ABSTRACT
The DEAD/DEAH box RNA helicases are a superfamily of proteins involved in the processing and transportation of RNA within the cell. A growing literature supports this family of proteins as contributing to various types of human disorders from neurodevelopmental disorders to syndromes with multiple congenital anomalies. This article presents a cohort of nine unrelated individuals with de novo missense alterations in DDX23 (Dead-Box Helicase 23). The gene is ubiquitously expressed and functions in RNA splicing, maintenance of genome stability, and the sensing of double-stranded RNA. Our cohort of patients, gathered through GeneMatcher, exhibited features including tone abnormalities, global developmental delay, facial dysmorphism, autism spectrum disorder, and seizures. Additionally, there were a variety of other findings in the skeletal, renal, ocular, and cardiac systems. The missense alterations all occurred within a highly conserved RecA-like domain of the protein, and are located within or proximal to the DEAD box sequence. The individuals presented in this article provide evidence of a syndrome related to alterations in DDX23 characterized predominantly by atypical neurodevelopment.
Subject(s)
Autism Spectrum Disorder/genetics , DEAD-box RNA Helicases/genetics , Intellectual Disability/genetics , Neurodevelopmental Disorders/genetics , Autism Spectrum Disorder/complications , Autism Spectrum Disorder/epidemiology , Autism Spectrum Disorder/physiopathology , Child , Child, Preschool , Female , Genetic Predisposition to Disease , Genomic Instability/genetics , Humans , Infant , Infant, Newborn , Intellectual Disability/complications , Intellectual Disability/epidemiology , Intellectual Disability/physiopathology , Male , Mutation, Missense/genetics , Neurodevelopmental Disorders/complications , Neurodevelopmental Disorders/epidemiology , Neurodevelopmental Disorders/physiopathology , RNA Splicing/genetics , RNA, Double-Stranded/genetics , Seizures/complications , Seizures/genetics , Seizures/physiopathologyABSTRACT
Thousand and one amino-acid kinase 1 (TAOK1) is a MAP3K protein kinase, regulating different mitogen-activated protein kinase pathways, thereby modulating a multitude of processes in the cell. Given the recent finding of TAOK1 involvement in neurodevelopmental disorders (NDDs), we investigated the role of TAOK1 in neuronal function and collected a cohort of 23 individuals with mostly de novo variants in TAOK1 to further define the associated NDD. Here, we provide evidence for an important role for TAOK1 in neuronal function, showing that altered TAOK1 expression levels in the embryonic mouse brain affect neural migration in vivo, as well as neuronal maturation in vitro. The molecular spectrum of the identified TAOK1 variants comprises largely truncating and nonsense variants, but also missense variants, for which we provide evidence that they can have a loss of function or dominant-negative effect on TAOK1, expanding the potential underlying causative mechanisms resulting in NDD. Taken together, our data indicate that TAOK1 activity needs to be properly controlled for normal neuronal function and that TAOK1 dysregulation leads to a neurodevelopmental disorder mainly comprising similar facial features, developmental delay/intellectual disability and/or variable learning or behavioral problems, muscular hypotonia, infant feeding difficulties, and growth problems.
Subject(s)
Intellectual Disability , Neurodevelopmental Disorders , Amino Acids , Animals , Humans , Intellectual Disability/genetics , MAP Kinase Signaling System , Mice , Muscle Hypotonia , Neurodevelopmental Disorders/geneticsABSTRACT
Chronic inflammation is a hallmark of obesity and is linked to the development of numerous diseases. The activation of toll-like receptor 4 (TLR4) by long-chain saturated fatty acids (lcSFAs) is an important process in understanding how obesity initiates inflammation. While experimental evidence supports an important role for TLR4 in obesity-induced inflammation in vivo, via a mechanism thought to involve direct binding to and activation of TLR4 by lcSFAs, several lines of evidence argue against lcSFAs being direct TLR4 agonists. Using multiple orthogonal approaches, we herein provide evidence that while loss-of-function models confirm that TLR4 does, indeed, regulate lcSFA-induced inflammation, TLR4 is not a receptor for lcSFAs. Rather, we show that TLR4-dependent priming alters cellular metabolism, gene expression, lipid metabolic pathways, and membrane lipid composition, changes that are necessary for lcSFA-induced inflammation. These results reconcile previous discordant observations and challenge the prevailing view of TLR4's role in initiating obesity-induced inflammation.
