Isolated paroxysmal kinesigenic dyskinesia (PKD) is mainly caused by PRRT2 variants and TMEM151A variants. Patients with proximal 16p11.2 microdeletion (16p11.2MD) (including PRRT2) often have neurodevelopmental phenotypes, whereas a few patients have PKD. Here, we aimed to identify 16p11.2MD in patients with PKD and describe the related phenotypes.Whole-exome sequencing and bioinformatics analysis of copy number variant (CNV) were performed in patients with PKD carrying neither PRRT2 nor TMEM151A variant. Quantitative PCR and low-coverage whole-genome sequencing verified the CNV.We identified 9 sporadic patients with PKD and 16p11.2MD (∼535 kb), accounting for 9.6% (9/94) of our patients. Together with 9 previously reported patients with PKD and 16p11.2MD, we found that 16p11.2MD was de novo in 11 of 12 tested patients and inherited from a parent in the other patient. And 80% (12/15) of these patients had a mild language delay, 64.3% (9/14) had compromised learning ability, 42.9% (6/14) had a mild motor delay, and 50% (6/12) had abnormal neuroimaging findings. No severe autism disorders were observed.Mild developmental problems may be overlooked. A detailed inquiry of developmental history and CNV testing are necessary to distinguish patients with 16p11.2MD from isolated PKD.
The natural dibenzylbutyrolactone type lignanolide (–)-arctigenin, which was prepared from fructus arctii, showed obvious anticancer activity. The synthesis of four new (–)-arctigenin derivatives and their anticancer bioactivities were examined. The structures of the four new synthetic derivatives were elucidated.
Neuroferritinopathy is a rare autosomal dominant movement disorder caused by mutations of the FTL gene.(1) It is clinically characterized by adult-onset progressive extrapyramidal syndrome, including chorea, dystonia, and parkinsonism.(2) Brain MRI demonstrates the deposition of iron and ferritin in the basal ganglia.(3) To date, several Caucasian families and 2 Japanese families have been reported worldwide.(2) We present a Chinese neuroferritinopathy pedigree with 5 patients and the FTL mutation.
Disease-associated microglia (DAM) are observed in neurodegenerative diseases, demyelinating disorders, and aging. However, the spatiotemporal dynamics and evolutionary trajectory of DAM during the progression of amyotrophic lateral sclerosis (ALS) remain unclear. Using a mouse model of ALS that expresses a human SOD1 gene mutation, we found that the microglia subtype DAM begins to appear following motor neuron degeneration, primarily in the brain stem and spinal cord. Using reverse transcription quantitative polymerase chain reaction, RNAscope in situ hybridization, and flow cytometry, we found that DAM increased in number as the disease progressed, reaching their peak in the late disease stage. DAM responded to disease progression in both SOD1 G93A mice and sporadic ALS and C9orf72 -mutated patients. Motor neuron loss in SOD1 G93A mice exhibited 2 accelerated phases: P90 to P110 (early stage) and P130 to P150 (late stage). Some markers were synchronized with the accelerated phase of motor neuron loss, suggesting that these proteins may be particularly responsive to disease progression. Through pseudotime trajectory analysis, we tracked the dynamic transition of homeostatic microglia into DAM and cluster 6 microglia. Interestingly, we used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia in SOD1 G93A mice and observed that DAM survival is independent of CSF1R. An in vitro phagocytosis assay directly confirmed that DAM could phagocytose more beads than other microglia subtypes. These findings reveal that the induction of the DAM phenotype is a shared cross-species and cross-subtype characteristic in ALS. Inducing the DAM phenotype and enhancing its function during the early phase of disease progression, or the time window between P130 and P150 where motor neuron loss slows, could serve as a neuroprotective strategy for ALS.
