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1.
Clin Genet ; 2019 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-31628766

RESUMO

Patients with dystonia are particularly appropriate for diagnostic exome sequencing (DES), due to the complex, diverse features and genetic heterogeneity. Personal and family history data were collected from test requisition forms and medical records from 189 patients with reported dystonia and available family members received for clinical DES. Of them, 20.2% patients had a positive genetic finding associated with dystonia. Detection rates for cases with isolated and combined dystonia were 22.4% and 25.0%, respectively. 71.4% of the cohort had co-occurring non-movement-related findings and a detection rate of 24.4%. Patients with childhood-onset dystonia trended toward higher detection rates (31.8%) compared to infancy (23.6%), adolescence (12.5%), and early-adulthood onset (16%). Uncharacterized gene findings were found in 6.7% (8/119) of cases that underwent analysis for genes without an established disease relationship. Patients with intellectual disability/developmental delay, seizures/epilepsy and/or multifocal dystonia were more likely to have positive findings (P = .0093, .0397, .0006). Four (2.1%) patients had findings in two genes, and seven (3.7%) had reclassification after the original report due to new literature, new clinical information or reanalysis request. Pediatric patients were more likely to have positive findings (P = .0180). Our observations show utility of family-based DES in patients with dystonia and illustrate the complexity of testing.

2.
Clin Genet ; 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31397880

RESUMO

Pathogenic MAGEL2 variants result in the phenotypes of Chitayat-Hall syndrome (CHS), Schaaf-Yang syndrome (SYS) and Prader-Willi syndrome (PWS). We present five patients with mutations in MAGEL2, including the first patient reported with a missense variant, adding to the limited literature. Further, we performed a systematic review of the CHS and SYS literature, assess the overlap between CHS, SYS and PWS, and analyze genotype-phenotype correlations among them. We conclude that there is neither a clinical nor etiological difference between CHS and SYS, and propose that the two syndromes simply be referred to as MAGEL2-related disorders.

3.
Am J Hum Genet ; 105(2): 403-412, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31303265

RESUMO

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

4.
Allergy Asthma Proc ; 40(4): 250-260, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262380

RESUMO

Background: Probiotic supplementary therapy to prevent allergic diseases, including asthma in children, has been widely explored in many randomized controlled trials. However, there is conflicting evidence on the effect of probiotic supplementation during pregnancy and infancy to the incidence of asthma and allergic rhinitis. Method: This study was designed to systematically explore the potential effects of probiotic supplementation on the occurrence and development of asthma, wheeze, and allergic rhinitis. Randomized controlled trials were searched in several medical literature data bases. A meta-analysis was undertaken by using the fixed-effects model or the random effects model to calculate the pooled risk of significant heterogeneity. Two writers were designated to perform the study selection and data extraction. The primary outcome was clinically diagnosed asthma; the secondary outcomes included wheeze, allergic rhinitis, and a positive aeroallergen skin-prick test result. Results: Seventeen randomized controlled trials, which composed a total of 5264 children, were analyzed. The pooled data for risk of developing asthma after probiotic supplementation showed no significant reduction compared with controls (risk ratio [RR] 0.86 [95% confidence interval {CI}, 0.73-1.01]; I² = 0%; p = 0.06). A subgroup of strains indicated that Lactobacillus rhamnosus GG supplementation only had a reduction to the occurrence of asthma (RR 0.75 [95% CI, 0.57-0.99]; I² = 11%; p = 0.04). The supplement in the postnatal group had a similar result, but the incorporated data were limited. Meanwhile, it is failed to identify that probiotic supplementary therapy have a clear benefit to the secondary outcomes: wheeze, allergic rhinitis, positive aeroallergen skin-prick test result. Conclusion: This study showed a significant benefit that supplementation with probiotics in pre- and postnatal periods was likely to play an essential strategic role in the prevention of asthma. However, these effects were based on the type of probiotics used, which also need more large-sample and high-quality RCTs to confirm the reliability of this study.

