Yi-Wu Shi

Guangzhou Medical University | gzhmc · the second affiliated hospital

USP25 encodes ubiquitin-specific proteases 25, a key member of deubiquitinating enzyme family and is involved in neural fate determination. Although abnormal expression in Down’s syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a coh...

NUS1 encodes the Nogo-B receptor, a critical regulator for unfolded protein reaction (UPR) signaling. Although several loss-of-function variants of NUS1 have been identified in patients with developmental and epileptic encephalopathy (DEE), the role of the NUS1 variant in Lennox-Gastaut syndrome (LGS), a severe child-onset DEE, remains unknown. In...

Background The GABRA1 gene, encoding the GABRAR subunit α1, plays vital roles in inhibitory neurons. Previously, the GABRA1 gene has been identified to be associated with developmental and epileptic encephalopathy (DEE) and idiopathic generalized epilepsy (IGE). This study aims to explore the phenotypic spectrum of GABRA1 and molecular subregional...

Interpreting the sequence variants is a scientific challenge, as well as realistic task in clinical practice. The pathogenicity of variants depends not only on the damage but also the genetic dependent quantity (GDQ, quantitative genetic function required for normal life) that differs in each gene, but was not considered in previous protocols. We d...

Interpreting sequence variants is a scientific challenge as well as a realistic task in clinical practice. The pathogenicity of a variant depends on not only its damage but also the genetic dependent quantity (GDQ, quantitative genetic function required for normal life) that differs in each gene but was not considered in previous protocols. We deve...

The human life depends on the function of proteins that are encoded by about twenty-thousand genes. The gene-disease associations in majority genes are unknown and the mechanisms underlying pathogenicity of genes/variants and common diseases remain unclear. We studied how human life depends on the genes, i.e., the genetic-dependence, which was clas...

Objectives: Variants in NEXMIF had been reported associated with intellectual disability (ID) without epilepsy or developmental epileptic encephalopathy (DEE). It is unkown whether NEXMIF variants are associated with epilepsy without ID. This study aims to explore the phenotypic spectrum of NEXMIF and the genotype-phenotype correlations. Material...

Background Epileptic encephalopathy is a devastating epilepsy with etiologies largely elusive, despite whole-gene/exon sequencing of large cohorts. This study targeted the genetic causes of childhood epileptic encephalopathy, typically Lennox-Gastaut syndrome (LGS) featured by age-dependent onset and characteristic clinical manifestations. Methods...

Background: HCFC1 encodes transcriptional co-regulator HCF-1, which undergoes an unusual proteolytic maturation at a centrally located proteolysis domain. HCFC1 variants were associated with X-linked cobalamin metabolism disorders and mental retardation-3. This study aimed to explore the role of HCFC1 variants in common epilepsy and the mechanism...

Determining gene-disease association is a major challenge of genetics and also the precondition for evaluating the pathogenicity of variants. With considerations on the genetic dependent features and the clinical/genetic characteristics that are associated with gene-disease association, we proposed a pathogenic potential and pathogenic feature asse...

Determining gene-disease associationsis an essential task but a major challenge of genetic studies. It is also the precondition for evaluating the pathogenicity of variants. Considering what determines the gene-disease association and which clinical-genetic features reflect the gene-disease association, we proposed a pathogenic potential and pathog...

Purpose Previously, mutations in the voltage-gated calcium channel subunit alpha1 A ( CACNA1A ) gene have been reported to be associated with paroxysmal disorders, typically as episodic ataxia type 2. To determine the relationship between CACNA1A and epilepsies and the role of molecular sub-regional on the phenotypic heterogeneity. Methods Trio-ba...

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare genetic disorder caused by mutations in the mitochondrial pantothenate kinase 2 ( PANK2 ) gene and displays an inherited autosomal recessive pattern. In this study, we identified eight PANK2 mutations, including three novel mutations (c.1103A > G/p.D368G, c.1696C > G/p.L566V, and c.1...

Objective Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions. Antiseizure medications (ASMs) with aromatic ring structure, including carbamazepine, are among the most common culprits. Screening for human leukocyte antigen (HLA) allele HLA‐B*15:02 is recommended prior to initiating treatme...

Aims To identify novel pathogenic gene of febrile seizures (FS)/epilepsy with antecedent FS (EFS+). Methods The trio‐based whole‐exome sequencing was performed in a cohort of 462 cases with FS/EFS+. Silico programs, sequence alignment, and protein modeling were used to predict the damaging of variants. Statistical testing was performed to analyze...

Objective: The objective of this study is to explore the role of GRIN2A gene in idiopathic generalized epilepsies and the potential underlying mechanism for phenotypic variation. Methods: Whole-exome sequencing was performed in a cohort of 88 patients with idiopathic generalized epilepsies. Electro-physiological alterations of the recombinant N -me...