Subject(s)
Inflammation/metabolism , Macrophages/metabolism , Obesity/metabolism , Palmitates/metabolism , Toll-Like Receptor 4/metabolism , Animals , Humans , Inflammation/etiology , Macrophages/cytology , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Obesity/complications , Signal TransductionABSTRACT
Exome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in vitro, and in vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation.
Subject(s)
Abnormalities, Multiple/genetics , Craniofacial Abnormalities/genetics , Genetic Heterogeneity , Muscular Atrophy/genetics , Mutation, Missense , Neurodevelopmental Disorders/genetics , Noonan Syndrome/genetics , cdc42 GTP-Binding Protein/genetics , Abnormalities, Multiple/metabolism , Abnormalities, Multiple/pathology , Adolescent , Adult , Child , Child, Preschool , Craniofacial Abnormalities/metabolism , Craniofacial Abnormalities/pathology , Female , Gene Expression , Humans , Infant , Male , Models, Molecular , Muscular Atrophy/metabolism , Muscular Atrophy/pathology , Neurodevelopmental Disorders/metabolism , Neurodevelopmental Disorders/pathology , Noonan Syndrome/metabolism , Noonan Syndrome/pathology , Phenotype , Protein Structure, Secondary , Severity of Illness Index , cdc42 GTP-Binding Protein/chemistry , cdc42 GTP-Binding Protein/metabolismABSTRACT
OBJECTIVE: Parental obesity can induce metabolic phenotypes in offspring independent of the inherited DNA sequence. Here we asked whether such non-genetic acquired metabolic traits can be passed on to a second generation that has never been exposed to obesity, even as germ cells. METHODS: We examined the F1, F2, and F3 a/a offspring derived from F0 matings of obese prediabetic A (vy) /a sires and lean a/a dams. After F0, only lean a/a mice were used for breeding. RESULTS: We found that F1 sons of obese founder males exhibited defects in glucose and lipid metabolism, but only upon a post-weaning dietary challenge. F1 males transmitted these defects to their own male progeny (F2) in the absence of the dietary challenge, but the phenotype was largely attenuated by F3. The sperm of F1 males exhibited changes in the abundance of several small RNA species, including the recently reported diet-responsive tRNA-derived fragments. CONCLUSIONS: These data indicate that induced metabolic phenotypes may be propagated for a generation beyond any direct exposure to an inducing factor. This non-genetic inheritance likely occurs via the actions of sperm noncoding RNA.
ABSTRACT
Intellectual disability (ID) is estimated to affect 1-3% of the general population and is a common reason for referrals to pediatric and adult geneticists, as well as neurologists. There are many genetic and non-genetic causes of ID; X-linked forms are identifiable through their characteristic inheritance pattern. Current testing methods have been able to identify over 100 genes on the X chromosome responsible for X-linked intellectual disability (XLID) syndromes. MED12 [MIM *300188] (mediator complex subunit 12) mutations have been linked to numerous XLID syndromes, including Lujan, FG, and Ohdo, and MED12 is included in many XLID panels. MED12 is located at Xq13.1 and its product has roles in transcriptional activation and repression. We describe two affected male siblings and their unaffected mother with a novel missense mutation in MED12, c.4147G>A (p.Ala1383Thr). The siblings share some features of Ohdo syndrome, including feeding difficulties, microcephaly, and speech delay. However, additional attributes such as hypertonia, eosinophilic esophagitis, penile chordee, and particular facial dysmorphisms depart sufficiently from individuals previously described such that they appear to represent a new and expanded phenotype. This case lends credence to the evolving theory that the subtypes of Ohdo, and perhaps other MED12 disorders, reflect a spectrum of characteristics, rather than distinct syndromes. As XLID panel testing and whole exome sequencing (WES) becomes a standard of care for affected males, further MED12 mutations will broaden the phenotype of these intriguing disorders and challenge clinicians to rethink the current diagnostic boundaries.