5.
Toxicol Appl Pharmacol ; 378: 114608, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31173788

RESUMO

Autophagy and apoptosis are two important cellular processes that are crucial for neurodevelopment. Evidence shows that apoptosis is implicated in fluoride neurotoxicity. However, the biological roles of autophagy, especially its interplay with apoptosis in the neurotoxicity induced by long-term fluoride exposure remain unclear. Here we present in vivo and in vitro evidence that fluoride-induced defective autophagy elicits excessive apoptosis, thus inducing neurotoxicity. Using Sprague-Dawley rats exposed to sodium fluoride from 60 days before pregnancy until 6 months post-delivery as in vivo model, we showed that fluoride impaired the learning and memory abilities of offspring rats, with decreased neuronal number, suppressed autophagy and enhanced apoptosis in hippocampus. These results were validated in human neuroblastoma SH-SY5Y cells in vitro. Mechanistically, mTOR signaling, responsible for autophagy induction, was activated in vivo and in vitro, and targeting inhibition of mTOR with rapamycin protected SH-SY5Y cells from defective autophagy and excessive apoptosis, thereby enhancing neuronal survival. Furthermore, circulating levels of autophagy markers were low in children with higher fluoride body burden and lower intelligence quotient scores. Collectively, our results suggest that defective autophagy plays a pivotal role in fluoride neurotoxicity, and mTOR might be a promising target for the prevention and treatment of fluoride neurotoxicity.

6.
Am J Hum Genet ; 104(6): 1060-1072, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31104773

RESUMO

The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the µ-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the µ-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2µ conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy.

7.
Genet Med ; 21(10): 2199-2207, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30894705

RESUMO

PURPOSE: We evaluated clinical and genetic features enriched in patients with multiple Mendelian conditions to determine which patients are more likely to have multiple potentially relevant genetic findings (MPRF). METHODS: Results of the first 7698 patients who underwent exome sequencing at Ambry Genetics were reviewed. Clinical and genetic features were examined and degree of phenotypic overlap between the genetic diagnoses was evaluated. RESULTS: Among patients referred for exome sequencing, 2% had MPRF. MPRF were more common in patients from consanguineous families and patients with greater clinical complexity. The difference in average number of organ systems affected is small: 4.3 (multiple findings) vs. 3.9 (single finding) and may not be distinguished in clinic. CONCLUSION: Patients with multiple genetic diagnoses had a slightly higher number of organ systems affected than patients with single genetic diagnoses, largely because the comorbid conditions affected overlapping organ systems. Exome testing may be beneficial for all cases with multiple organ systems affected. The identification of multiple relevant genetic findings in 2% of exome patients highlights the utility of a comprehensive molecular workup and updated interpretation of existing genomic data; a single definitive molecular diagnosis from analysis of a limited number of genes may not be the end of a diagnostic odyssey.

8.
Medicine (Baltimore) ; 98(4): e14090, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30681567

RESUMO

The objective of the study was to determine the geometric changes in mitral annular and/or leaflets spatial conformation in patients with atrial fibrillation (AF) complicated with severe atrial mitral regurgitation (AMR) by using real-time 3-dimensional transesophageal echocardiography, aiming to explore whether this condition could be improved through self-modulation of mitral annulus and/or leaflets after the restoration of sinus rhythm.Fifty-five patients who were diagnosed with AMR and subject to 1-year follow-up were recruited in this clinical trial. All patients successfully received AF ablation. The intercommissural and anteroposterior diameter, annular height, mitral valve area (MVA), tenting height and volume, annular spherical index, fractional area change of MVA (MVA-FAC), and coaptation index (CP-I) were defined and measured by mitral-valve quantification software. Left ventricular size and function, maximum LA volume (LAV), and LA dimensions were equally recorded.During 1-year follow-up, AMR was significantly decreased in patients with sinus rhythm (P < 0.001). CP-I, MVA-FAC, and LAV index were independently associated with the reduction of AMR.AMR can be improved through the recovery of LAV after ablation, which probably affects the configuration of the annular space and the coaptation of the leaflets.