Aims CHD4 gene, encoding chromodomain helicase DNA‐binding protein 4, is a vital gene for fetal development. In this study, we aimed to explore the association between CHD4 variants and idiopathic epilepsy. Methods Trios‐based whole‐exome sequencing was performed in a cohort of 482 patients with childhood idiopathic epilepsy. The Clinical Validity...

To characterize human leukocyte antigen (HLA) loci as risk factors in aromatic antiepileptic drug-induced maculopapular exanthema (AED-MPE). A case-control study was performed to investigate HLA loci involved in AED-MPE in a southern Han Chinese population. Between January 2007 and June 2019, 267 patients with carbamazepine (CBZ), oxcarbazepine (OX...

The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein, mammalian uncoordinated 13-2 (Munc13-2), which is highly expressed in the brain—predominantly in the cerebral cortex—and plays an essential role in synaptic vesicle priming and fusion, potentially affecting neuronal excitability. However, the functional significance of the UNC13B mut...

RYR2 encodes ryanodine receptor 2 protein (RYR-2) that is mainly located on endoplasmic reticulum membrane and regulates intracellular calcium concentration. The RYR-2 protein is ubiquitously distributed and highly expressed in the heart and brain. Previous studies have identified the RYR2 mutations in the etiology of arrhythmogenic right ventricul...

Mutations in SLC6A1, encoding γ-aminobutyric acid (GABA) transporter 1 (GAT-1), have been recently associated with a spectrum of epilepsy syndromes, intellectual disability and autism in clinic. However, the pathophysiology of the gene mutations is far from clear. Here we report a novel SLC6A1 missense mutation in a patient with epilepsy and autism...

Ilepcimide (ICM), a clinically effective antiepileptic drug, has been used in China for decades; however, its antiepileptic mechanism remains unclear. ICM is structurally similar to antiepileptic drug lamotrigine (LTG). LTG exerts its anticonvulsant effect by inhibiting voltage-gated Na⁺ channel (NaV) activity. Thus it is speculated that ICM also e...

Introduction Idiopathic focal epilepsy (IFE) is a group of self-limited epilepsies. The etiology for the majority of the patients with IFE remains elusive. We thus screened disease-causing variants in the patients with IFE. Methods Whole-exome sequencing was performed in a cohort of 323 patients with IFE. Protein modeling was performed to predict...

Background: Mutations in SLC6A1 have been associated mainly with myoclonic atonic epilepsy (MAE) and intellectual disability. We identified a novel missense mutation in a patient with Lennox-Gastaut syndrome (LGS) characterized by severe seizures and developmental delay. Methods: Exome Sequencing was performed in an epilepsy patient cohort. The...

GABRB3 is highly expressed early in the developing brain, and its encoded β3 subunit is critical for GABAA receptor assembly and trafficking as well as stem cell differentiation in embryonic brain. To date, over 400 mutations or variants have been identified in GABRB3. Mutations in GABRB3 have been increasingly recognized as a major cause for sever...

Antiepileptic drugs frequently cause cutaneous adverse reactions (cADRs). Numerous studies have reported associations between human leukocyte antigen (HLA) alleles and cADRs caused by single antiepileptic drug in Southern Han Chinese people. However, the relationship between the HLA allele and cADRs sequentially induced by two or more antiepileptic...

Epileptic encephalopathies comprise a group of catastrophic epilepsies with heterogeneous genetic etiology. Although next-generation sequencing techniques can reveal a number of de novo variants in epileptic encephalopathies, evaluating the pathogenicity of these variants can be challenging. Determining the pathogenic potential of genes in epilepti...

Background: Autism spectrum disorder (ASD) in epilepsy has been a topic of increasing interest, which in general occurs in 15-35% of the patients with epilepsy, more frequently in those with intellectual disability (ID). Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) are two typical forms of intractable epileptic encephalopathy associated...

Epileptic encephalopathies are severe epilepsy disorders with strong genetic bases. We performed targeted next-generation sequencing in 70 patients with epileptic encephalopathies. The likely pathogenicity of variants in candidate genes was evaluated by American College of Medical Genetics and Genomics (ACMG) scoring taken together with the accepte...

ARHGEF9 resides on Xq11.1 and encodes collybistin, which is crucial in gephyrin clustering and GABAA receptor localization. ARHGEF9 mutations have been identified in patients with heterogeneous phenotypes, including epilepsy of variable severity and intellectual disability. However, the mechanism underlying phenotype variation is unknown. Using nex...

