cortical circuits. Perturbing this SERT function could be involved in the origin of sensory and cognitive deficits associated with neurodevelopmental disorders.
ABSTRACT
Autism spectrum disorder (ASD) is a syndrome that affects normal brain development and is characterized by impaired social interaction as well as verbal and non-verbal communication and by repetitive, stereotypic behavior. ASD is a complex disorder arising from a combination of multiple genetic and environmental factors that are independent from racial, ethnic and socioeconomical status. The high heritability of ASD suggests a strong genetic basis for the disorder. Furthermore, a mounting body of evidence implies a role of various ion channel gene defects (channelopathies) in the pathogenesis of autism. Indeed, recent genome-wide association, and whole exome- and whole-genome resequencing studies linked polymorphisms and rare variants in calcium, sodium and potassium channels and their subunits with susceptibility to ASD, much as they do with bipolar disorder, schizophrenia and other neuropsychiatric disorders. Moreover, animal models with these genetic variations recapitulate endophenotypes considered to be correlates of autistic behavior seen in patients. An ion flux across the membrane regulates a variety of cell functions, from generation of action potentials to gene expression and cell morphology, thus it is not surprising that channelopathies have profound effects on brain functions. In the present work, we summarize existing evidence for the role of ion channel gene defects in the pathogenesis of autism with a focus on calcium signaling and its downstream effects.
ABSTRACT
The calcium ion is one of the most versatile, ancient, and universal of biological signaling molecules, known to regulate physiological systems at every level from membrane potential and ion transporters to kinases and transcription factors. Disruptions of intracellular calcium homeostasis underlie a host of emerging diseases, the calciumopathies. Cytosolic calcium signals originate either as extracellular calcium enters through plasma membrane ion channels or from the release of an intracellular store in the endoplasmic reticulum (ER) via inositol triphosphate receptor and ryanodine receptor channels. Therefore, to a large extent, calciumopathies represent a subset of the channelopathies, but include regulatory pathways and the mitochondria, the major intracellular calcium repository that dynamically participates with the ER stores in calcium signaling, thereby integrating cellular energy metabolism into these pathways, a process of emerging importance in the analysis of the neurodegenerative and neuropsychiatric diseases. Many of the calciumopathies are common complex polygenic diseases, but leads to their understanding come most prominently from rare monogenic channelopathy paradigms. Monogenic forms of common neuronal disease phenotypes-such as seizures, ataxia, and migraine-produce a constitutionally hyperexcitable tissue that is susceptible to periodic decompensations. The gene families and genetic lesions underlying familial hemiplegic migraine, FHM1/CACNA1A, FHM2/ATP1A2, and FHM3/SCN1A, and monogenic mitochondrial migraine syndromes, provide a robust platform from which genes, such as CACNA1C, which encodes the calcium channel mutated in Timothy syndrome, can be evaluated for their role in autism and bipolar disease.
Subject(s)
Autistic Disorder/genetics , Autistic Disorder/metabolism , Calcium Signaling/genetics , Migraine Disorders/genetics , Migraine Disorders/metabolism , Seizures/genetics , Seizures/metabolism , Autistic Disorder/diagnosis , Central Nervous System Diseases/genetics , Central Nervous System Diseases/metabolism , Central Nervous System Diseases/pathology , Humans , Migraine Disorders/diagnosis , Seizures/diagnosisSubject(s)
Migraine Disorders/etiology , Anticonvulsants/therapeutic use , Antidepressive Agents/therapeutic use , Antihypertensive Agents/therapeutic use , Cortical Spreading Depression/drug effects , Humans , Migraine Disorders/drug therapy , Migraine Disorders/physiopathology , Migraine with Aura/drug therapy , Migraine with Aura/etiology , Migraine with Aura/physiopathology , Trigeminal Nerve/drug effects , Trigeminal Nerve/physiopathologyABSTRACT
Although SCN1A, the gene encoding the neuronal voltage-gated sodium channel, type 1A, is a well-recognized target of mutations underlying a spectrum of epilepsy syndromes, and lies within an extended 12-Mb disease-associated haplotype at the familial hemiplegic migraine-3 locus, it remains to be confirmed that mutations within this gene itself cause syndromes that include migraine phenotypes. The novel T1174S missense mutation of this gene was detected segregating in a family with a heterozygous female child who presented with myoclonus and an abnormal electroencephalogram, and in her heterozygous mother, who had an ataxic migraine syndrome similar to that of her own mother. This three-generation family exhibits the broad phenotypic spectrum of the dominant neuronal hyperexcitability syndromes produced by even a given allele of this sodium channel gene. It also exhibits the second allele of this sodium channel gene associated with a migraine syndrome similar to those caused at the two other familial hemiplegic migraine loci, confirming that this gene itself, not some linked gene, is the familial hemiplegic migraine-3 locus.