Summary Aims PRRT 2 was recently identified as a causative gene for paroxysmal kinesigenic dyskinesia ( PKD ), and the c.649dup C mutation was shown to be a “high frequency” mutation. This mutation was also identified in many sporadic cases. This might be attributed to the incomplete penetrance of c.649dup C . Alternatively, c.649dup C might derive from de novo . The aim of this study is to elucidate the possibility concerning de novo mutagenesis of PRRT 2 mutations in PKD . Methods Nine sporadic C hinese PKD patients including one M ongolian patient were recruited. Direct sequencing of PRRT 2 was performed in them and their parents. Haplotype analysis was conducted to confirm the biological relationship. Results A novel mutation, c.133_136del CCAG , was identified in one H an patient and his unaffected mother. The c.649dup C mutation was detected in another H an patient and his unaffected father. To our interest, c.649dup C was detected in the M ongolian patient but not in his parents. Haplotype analysis confirmed the biological relationship among the trio. No mutations were identified in the remaining six patients. Conclusion These findings demonstrate the heterogeneity of PKD , and the de novo mutagenesis of PRRT 2 gene might indicate the genetic instability of this region.
It remains difficult to make a quantitative trading strategy by predicting the former statistics, with the aim of balancing the risks and profits. In this article, we presented an innovative price forecasting and quantitative trading strategy based on ensemble forecaster. The strategy program was designed by the modified Sharpe ratio and PSO, which overcame the original Sharpe ratio's conservation and the slow program's convergence rate. And the model was effective and sensitive proved by the disturbance evaluation.
Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases predominately presented with weakness and spasticity in lower extremities. HSPs have high clinical and genetic heterogeneity and over 80 genes or loci have been linked to HSP over the past two decades (Mackay-Sim, 2021). Even so, appropriately 50% of affected individuals were still not genetically diagnosed. In 2019, two studies (Farazi Fard et al., 2019; Lin et al., 2019) identified pathological truncating variants within UBAP1 in autosomal dominant HSP pedigrees. These families are from Iran, USA, Germany, Canada, Bulgaria, Spain, and China, respectively, implying the diverse geographic origin for the UBAP1 variants. The phenotypes are predominantly pure early-onset HSP in these families (MIM # 618418). In this study, we reported a novel UBAP1 (NM_016525.5) truncating variant c.371dupT (p.Leu124Phefs*15) in a Chinese autosomal dominant HSP pedigree (Figure 1a). This study was approved by the Ethics Committee of Second Affiliated Hospital, Zhejiang University School of Medicine and written informed consents were obtained from the participants. The proband is 33-year-old female with a history of progressive weakness and rigidity of lower limbs for 25 years. She had difficulty in climbing the stairs and walking stably. There is no muscle atrophy of lower extremities. Her mother had similar symptoms, while other familial members were unaffected. Physical examinations revealed normal muscle strength but increased muscle tension in lower extremities. Tendon reflex was brisk in four limbs and Babinski sign was positive bilaterally. Vibratory sensibility was lost in the distal end of lower limbs. Brain MRI revealed unremarkable information, except for several lacunar infarcts. Thoracic MRI displayed extensive atrophy. EMG revealed normal amplitude and conduction velocity of motor nerves and sensory nerves. We performed whole exome sequencing in the proband. After verifying by Sanger sequencing, we identified a heterozygous UBAP1 truncated variant c.371dupT (p.Leu124Phefs*15) (Figure 1b). We then performed Sanger sequencing in her available family members and found that her affected mother carried the same c.371dupT variant. This variant was absent in the ExAC, 1000G, gnomAD, and our in-house WES database that contain 500 Chinese controls. The affected residue was much conserved in different species (Figure 1c). According to the ACMG guideline (Richards et al., 2015), this variant should be assigned as pathogenic. UBAP1, encodes the ubiquitin-associated protein 1 (UBAP1), a subunit of ESCRT-I complex. UBAP1 has two main domains, the UMA domain in the N-terminal region (17–63 aa) and a SOUBA domain in the C-terminal region. The former domain is associated with ESCRT-I complex, while the latter domain maintains ubiquitin homeostasis of early endosome processing. We constructed plasmids containing wild-type (WT) or mutant UBAP1 gene (NM_016525.5) and transfected the plasmids in HEK 293T cells. Western blot analysis revealed that this truncating variant actually led to the production of truncated mutant form of UBAP1, lacking the SOUBA domain (Figure 1d). We performed immunocytochemical staining for the EEA1 (early endosome marker) and Flag-fused UBAP1 in HeLa cells to elucidate the endosome function. The