Subject(s)
Abnormalities, Multiple/genetics , Blepharophimosis/genetics , Blepharoptosis/genetics , Craniofacial Abnormalities/genetics , Eosinophilic Esophagitis/genetics , Genes, X-Linked/genetics , Heart Defects, Congenital/genetics , Intellectual Disability/genetics , Mediator Complex/genetics , Muscle Hypertonia/genetics , Muscular Atrophy/genetics , Mutation, Missense/genetics , Abnormalities, Multiple/pathology , Adult , Blepharophimosis/pathology , Blepharoptosis/pathology , Child , Craniofacial Abnormalities/pathology , Eosinophilic Esophagitis/pathology , Heart Defects, Congenital/pathology , Humans , Infant , Intellectual Disability/pathology , Male , Muscle Hypertonia/pathology , Muscular Atrophy/pathology , Phenotype , PrognosisABSTRACT
Allan-Herndon-Dudley syndrome (AHDS, MIM 300523) is an X-linked neurodegenerative disorder characterized by intellectual disability, severe hypotonia, diminished muscle mass, and progressive spastic paraplegia. All affected males have pathognomonic thyroid profiles with an elevated T3 , low-normal free T4 , and normal TSH. Mutations in the monocarboxylate transporter 8 (MCT8) gene, SLC16A2, have been found to be causative. Here, we describe a proband whose extensive evaluation and ultimate diagnosis of AHDS unmasked three previously undiagnosed generations of affected individuals in one family. This case illustrates the need for clinicians to consider obtaining full thyroid studies on individuals with the non-specific findings of severe hypotonia, failure to thrive, and gross motor delay.
Subject(s)
Mental Retardation, X-Linked/genetics , Muscle Hypotonia/genetics , Muscular Atrophy/genetics , Paraplegia/genetics , Triiodothyronine/blood , Abnormalities, Multiple , Humans , Infant , Intellectual Disability/blood , Intellectual Disability/genetics , Intellectual Disability/physiopathology , Male , Mental Retardation, X-Linked/blood , Mental Retardation, X-Linked/physiopathology , Muscle Hypotonia/blood , Muscle Hypotonia/physiopathology , Muscular Atrophy/blood , Muscular Atrophy/physiopathology , Mutation , Paraplegia/blood , Paraplegia/physiopathology , Pedigree , Triiodothyronine/geneticsABSTRACT
Alterations in the immune cell profile and the induction of inflammation within adipose tissue are a hallmark of obesity in mice and humans. Dual-specificity phosphatase 2 (DUSP2) is widely expressed within the immune system and plays a key role promoting immune and inflammatory responses dependent on mitogen-activated protein kinase (MAPK) activity. We hypothesised that the absence of DUSP2 would protect mice against obesity-associated inflammation and insulin resistance. Accordingly, male and female littermate mice that are either wild-type (wt) or homozygous for a germ-line null mutation of the dusp2 gene (dusp2-/-) were fed either a standard chow diet (SCD) or high fat diet (HFD) for 12 weeks prior to metabolic phenotyping. Compared with mice fed the SCD, all mice consuming the HFD became obese, developed glucose intolerance and insulin resistance, and displayed increased macrophage recruitment and markers of inflammation in epididymal white adipose tissue. The absence of DUSP2, however, had no effect on the development of obesity or adipose tissue inflammation. Whole body insulin sensitivity in male mice was unaffected by an absence of DUSP2 in response to either the SCD or HFD; however, HFD-induced insulin resistance was slightly, but significantly, reduced in female dusp2-/- mice. In conclusion, DUSP2 plays no role in regulating obesity-associated inflammation and only a minor role in controlling insulin sensitivity following HFD in female, but not male, mice. These data indicate that rather than DUSP2 being a pan regulator of MAPK dependent immune cell mediated inflammation, it appears to differentially regulate inflammatory responses that have a MAPK component.