Subject(s)
Family Health , Migraine with Aura/genetics , Mutation, Missense/genetics , Nerve Tissue Proteins/genetics , Seizures/genetics , Sodium Channels/genetics , Adult , Child, Preschool , DNA Mutational Analysis/methods , Female , Humans , Male , Migraine with Aura/complications , NAV1.1 Voltage-Gated Sodium Channel , Neurologic Examination/methods , Seizures/complications , Serine/genetics , Threonine/geneticsABSTRACT
Stress response is a fundamental form of behavioral and physiological plasticity. Here we describe how serotonin (5HT) governs stress behavior by regulating DAF-2 insulin/IGF-1 receptor signaling to the DAF-16/FOXO transcription factor at the nexus of development, metabolism, immunity, and stress responses in C. elegans. Serotonin-deficient tph-1 mutants, like daf-2 mutants, exhibit DAF-16 nuclear accumulation and constitutive physiological stress states. Exogenous 5HT and fluoxetine (Prozac) prevented DAF-16 nuclear accumulation in wild-type animals under stresses. Genetic analyses imply that DAF-2 is a downstream target of 5HT signaling and that distinct serotonergic neurons act through distinct 5HT receptors to influence distinct DAF-16-mediated stress responses. We suggest that modulation of FOXO by 5HT represents an ancient feature of stress physiology and that the C. elegans is a genetically tractable model that can be used to delineate the molecular mechanisms and drug actions linking 5HT, neuroendocrine signaling, immunity, and mitochondrial function.
Subject(s)
Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/metabolism , Neurons/metabolism , Serotonin/metabolism , Signal Transduction , Transcription Factors/metabolism , Active Transport, Cell Nucleus/genetics , Animals , Animals, Genetically Modified , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/genetics , Cell Nucleus/genetics , Cell Nucleus/metabolism , Fluoxetine/pharmacology , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Models, Animal , Mutation , Neurosecretory Systems/metabolism , Receptor, IGF Type 1/genetics , Receptor, IGF Type 1/immunology , Receptor, Insulin/genetics , Receptor, Insulin/metabolism , Serotonin/genetics , Selective Serotonin Reuptake Inhibitors/pharmacology , Signal Transduction/drug effects , Transcription Factors/geneticsSubject(s)
Hemiplegia/genetics , Migraine with Aura/genetics , Mutation, Missense , Point Mutation , Sodium-Potassium-Exchanging ATPase/physiology , Amino Acid Substitution , Animals , Brain/enzymology , Humans , Ion Transport/genetics , Isoenzymes/chemistry , Isoenzymes/genetics , Isoenzymes/physiology , Mammals/metabolism , Mice , Mice, Knockout , Migraine with Aura/classification , Models, Molecular , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/physiology , Protein Conformation , Sodium-Potassium-Exchanging ATPase/chemistry , Sodium-Potassium-Exchanging ATPase/geneticsABSTRACT
Scores of monogenic Mendelian ion channel diseases serve to anchor the pathophysiology of the channelopathies, but there are also now clear examples of environmental, pharmacogenetic, and acquired channelopathy mechanisms. The cardinal feature of heritable ion channel disease is a periodic disturbance of rhythmic function in constitutionally hyperexcitable tissue. While the complexity of neuroanatomy obscures functional analysis of mutations causing monogenic seizure, ataxia, or migraine syndromes, extrapolation from the cardiac (Long QT [LQT]) and muscle (Periodic Paralysis) channelopathy syndromes provides a simplified predictive framework of molecular pathology: electrically stabilizing potassium ion (K(+)) and chloride ion (Cl(-)) channels, likely having lesions that diminish their current, and excitatory Na(+) channels, likely having gain-of-function lesions. The voltage-gated calcium channel gene family that contains CACNA1C, the newest LQT locus, causing Timothy Syndrome with a phenotype including autism, has proven to be particularly informative for its members' ability to tie the various central nervous system (CNS) phenotypes together in an interpretable fashion, now including direct extension to the classically multigenic neuropsychiatric phenotypes. Features of a promising ion channel candidate gene arise from its broad locus, gene family, nature of alleles, physiology and pharmacology, tissue expression profile, and phenotype in model organisms. KCNN3 is explored as a paradigm to consider.