Assuntos
Fibrilação Atrial/complicações , Insuficiência da Valva Mitral/complicações , Insuficiência da Valva Mitral/patologia , Valva Mitral/anatomia & histologia , Idoso , Fibrilação Atrial/cirurgia , Função do Átrio Esquerdo/fisiologia , Ablação por Cateter/métodos , Ecocardiografia Tridimensional , Ecocardiografia Transesofagiana , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/diagnóstico por imagem , Índice de Gravidade de Doença , Função Ventricular Esquerda/fisiologia
9.
FEBS J ; 286(6): 1191-1203, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30636108

RESUMO

Aging is characterized by a progressive loss of physiological integrity, leading to impaired organ function and, ultimately, increased vulnerability to death. Many complex diseases are related to aging, including asthma. In the lung, the airway epithelium serves as the first barrier to prevent the access of inspired external stimuli and dictates the initial stress responses. Notably, in the airway mucosa of asthma patients, an increase in senescent airway epithelial cells has been detected. Although it has been speculated that the senescence of airway epithelial cells could increase asthma susceptibility and aggravate asthma severity, the role of cell senescence in the development of asthma remains unclear. Integrin ß4 (ITGB4) is a structural adhesion molecule with complex physiological functions that is downregulated in airway epithelial cells of asthma patients. This study demonstrates that the expression of ITGB4 in airway epithelial cells is downregulated significantly under oxidative stress or upon inflammatory stimulation. Moreover, we show that ITGB4 deficiency induces the senescence of airway epithelial cells through the activation of the p53 pathway both in vitro and in vivo. Together, our results demonstrate that airway epithelial senescence induced by ITGB4 deficiency after oxidative stress or inflammatory stimulation may be involved in the pathogenesis of asthma. Understanding the contribution of ITGB4 deficiency to the senescence of airway epithelial cells in asthma patients may provide new therapeutic approaches for the treatment of asthma.

10.
J Exp Bot ; 70(4): 1167-1182, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30534992

RESUMO

The activity of ribonucleotide reductase (RNR), which catalyses the transformation of four ribonucleoside diphosphates (NDPs) to their corresponding deoxyribonucleoside diphosphates (dNDPs), is the main determiner of the cellular concentration of dNTP pools and should be tightly coordinated with DNA synthesis and cell-cycle progression. Constitutively increased or decreased RNR activity interferes with DNA replication and leads to arrested cell cycle progression; however, the mechanisms underlying these disruptive effects in higher plants remain to be uncovered. In this study, we identified a RNR large subunit mutant, sistl1, in Setaria italica (foxtail millet), which exhibited growth retardation as well as striped leaf phenotype, i.e. irregularly reduced leaf vein distances and decreased chloroplast biogenesis. We determined that a Gly737 to Glu substitution occurring in the C-terminus of the SiSTL1 protein slightly affected its optimal function, leading in turn to the reduced expression of genes variously involved in the assembly and activation of the DNA pre-replicative complex, elongation of replication forks and S phase entry. Our study provides new insights into how SiSTL1 regulates plant growth, chloroplast biogenesis, and cell cycle progression in Poaceae crops.

11.
Mol Genet Metab ; 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30473481

RESUMO

Primary mitochondrial complex I deficiency is the most common defect of the mitochondrial respiratory chain. It is caused by defects in structural components and assembly factors of this large protein complex. Mutations in the assembly factor NDUFAF5 are rare, with only five families reported to date. This study provides clinical, biochemical, molecular and functional data for four unrelated additional families, and three novel pathogenic variants. Three cases presented in infancy with lactic acidosis and classic Leigh syndrome. One patient, however, has a milder phenotype, with symptoms starting at 27 months and a protracted clinical course with improvement and relapsing episodes. She is homozygous for a previously reported mutation, p.Met279Arg and alive at 19 years with mild neurological involvement, normal lactate but abnormal urine organic acids. We found the same mutation in one of our severely affected patients in compound heterozygosity with a novel p.Lys52Thr mutation. Both patients with p.Met279Arg are of Taiwanese descent and had severe hyponatremia. Our third and fourth patients, both Caucasian, shared a common, newly described, missense mutation p.Lys109Asn which we show induces skipping of exon 3. Both Caucasian patients were compound heterozygotes, one with a previously reported Ashkenazi founder mutation while the other was negative for additional exonic variants. Whole genome sequencing followed by RNA studies revealed a novel deep intronic variant at position c.223-907A>C inducing an exonic splice enhancer. Our report adds significant new information to the mutational spectrum of NDUFAF5, further delineating the phenotypic heterogeneity of this mitochondrial defect.