Subject(s)
Dual Specificity Phosphatase 2/genetics , Glucose Intolerance/genetics , Inflammation/genetics , Insulin Resistance/genetics , Obesity/genetics , Adipose Tissue/metabolism , Animals , Blood Glucose/metabolism , Diet, High-Fat , Dual Specificity Phosphatase 2/metabolism , Female , Glucose Intolerance/metabolism , Glucose Tolerance Test , Inflammation/etiology , Inflammation/metabolism , Insulin/blood , Male , Mice , Mutation , Obesity/complications , Obesity/metabolism , Sex FactorsABSTRACT
Menopause is associated with an increased incidence of insulin resistance and metabolic diseases. In a chronic palmitate treatment model, we investigated the role of skeletal muscle fatty acid exposure in relation to the metabolic deterioration observed with menopause. Human skeletal muscle satellite cells were isolated from premenopausal (nâ=â6) and postmenopausal (nâ=â5) women. In an in vitro model, the myotubes were treated with palmitate (300 µM) for one-, two- or three days during differentiation. Effects on lipid accumulation, inflammation and insulin signaling were studied. Palmitate treatment led to a 108% (CI 95%: 50%; 267%) increase in intramyocellular ceramide in the myotubes from the postmenopausal women (post-myotubes) compared with a 26% (CI 95%: -57%; 96%) increase in myotubes from the premenopausal women (pre-myotubes), (p<0.05). Furthermore, post-myotubes had a 22% (CI 95%: 4%; 34%) increase in pJNK (pâ=â0.04) and a 114% (CI 95%: 50%; 177%) increase in Hsp70 protein expression (pâ=â0.03) after three days of palmitate treatment, compared with pre-myotubes, in which no increase in either pJNK (-12% (CI 95: -26%; 2%)) or Hsp70 (7% (CI 95: -78%; 91%)) was detected. Furthermore, post-myotubes showed a blunted insulin stimulated phosphorylation of AS160 in response to chronic palmitate treatment compared with pre-myotubes (pâ=â0.02). The increased intramyocellular ceramide content in the post-myotubes was associated with a significantly higher mRNA expression of Serine Palmitoyltransferase1 (SPT1) after one day of palmitate treatment (pâ=â0.03) in post-myotubes compared with pre-myotubes. Our findings indicate that post-myotubes are more prone to develop lipid accumulation and defective insulin signaling following chronic saturated fatty acid exposure as compared to pre-myotubes.
Subject(s)
Ceramides/metabolism , Insulin/metabolism , Muscle Fibers, Skeletal/cytology , Muscle Fibers, Skeletal/metabolism , Palmitates/pharmacology , Postmenopause/metabolism , Signal Transduction/drug effects , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Female , HSP70 Heat-Shock Proteins/metabolism , Humans , Insulin Resistance , JNK Mitogen-Activated Protein Kinases/metabolism , Lipid Metabolism/drug effects , Middle Aged , Muscle Fibers, Skeletal/drug effects , Oxidative Stress/drug effects , Phosphoproteins/metabolism , Postmenopause/drug effectsABSTRACT
In the present study, we have examined whether IKKß [IκB (inhibitor of nuclear factor κB) kinase ß] plays a role in feedback inhibition of the insulin signalling cascade. Insulin induces the phosphorylation of IKKß, in vitro and in vivo, and this effect is dependent on intact signalling via PI3K (phosphoinositide 3-kinase), but not PKB (protein kinase B). To test the hypothesis that insulin activates IKKß as a means of negative feedback, we employed a variety of experimental approaches. First, pharmacological inhibition of IKKß via BMS-345541 did not potentiate insulin-induced IRS1 (insulin receptor substrate 1) tyrosine phosphorylation, PKB phosphorylation or 2-deoxyglucose uptake in differentiated 3T3-L1 adipocytes. BMS-345541 did not prevent insulin-induced IRS1 serine phosphorylation on known IKKß target sites. Secondly, adenovirus-mediated overexpression of wild-type IKKß in differentiated 3T3-L1 adipocytes did not suppress insulin-stimulated 2-deoxyglucose uptake, IRS1 tyrosine phosphorylation, IRS1 association with the p85 regulatory subunit of PI3K or PKB phosphorylation. Thirdly, insulin signalling was not potentiated in mouse embryonic fibroblasts lacking IKKß. Finally, insulin treatment of 3T3-L1 adipocytes did not promote the recruitment of IKKß to IRS1, supporting our findings that IKKß, although activated by insulin, does not promote direct serine phosphorylation of IRS1 and does not contribute to the feedback inhibition of the insulin signalling cascade.