Subject(s)
Ion Channels/physiology , Mental Disorders/physiopathology , Nervous System Diseases/physiopathology , Central Nervous System/physiopathology , Humans , PhenotypeABSTRACT
A number of missense mutations in the Na,K-ATPase alpha2 catalytic subunit have been identified in familial hemiplegic migraine with aura. Two alleles (L764P and W887R) showed loss-of-function, whereas a third (T345A) is fully functional but with altered Na,K-ATPase kinetics. This study describes two additional mutants, R689Q and M731T, originally identified by Vanmolkot et al. [Vanmolkot, K. R., et al. (2003) Ann. Neurol. 54, 360-366], which we show here to also be functional and kinetically altered. Both mutants have reduced catalytic turnover and increased apparent affinity for extracellular K(+). For both R689Q and M731T, sensitivity to vanadate inhibition is decreased, suggesting that the steady-state E(1) <==> E(2) poise of the enzyme is shifted toward E(1). Whereas the K'(ATP) is not affected by the R689Q replacement, the M731T mutant has an increase in apparent affinity for ATP. Analysis of the structural changes effected by T345A, R689Q, and M731T mutations, based on homologous replacements in the known crystal structure of the sarcoplasmic reticulum Ca-ATPase, provides insights into the molecular bases for the kinetic alterations. It is suggested that the disease phenotype is the consequence of lowered molecular activity of the alpha2 pump isoform due to either decreased K(+) affinity (T345A) or catalytic turnover (R689Q and M731T), thus causing a delay in extracellular K(+) clearance and/or altered localized Ca(2+) handling/signaling secondary to reduced activity in colocalized Na(+)/Ca(2+) exchange.
Subject(s)
Hemiplegia/genetics , Hemiplegia/metabolism , Migraine Disorders/genetics , Migraine Disorders/metabolism , Sodium-Potassium-Exchanging ATPase/genetics , Sodium-Potassium-Exchanging ATPase/metabolism , Adenosine Triphosphate/metabolism , Alleles , Animals , HeLa Cells , Humans , In Vitro Techniques , Kinetics , Models, Molecular , Mutation, Missense , Phenotype , Potassium/metabolism , Rats , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Sodium/metabolism , Sodium-Potassium-Exchanging ATPase/chemistry , TransfectionABSTRACT
A number of missense mutations in the ATP1A2 gene, which encodes the Na,K-ATPase alpha2 subunit, have been identified in familial hemiplegic migraine with aura. Loss of function and haploinsufficiency have been the suggested mechanisms in mutants for which functional analysis has been reported. This paper describes a kinetic analysis of mutant T345A, recently identified in a detailed genetic analysis of a large Finnish family (Kaunisto, M. A., Harno, H., Vanmolkot, K. R., Gargus, J. J., Sun, G., Hamalainen, E., Liukkonen, E., Kallela, M., van den Maagdenberg, A. M., Frants, R. R., Farkkila, M., Palotie, A., and Wessman, M. (2004) Neurogenetics 5, 141-146). Introducing T345A into the conserved rat alpha2 enzyme does not alter cell growth or catalytic turnover but causes a substantial decrease in apparent K+ affinity (2-fold increase in K0.5(K+)). In view of the location of Thr-345 in the cytoplasmic stalk domain adjacent to transmembrane segment 4, the 2-fold increase in K0.5(K+) is probably due to T345A replacement altering K+ occlusion/deocclusion. Faster K+ deocclusion of the mutant via the E2(K) + ATP --> E1.ATP + K+ partial reaction is evidenced in (i) a marked increase (300%) in K+ stimulation of Na-ATPase at micromolar ATP, (ii) a 4-fold decrease in KATP, and (iii) only a modest increase (approximately 3-fold) in I50 for vanadate, which was used as a probe of the steady state E1/E2 conformational equilibrium. We suggest that the decreased apparent K+ affinity is the basis for a reduced rate of extracellular K+ removal, which delays the recovery phase of nerve impulse transmission in the central nervous system and, thereby, the clinical picture of migraine with aura. This is the first demonstration of a mutation that leads to a disease associated with a kinetically altered but fully functional Na,K-ATPase, refining the molecular mechanism of pathogenesis in familial hemiplegic migraine.