12.
J Med Genet ; 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30478137

RESUMO

BACKGROUND: During mouse embryonic development the protein kinase domain containing, cytoplasmic (Pkdcc) gene, also known as Vlk, is expressed in several tissues including the ventral midbrain, with particularly strong expression in branchial arches and limb buds. Homozygous Pkdcc knockout mice have dysmorphic features and shortened long bones as the most obvious morphological abnormalities. The human PKDCC gene has currently not been associated with any disorders. OBJECTIVE: To use clinical diagnostic exome sequencing (DES) for providing genetic diagnoses to two apparently unrelated patients with similar skeletal abnormalities comprising rhizomelic shortening of limbs and dysmorphic features. METHODS: Patient-parents trio DES was carried out and the identified candidate variants were confirmed by Sanger sequencing. RESULTS: Each patient had a homozygous gene disrupting variant in PKDCC considered to explain the skeletal phenotypes shared by both. The first patient was homozygous for the nonsense variant p.(Tyr217*) (NM_1 38 370 c.651C>A) expected to result in nonsense-mediated decay of the mutant transcripts, whereas the second patient was homozygous for the splice donor variant c.639+1G>T predicted to abolish the donor splice site by three in silico splice prediction algorithms. CONCLUSIONS: Biallelic gene disrupting variants in PKDCC in humans, just like in mice, cause dysmorphic features and rhizomelic shortening of limbs.

13.
Front Plant Sci ; 9: 1650, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30487807

RESUMO

C4 plants exhibit significantly higher photosynthetic, water and nutrient use efficiency compared with C3 plants. Kranz anatomy is associated with many C4 plants in which bundle sheath cells surround the veins and are themselves surrounded by mesophyll cells. This specialized Kranz anatomy is elucidated as an important contributor to C4 photosynthetic activities in C4 plant. Characterizing the molecular basis of Kranz structure formation has become a key objective for studies of C4 photosynthesis. However, severe mutants that specifically disrupt Kranz anatomy have not been identified. In this study, we detected 549 stable ethyl methane sulfonate-induced foxtail millet (cultivar Yugu1) mutants related to leaf development and photosynthesis among 2,709 mutants screened (M3/M4 generation). The identified mutants included 52 that had abnormal leaf veins (with abnormal starch accumulation based on iodine staining). Each of the 52 mutants was characterized through an analysis of leaf morphology, and through microscopic observations of leaf tissue sections embedded in resin and paraffin. In total, 14 mutants were identified with abnormal Kranz structures exemplified by small bundle sheath cell size. Additional phenotypes of the mutants included poorly differentiated mesophyll and bundle sheath cells, increased vein density and the absence of chloroplasts in the bundle sheath cells. Kranz structure mutations were accompanied by varying leaf thickness, implying these mutations induced complex effects. We identified mutations related to Kranz structure development in this trial, which may be useful for the mapping and cloning of genes responsible for mediating Kranz structure development.

14.
Front Plant Sci ; 9: 1308, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30233633

RESUMO

A yellow-green leaf mutant was isolated from EMS-mutagenized lines of Setaria italica variety Yugu1. Map-based cloning revealed the mutant gene is a homolog of Arabidopsis thaliana AtEGY1. EGY1 (ethylene-dependent gravitropism-deficient and yellow-green 1) is an ATP-independent metalloprotease (MP) that is required for chloroplast development, photosystem protein accumulation, hypocotyl gravitropism, leaf senescence, and ABA signal response in A. thaliana. However, the function of EGY1 in monocotyledonous C4 plants has not yet been described. The siygl2 mutant is phenotypically characterized by chlorotic organs, premature senescence, and damaged PS II function. Sequence comparisons of the AtEGY1 and SiYGL2 proteins reveals the potential for SiYGL2 to encode a partially functional protein. Phenotypic characterization and gene expression analysis suggested that SiYGL2 participates in the regulation of chlorophyll content, leaf senescence progression, and PS II function. Additionally, our research will contribute to further characterization of the mechanisms regulating leaf senescence and photosynthesis in S. italica, and in C4 plants in general.