N-methyl-D-aspartate receptors (NMDARs), a subtype of glutamate-gated ion channels, play a central role in epileptogenesis. Recent studies have identified an increasing number of GRIN2A (a gene encoding the NMDAR GluN2A subunit) mutations in patients with epilepsy. Phenotypes of GRIN2A mutations include epilepsy-aphasia disorders and other epilepti...

Ion channels are crucial in the generation and modulation of excitability in the nervous system and have been implicated in human epilepsy. Forty-one epilepsy-associated ion channel genes and their mutations are systematically reviewed. In this paper, we analyzed the genotypes, functional alterations (funotypes), and phenotypes of these mutations....

Objective To investigate the involvement of human leukocyte antigen (HLA) loci in aromatic antiepileptic drug–induced cutaneous adverse reactions. Methods A case-control study was performed to detect HLA loci involved in aromatic antiepileptic drug–induced Stevens-Johnson syndrome in a southern Han Chinese population. Between January 1, 2006, and...

The SCN1A gene with 1274 point mutations in the coding regions or genomic rearrangements is the most clinically relevant epilepsy gene. Recent studies have demonstrated that variations in the noncoding regions are potentially associated with epilepsies, but no distinct mutation has been reported. We sequenced the 5′ upstream region of SCN1A in 166...

Development in genetic technology has led to the identification of an increasing number of genes associated with epilepsy. These discoveries will both provide the basis for including genetic tests in clinical practice and improve diagnosis and treatment of epilepsy. By searching through several databases (OMIM, HGMD, and EpilepsyGene) and recent pu...

Mutations in the SCN1A gene have been identified in epilepsy patients with widely variable phenotypes and modes of inheritance, and in asymptomatic carriers. This raises challenges in evaluating the pathogenicity of SCN1A mutations. We systematically reviewed all SCN1A mutations and established a database containing information on functional altera...

Despite several studies investigating the association between the human leukocyte antigen HLA-B*1502 allele and lamotrigine-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Han Chinese subjects, the relationship remains unclear. We performed a systematic review and meta-analysis to ascertain the association between the...

Mutations in the sodium channel gene, SCN1A (NaV1.1), have been linked to a spectrum of epilepsy syndromes, and many of these mutations occur in the pore region of the channel. Electrophysiological characterization has revealed that most SCN1A mutations in the pore region result in complete loss of function. SCN3A mutations have also been identifie...

Mutations in the SCN1A gene-encoding voltage-gated sodium channel α-I subunit (Nav1.1) cause various spectrum of epilepsies including Dravet syndrome (DS), a severe and intractable form. A large number of SCN1A mutations identified from the DS patients lead to the loss of function or truncation of Nav1.1 that result in a haploinsufficiency effects,...

We investigated the association between oxcarbazepine (OXC)-induced maculopapular eruption (MPE) and HLA-B alleles in a northern Han Chinese population, and conducted an analysis of clinical risk factors for OXC-MPE. Forty-two northern Han Chinese patients who had been treated with OXC in Changchun, China were genotyped. Among them were 14 cases wi...

Paroxysmal dyskinesias (PDs) are a group of episodic movement disorders with marked variability in clinical manifestation and potential association with epilepsy. PRRT2 has been identified as a causative gene for PDs, but the phenotypes and inheritance patterns of PRRT2 mutations need further clarification. In this study, ten familial and 21 sporad...

Oxcarbazepine (OXC) is a promising alternative for patients who cannot tolerate carbamazepine. Recently, however, it has been reported that OXC-induced cutaneous adverse drug reactions (cADRs) are prevalent and may lead to drug discontinuation. Additionally, these reactions are thought to be associated with HLA-B*1502. This study aims to investigat...

Previous studies have demonstrated a strong association between carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (CBZ-induced SJS/TEN) and HLA-B*1502 in Chinese, and HLA-A*3101 but not HLA-B*1502 in Caucasians and Japanese. Cases with CBZ-induced SJS/TEN negative for HLA-B*1502 were reported recently in Southeast Asia....

SCN1A is the most relevant epilepsy gene. Mutations of SCN1A generate phenotypes ranging from the extremely severe form of Dravet syndrome (DS) to a mild form of generalized epilepsy with febrile seizures plus (GEFS+). Mosaic SCN1A mutations have been identified in rare familial DS. It is suspected that mosaic mutations of SCN1A may cause other typ...

Voltage-gated sodium channel α-subunit type III (Na(v)1.3) is mainly expressed in the central nervous system and is associated with neurological disorders. The expression of mouse Scn3a product (Na(v)1.3) mainly occurs in embryonic and early postnatal brain but not in adult brain. Here, we report for the first time the identification and characteri...