results showed the aberrant endosome aggregates (Figure 1e) and prominent enlarged endosome in cells over-expressing mutant UBAP1 (Figure 1f). To date, 18 UBAP1 variants including the one identified here have been described (Bian et al., 2021; Bourinaris et al., 2020; Gu et al., 2020; Wang et al., 2020), and 17 of them occurred in Exon 4 of UBAP1 (Figure 1g), implying that Exon 4 is a potential hotspot region of UBAP1. In addition, all identified variants preserve the UMA domain but cause a loss of the SOUBA domain, implying that loss of ubiquitin binding would be detrimental. Further studies are required to elucidate the mechanism of SOUBA impairment causing HSP. In summary, we identified a novel UBAP1 truncating variant in a Chinese autosomal dominant HSP pedigree. Our findings expanded variant spectrum of UBAP1 and further confirmed the pathogenicity of UBAP1 variants in HSP. The authors would like to thank all the participants for their supports and willingness to participate in this study. Thanks for the technical support by the Core Facilities, Zhejiang University School of Medicine. This study was supported by the research foundation for distinguished scholar of Zhejiang University to Zhi-Ying Wu (188020-1938 10101/089) and the Fundamental Research Funds for the Central Universities. The authors have declared no conflict of interest. Qiao Wei: data acquisition, analysis, and interpretation of data, statistical analysis, drafting the manuscript. Pei-Shan Wang: data acquisition, analysis, and interpretation of data. Hai-Lin Dong: data acquisition, interpretation of data. Wen-Jiao Luo: data acquisition. Zhi-Ying Wu and Hong-Fu Li: funding, study design and conceptualization, data acquisition, analysis and interpretation of data, technical and material support, drafting, and critical revision of the manuscript. The study was approved by the Ethics Committees of Second Affiliated Hospital of Zhejiang University School of Medicine and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Specific national laws have been observed, too. Written informed consent was obtained for this study from all the patients prior to their inclusion in the study. Data available on request from the authors.
Abstract Background X‐linked adrenoleukodystrophy (ALD) is one of the most common peroxisomal disorders characterized by abnormal accumulation of very long‐chain fatty acids (VLCFA) in plasma and tissues and caused by mutations within ABCD1 . Clinically, ALD present with various phenotypes, ranging from asymptomatic type to rapidly progressive childhood cerebral form. However, no remarkable abnormality in cerebral white matter usually makes it difficult to distinguish adult ALD from hereditary spastic paraplegia (HSP). Methods We analyzed the features of seven Chinese ALD patients who had a primary phenotype of spastic paraplegia. Sequencing was performed in the probands and their familial members. Detailed clinical, VLCFAs test, hormone test, magnetic resonance imaging, and electromyogram are presented. Results We reported seven ALD patients from a Chinese cohort of 142 HSP patients. Genetic investigations revealed five known ABCD1 mutations (c.346G>C, c.521A>G, c.829G>T, c.1415_1416delAG, and c.1849C>T) and two novel mutations (c.454C>G, c.1452_1482del). Further auxiliary testing revealed that they had higher VLCFA and/or adrenal insufficiency. Conclusions Our findings expand the mutation spectrum of ABCD1 and indicate that ALD represent a significant portion (4.9%, 7/142) of the spastic paraplegia entities. ALD should be considered in male patients with spastic paraplegia, even if there was no positive family history.
Abstract Aims PRRT2 variants are associated with various paroxysmal disorders. To date, more than 90 PRRT2 variants have been reported in PRRT2 ‐related disorders. Lack of functional study in majority of missense variants makes their pathogenicity uncertain. We aim to evaluate the clinical significance of PRRT2 missense variants by performing in vitro experiments. Methods We systematically reviewed PRRT2 ‐related disorders and summarized reported PRRT2 missense variants. Protein expression and subcellular localization of mutant PRRT2 were investigated in mammal cells. American College of Medical Genetics and Genomics (ACMG) guidelines were used to analyze the pathogenicity of PRRT2 missense variants. Results A total of 29 PRRT2 missense variants were identified in PRRT2 ‐related disorders. Ten variants were observed to affect both subcellular localization and protein level, three variants only affect membrane localization, and two variants only affect protein level. According to ACMG guidelines, 15 variants were finally classified as “likely pathogenic”, three as “benign”, three as “likely benign”, and eight as “uncertain significance” variants. The likely pathogenic variants were concentrated in the C‐terminal of PRRT2. Conclusions The pathogenicity of eight uncertain significance variants needs further investigation. C‐terminal of PRRT2 is crucial for its physiological function.
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