15.
J Neuroinflammation ; 15(1): 246, 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-30170608

RESUMO

BACKGROUND: Chronic persistent airway inflammation has been associated with the comorbidity of asthma and bipolar disorder (BD). However, the direct relevance between airway inflammation and BD-like psychiatric comorbidity is almost unknown. Integrin ß4 (ITGB4) is downregulated on the airway epithelial of asthma patients, which might play a critical role in the parthenogenesis of airway inflammation. So this study aimed to examine the role of ITGB4 deficiency in mediating airway inflammation and further leading to the BD-like behaviors. METHODS: ITGB4-/- mice were generated by mating ITGB4fl/fl mice with CCSP-rtTAtg/-/TetO-Cretg/tg mice. Mania-like behavior tests were performed, including hyperlocomotion, D-amphetamine-induced hyperactivity, open-field test, and elevated plus-maze test. Depressive-like behavior tests were carried out, including sucrose preference, forced swimming, and learned helplessness. Inflammatory cells (Th17, Th1, Th2) in the lung were examined by flow cytometry. Futhermore, inflammatory cytokines (IL-4, IL-13) in bronchoalveolar lavage fluid and sera were detected by ELISA. Protein expression of the IL-4Rα on choroid plexus, microglial marker (IBA1), and synapse-associated proteins (synaptophysin, SYP) in the hippocampus and prefrontal cortex were examined by western blotting. Additionally, proinflammatory cytokines (IL-1ß, IL-6, and TNF-α) in the hippocampus and prefrontal cortex were detected by immunohistochemistry. Inflammatory disorder in the lung, hippocampus, and prefrontal cortex was tested by hematoxylin and eosin (H&E) staining. And cell apoptosis in the hippocampus and prefrontal cortex was measured by TUNEL test. RESULTS: ITGB4-/- mice exhibited mania-like behavior, including hyperlocomotion, D-amphetamine-induced hyperactivity, and reduced anxiety-like behavior. While under stressful conditions, ITGB4-/- mice manifested depressive-like behavior, including anhedonia, behavioral despair, and enhanced learned helplessness. At the same time, ITGB4-/- mice mainly exerted Th2-type inflammation in periphery, like the number and major cytokines IL-4 and IL-13 of Th2-type inflammation. ITGB4-/- mice also showed a significant increase of microglia and pro-inflammatory cytokines such as IL-1ß, IL-6, and TNF-α in the hippocampus and prefrontal cortex. Additionally, neuron damage, increased neuron apoptosis, and the decrease of SYP were found in ITGB4-/- mice. CONCLUSIONS: These findings confirmed that airway inflammatory induced by ITGB4 deficiency is the important incentive for the BD-like behavior during asthma pathogenesis. The ITGB4-deficient mice provide a validated animal model for us to study the possible mechanism of BD-like psychiatric comorbidity of asthma patients.


Assuntos
Transtorno Bipolar/genética , Bronquite/genética , Bronquite/patologia , Células Epiteliais/patologia , Integrina beta4/metabolismo , Anfetamina/toxicidade , Animais , Antibacterianos/farmacologia , Modelos Animais de Doenças , Doxiciclina/farmacologia , Comportamento Exploratório/fisiologia , Regulação da Expressão Gênica/genética , Hipercinese/induzido quimicamente , Hipercinese/genética , Integrina beta4/genética , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/patologia , Subpopulações de Linfócitos T/patologia , Uteroglobina/genética , Uteroglobina/metabolismo
16.
Front Plant Sci ; 9: 1103, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30105043

RESUMO

Deoxycytidine monophosphate deaminase (DCD) is a key enzyme in the de novo dTTP biosynthesis pathway. Previous studies have indicated that DCD plays key roles in the maintenance of the balance of dNTP pools, cell cycle progression, and plant development. However, few studies have elucidated the functions of the DCD gene in Panicoideae plants. Setaria has been proposed as an ideal model of Panicoideae grasses, especially for C4 photosynthesis research. Here, a Setaria italica stripe leaf mutant (sistl2) was isolated from EMS-induced lines of "Yugu1," the wild-type parent. The sistl2 mutant exhibited semi-dwarf, striped leaves, abnormal chloroplast ultrastructure, and delayed cell cycle progression compared with Yugu1. High-throughput sequencing and map-based cloning identified the causal gene SiSTL2, which encodes a DCD protein. The occurrence of a single-base G to A substitution in the fifth intron introduced alternative splicing, which led to the early termination of translation. Further physiological and transcriptomic investigation indicated that SiSTL2 plays an essential role in the regulation of chloroplast biogenesis, cell cycle, and DNA replication, which suggested that the gene has conserved functions in both foxtail millet and rice. Remarkably, in contrast to DCD mutants in C3 rice, sistl2 showed a significant reduction in leaf cell size and affected C4 photosynthetic capacity in foxtail millet. qPCR showed that SiSTL2 had a similar expression pattern to typical C4 genes in response to a low CO2 environment. Moreover, the loss of function of SiSTL2 resulted in a reduction of leaf 13C content and the enrichment of DEGs in photosynthetic carbon fixation. Our research provides in-depth knowledge of the role of DCD in the C4 photosynthesis model S. italica and proposed new directions for further study of the function of DCD.