Previous studies have reported that patients with phenytoin-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (PHT-induced SJS/TEN) were positive for HLA-B*1502. We genotyped two patients with PHT-induced SJS using both polymerase chain reaction with sequence-specific primers and sequencing. The results revealed that one patient from...

Lamotrigine (LTG) is a commonly used antiepileptic drug. However, the use of LTG is limited because of its cutaneous adverse drug reactions (cADRs) ranging from mild maculopapular eruption (MPE) to severe Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). A strong association between HLA-B*1502 and carbamazepine-induced SJS/TEN ha...

To investigate the cutaneous adverse reactions to antiepileptic drugs (AEDs), clinical characteristic and the association with HLA-B*1502. A retrospective analysis of four cases of antiepileptic drug hypersensitive syndrome (AHS) were performed on the basis of clinical data, cutaneous adverse reactions to carbamazepine (CBZ) (n = 2) including Steve...

Generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy in infancy (SMEI) are associated with sodium channel α-subunit type-1 gene (SCN1A) mutations. Febrile seizures and partial seizures occur in both GEFS+ and SMEI; sporadic onset and seizure aggravation by antiepileptic drugs (AEDs) are features of SMEI. We thus sea...

Till now truncation mutations of voltage-gated sodium channel alpha subunit type I (SCN1A) gene were mostly found in severe myoclonic epilepsy of infancy (SMEI) patients. In this research we first identified two novel de novo truncation mutations (S662X and M145fx148) in two patients whose phenotypes were quite milder compared with SMEI patients. O...

A challenge in identifying the transcription regulatory region is that the locations of eukaryotic transcriptional elements are often diverse among different genes. SCN1A, a disease-related sodium channel gene, has a complex 5 0 -untranslated region and diverse mRNA transcripts, which might be driven by different promoters. By cross-species sequenc...

To investigate the clinical features and detection of pantothenate kinase 2 (PANK2) gene mutation in a Chinese patient with Hallervorden-Spatz syndrome (HSS). The clinical features were analyzed in one HSS patient. PANK2 gene mutations were detected by polymerase chain reaction (PCR) and DNA sequence analysis in this patient, her parents and 50 unr...

Voltage-gated sodium channels play critical roles in the excitability of the brain. A decreased level of Na(v)1.1 has been identified as the cause of severe myoclonic epilepsy in infancy. In the present study, we identified the transcription start site and three 5'-untranslated exons of SCN1A by using 5'-full RACE. The 2.5-kb region upstream of the...

Lipoprotein lipase (LPL), which plays an essential role in plasma lipoprotein metabolism and transportation, appears to be a risk factor for ischemic vascular diseases. Several studies have recently reported the presence of relationship between HindIII, PvuII, Ser447Ter (C-->G) polymorphisms of LPL and ischemic vascular diseases. We first studied t...

Our previous studies showed that DAZAP2 (deleted in azoospermia associated protein 2) was the most profoundly downregulated gene in bone marrow mononuclear cells from multiple meyloma (MM) patients. The results implicated a role for DAZAP2 as a potential tumor suppressor involved in the origin and development of MM. To further understand the molecu...

In our previous study, we found that DAZAP2 was the most significantly down regulated gene when differential screening of complementary DNA (cDNA) chips were used to analyze mRNA isolated from bone marrow mononuclear cells from newly diagnosed multiple myeloma (MM) patients without anticancer treatment. In this study, we observed DAZAP2 mRNA and pr...

Lycorine is a natural anti-tumor alkaloid extracted from Amaryllidaceae and has various biological effects on malignant cells. The present study explores the effects of lycorine on the human multiple meyloma cell line, KM3, and the possible mechanisms of these effects. An MTT assay showed that lycorine had significant inhibitory activity on KM3 cel...

To determine the difference in gene expression between human multiple myeloma (MM) and normal bone marrow. cDNA chip was used to detect the mRNA of mononuclear cell from 10 untreated MM patients and 10 cases of normal bone marrow. Of the 2,048 genes, we found 566 different expression genes, of which the expression of 237 genes was higher and 329 lo...

In order to look for the tumor-associated genes from human multiple myeloma (MM), a cDNA library of human multiple myeloma cell line ARH-77 was constructed with eukaryote expression vector pcDNA3.1(+). The length of inserted fragments in library was 1.2 kb in average. All clones in cDNA library were transferred in situ to nylon membrane, which was...

Objective: Febrile seizures (FS) are the most common convulsive events in humans. It can be a benign disorder occurring only in infancy or childhood between 3 months and 6 years. It also may be part of epilepsy syndromes such as generalized epilepsy with febrile seizure plus (GEFS+) and severe myoclonic epilepsy of infancy (SME or SMEI)). GEFS+ is...