Subject(s)
Hemiplegia/genetics , Migraine Disorders/genetics , Mutation, Missense , Sodium-Potassium-Exchanging ATPase/genetics , Amino Acid Substitution , Animals , Cell Line , HeLa Cells , Humans , Kinetics , Rats , Sodium-Potassium-Exchanging ATPase/metabolism , TransfectionABSTRACT
Small conductance Ca2+-activated K+ channels, products of the SK1-SK3 genes, regulate membrane excitability both within and outside the nervous system. We report the characterization of a SK3 variant (SK3-1C) that differs from SK3 by utilizing an alternative first exon (exon 1C) in place of exon 1A used by SK3, but is otherwise identical to SK3. Quantitative RT-PCR detected abundant expression of SK3-1C transcripts in human lymphoid tissues, skeletal muscle, trachea, and salivary gland but not the nervous system. SK3-1C did not produce functional channels when expressed alone in mammalian cells, but suppressed SK1, SK2, SK3, and IKCa1 channels, but not BKCa or KV channels. Confocal microscopy revealed that SK3-1C sequestered SK3 protein intracellularly. Dominant-inhibitory activity of SK3-1C was not due to a nonspecific calmodulin sponge effect since overexpression of calmodulin did not reverse SK3-1C-mediated intracellular trapping of SK3 protein, and calmodulin-Ca2+-dependent inactivation of CaV channels was not affected by SK3-1C overexpression. Deletion analysis identified a dominant-inhibitory segment in the SK3-1C C terminus that resembles tetramerization-coiled-coiled domains reported to enhance tetramer stability and selectivity of multimerization of many K+ channels. SK3-1C may therefore suppress calmodulin-gated SKCa/IKCa channels by trapping these channel proteins intracellularly via subunit interactions mediated by the dominant-inhibitory segment and thereby reduce functional channel expression on the cell surface. Such family-wide dominant-negative suppression by SK3-1C provides a powerful mechanism to titrate membrane excitability and is a useful approach to define the functional in vivo role of these channels in diverse tissues by their targeted silencing.
Subject(s)
Potassium Channels/genetics , Potassium Channels/metabolism , Alternative Splicing , Amino Acid Sequence , Animals , Base Sequence , Calmodulin/metabolism , Cell Line , DNA, Complementary/metabolism , Exons , Gene Deletion , Gene Silencing , Genes, Dominant , Green Fluorescent Proteins , Hematopoietic Stem Cells/metabolism , Humans , Intermediate-Conductance Calcium-Activated Potassium Channels , Introns , Luminescent Proteins/metabolism , Microscopy, Confocal , Models, Genetic , Molecular Sequence Data , Muscles/metabolism , PC12 Cells , Patch-Clamp Techniques , Potassium Channels, Calcium-Activated/genetics , Potassium Channels, Calcium-Activated/physiology , Protein Isoforms , Protein Structure, Tertiary , RNA, Messenger/metabolism , Rats , Reverse Transcriptase Polymerase Chain Reaction , Sequence Homology, Amino Acid , Signal Transduction , Small-Conductance Calcium-Activated Potassium Channels , Tissue Distribution , TransfectionABSTRACT
A random retrospective chart review was conducted to document serum carnitine levels on 100 children with autism. Concurrently drawn serum pyruvate, lactate, ammonia, and alanine levels were also available in many of these children. Values of free and total carnitine (p < 0.001), and pyruvate (p = 0.006) were significantly reduced while ammonia and alanine levels were considerably elevated (p < 0.001) in our autistic subjects. The relative carnitine deficiency in these patients, accompanied by slight elevations in lactate and significant elevations in alanine and ammonia levels, is suggestive of mild mitochondrial dysfunction. It is hypothesized that a mitochondrial defect may be the origin of the carnitine deficiency in these autistic children.