17.
Am J Hum Genet ; 103(3): 448-455, 2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-30122539

RESUMO

Neurodevelopment is a transcriptionally orchestrated process. Cyclin K, a regulator of transcription encoded by CCNK, is thought to play a critical role in the RNA polymerase II-mediated activities. However, dysfunction of CCNK has not been linked to genetic disorders. In this study, we identified three unrelated individuals harboring de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region and one individual harboring a de novo nonsynonymous variant c.331A>G (p.Lys111Glu) in CCNK. These four individuals, though from different ethnic backgrounds, shared a common phenotype of developmental delay and intellectual disability (DD/ID), language defects, and distinctive facial dysmorphism including high hairline, hypertelorism, thin eyebrows, dysmorphic ears, broad nasal bridge and tip, and narrow jaw. Functional assay in zebrafish larvae showed that Ccnk knockdown resulted in defective brain development, small eyes, and curly spinal cord. These defects were partially rescued by wild-type mRNA coding CCNK but not the mRNA with the identified likely pathogenic variant c.331A>G, supporting a causal role of CCNK variants in neurodevelopmental disorders. Taken together, we reported a syndromic neurodevelopmental disorder with DD/ID and facial characteristics caused by CCNK variations, possibly through a mechanism of haploinsufficiency.

18.
Clin Case Rep ; 6(7): 1208-1213, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29988648

RESUMO

Clinical diagnostic exome sequencing (DES) is currently infrequently used for detecting uniparental disomy (UPD). We present a patient with a dual diagnosis of GLI2 haploinsufficiency as well as UPD of chromosome 20, both identified through DES. We therefore recommend routine UPD analysis during DES to identify this genetic aberration.

19.
Eur J Hum Genet ; 26(11): 1623-1634, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29925855

RESUMO

We explored the clinico-genetic basis of spinocerebellar ataxia 29 (SCA29) by determining the frequency, phenotype, and functional impact of ITPR1 missense variants associated with early-onset ataxia (EOA). Three hundred thirty one patients from a European EOA target cohort (n = 120), US-American EOA validation cohort (n = 72), and early-onset epileptic encephalopathy (EOEE) control cohort (n = 139) were screened for de novo ITPR1 variants. The target cohort was also screened for inherited ITPR1 variants. The variants' functional impact was determined by IP3-induced Ca2+ release in HEK293 cells. 3/120 patients (2.5%) from the target cohort and 4/72 patients (5.5%) from the validation cohort, but none from the EOEE control cohort, carried de novo ITPR1 variants. However, most ITPR1 variants (7/10 = 70%) in the target cohort were inherited from a healthy parent, with 3/6 patients carrying disease-causing variants in other genes. This suggests limited or no phenotypic impact of many ITPR1 missense variants, even if ultra-rare and well-conserved. While common bioinformatics tools did not discriminate de novo from other ITPR1 variants, functional characterization demonstrated reduced IP3-induced Ca2+ release for all de novo variants, including the recurrent c.805C>T (p.(R269W)) variant. In sum, these findings show that de novo ITPR1 missense variants are a recurrent cause of EOA (SCA29) across independent cohorts, acting via loss of IP3 channel function. Inherited ITPR1 variants are also enriched in EOA, but often without strong impact, albeit rare and well-conserved. Functional studies allow identifying ITPR1 variants with large impact, likely disease-causing. Such functional confirmation is warranted for inherited ITPR1 variants before making a SCA29 diagnosis.

20.
Nat Genet ; 50(7): 1048-1053, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29942082

RESUMO

Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent-offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene. Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy. We further demonstrate the extent to which our results affect current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDDs with epilepsy.

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