Subject(s)
Autistic Disorder/metabolism , Carnitine/deficiency , Adolescent , Alanine/blood , Autistic Disorder/diagnosis , Carnitine/blood , Child , Child, Preschool , Diagnostic and Statistical Manual of Mental Disorders , Female , Humans , Hyperammonemia/blood , Lactic Acid/blood , Male , Pyruvic Acid/blood , Retrospective StudiesABSTRACT
Iron-sulfur proteins participate in a wide range of biochemical processes, including many that are central to mitochondrial electron transfer and energy metabolism. Mutations in two such proteins, frataxin and ABCB7, cause Friedreich ataxia and X-linked sideroblastic anemia with ataxia, respectively, rendering other participants in this pathway functional candidates for hereditary ataxia syndromes. Recently frataxin was shown to have an identical phylogenetic distribution with two genes and was most likely specifically involved in the same sub-process in iron-sulfur cluster assembly as one gene, designated hscB, in bacteria. To set the stage for an analysis of the potential role of this candidate gene in human disease, we defined the human HscB cDNA, its genomic locus, and its pattern of expression in normal human tissues. The isolated human HscB cDNA spans 785 bp and encodes a conserved 235-amino-acid protein, including a putative mitochondrial import leader. The HscB gene is found at chromosome 22q11-12 and is composed of six exons and five introns. Northern blot analyses of RNA from adult and fetal tissues defined a pattern of expression in mitochondria-rich tissues similar to that of frataxin, an expression pattern compatible with its implied role in mitochondrial energetics and related disease phenotypes.
Subject(s)
Ataxia/genetics , Escherichia coli Proteins , Heat-Shock Proteins/genetics , Iron/metabolism , Molecular Chaperones/genetics , Sulfur/metabolism , Amino Acid Sequence , Ataxia/metabolism , Base Sequence , Databases, Genetic , Escherichia coli/genetics , Genetic Predisposition to Disease , Heat-Shock Proteins/metabolism , Molecular Chaperones/metabolism , Molecular Sequence Data , Sequence Analysis, DNAABSTRACT
Two autistic children with a chromosome 15q11-q13 inverted duplication are presented. Both had uneventful perinatal courses, normal electroencephalogram and magnetic resonance imaging scans, moderate motor delay, lethargy, severe hypotonia, and modest lactic acidosis. Both had muscle mitochondrial enzyme assays that showed a pronounced mitochondrial hyperproliferation and a partial respiratory chain block most parsimoniously placed at the level of complex III, suggesting candidate gene loci for autism within the critical region may affect pathways influencing mitochondrial function.
Subject(s)
Autistic Disorder/genetics , Autistic Disorder/physiopathology , Chromosomes, Human, Pair 15/genetics , DNA-Binding Proteins/genetics , Gene Duplication , Mitochondria, Muscle/physiology , Nuclear Proteins/genetics , Child, Preschool , Female , Fibroblasts/metabolism , Humans , Male , Mitochondria, Muscle/enzymology , Mitochondria, Muscle/genetics , Muscle, Skeletal/enzymology , NADH Dehydrogenase/metabolism , Skin/metabolismABSTRACT
Ion channels are a large family of >400 related proteins representing >1% of our genetic endowment; however, ion-channel diseases reflect a relatively new category of inborn error. They were first recognized in 1989, with the discovery of cystic fibrosis transmembrane conductance regulator, and rapidly advanced as positional and functional studies converged in the dissection of components of the action potential of excitable tissues. Although it remains true that diseases of excitable tissue still most clearly illustrate this family of disease, ion-channel disorders now cover the gamut of medical disciplines, causing significant pathology in virtually every organ system, producing a surprising range of often unanticipated symptoms, and providing valuable targets for pharmacological intervention. Many of the features shared among the monogenic ion-channel diseases provide a general framework for formulating a foundation for considering their intrinsically promising role in polygenic disease. Since an increasingly important approach to the identification of genes underlying polygenic disease is to identify "functional candidates" within a critical region and to test their disease association, it becomes increasingly important to appreciate how these ion-channel mechanisms can be implicated in pathophysiology.