OBJECTIVE: To summarize the gene therapy strategies for neurofibromatosis type 1 (NF1) and related research progress. METHODS: The recent literature on gene therapy for NF1 at home and abroad was reviewed. The structure and function of the NF1 gene and its mutations were analyzed, and the current status as well as future prospects of the transgenic therapy and gene editing strategies were summarized. RESULTS: NF1 is an autosomal dominantly inherited tumor predisposition syndrome caused by mutations in the NF1 tumor suppressor gene, which impair the function of the neurofibromin and lead to the disease. It has complex clinical manifestations and is not yet curable. Gene therapy strategies for NF1 are still in the research and development stage. Existing studies on the transgenic therapy for NF1 have mainly focused on the construction and expression of the GTPase-activating protein-related domain in cells that lack of functional neurofibromin, confirming the feasibility of the transgenic therapy for NF1. Future research may focus on split adeno-associated virus (AAV) gene delivery, oversized AAV gene delivery, and the development of new vectors for targeted delivery of full-length NF1 cDNA. In addition, the gene editing tools of the new generation have great potential to treat monogenic genetic diseases such as NF1, but need to be further validated in terms of efficiency and safety. CONCLUSION Gene therapy, including both the transgenic therapy and gene editing, is expected to become an important new therapeutic approach for NF1 patients.
Humans ; Neurofibromatosis 1/pathology* ; Neurofibromin 1/metabolism* ; GTPase-Activating Proteins ; Mutation ; Genetic Predisposition to Disease ; Genetic Therapy

OBJECTIVE: To explore the genetic basis for a child with mental retardation. METHODS: Whole exome sequencing was carried out for the child. Candidate variant was screened based on his clinical features and verified by Sanger sequencing. RESULTS: The child was found to harbor a c.995_1002delAGACAAAA(p.Asp332AlafsTer84) frameshift variant in the SYNGAP1 gene. Bioinformatic analysis suggested it to be pathogenic. The same variant was not detected in either parent. CONCLUSION The c.995_1002delAGACAAAA(p.Asp332AlafsTer84) frameshift variant of the SYNGAP1 gene probably underlay the mental retardation in this child. Above finding has expanded the spectrum of SYNGAP1 gene variants and provided a basis for the diagnosis and treatment for this child.
Child ; Humans ; Intellectual Disability/genetics* ; Frameshift Mutation ; High-Throughput Nucleotide Sequencing ; Computational Biology ; Heterozygote ; Mutation ; ras GTPase-Activating Proteins/genetics*

OBJECTIVES: To summarize the clinical phenotype and genetic characteristics of children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations. METHODS: A retrospective analysis was performed on the medical data of 8 children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations who were diagnosed and treated in the Department of Pediatrics, Xiangya Hospital of Central South University. RESULTS: The mean age of onset was 9 months for the 8 children. All children had moderate-to-severe developmental delay (especially delayed language development), among whom 7 children also had seizures. Among these 8 children, 7 had novel heterozygous mutations (3 with frameshift mutations, 2 with nonsense mutations, and 2 with missense mutations) and 1 had 6p21.3 microdeletion. According to the literature review, there were 48 Chinese children with mental retardation caused by SYNGAP1 gene mutations (including the children in this study), among whom 40 had seizures, and the mean age of onset of seizures was 31.4 months. Frameshift mutations (15/48, 31%) and nonsense mutations (19/48, 40%) were relatively common in these children. In terms of treatment, among the 33 children with a history of epileptic medication, 28 (28/33, 85%) showed response to valproic acid antiepileptic treatment and 16 (16/33, 48%) achieved complete seizure control after valproic acid monotherapy or combined therapy. CONCLUSIONS Children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations tend to have an early age of onset, and most of them are accompanied by seizures. These children mainly have frameshift and nonsense mutations. Valproic acid is effective for the treatment of seizures in most children.
Child ; Humans ; Intellectual Disability/diagnosis* ; Codon, Nonsense ; Retrospective Studies ; Valproic Acid ; ras GTPase-Activating Proteins/genetics* ; Mutation ; Seizures/genetics*

Cardiovascular System/pathology* ; Constriction, Pathologic/genetics* ; Point Mutation ; Neurofibromin 1/genetics* ; Animals ; Mice

Toxoplasma gondii is a worldwide parasite that can infect almost all kinds of mammals and cause fatal toxoplasmosis in immunocompromised patients. Apoptosis is one of the principal strategies of host cells to clear pathogens and maintain organismal homeostasis, but the mechanism of cell apoptosis induced by T. gondii remains obscure. To explore the apoptosis influenced by T. gondii, Vero cells infected or uninfected with the parasite were subjected to apoptosis detection and subsequent dual RNA sequencing (RNA-seq). Using high-throughput Illumina sequencing and bioinformatics analysis, we found that pro-apoptosis genes such as DNA damage-inducible transcript 3 (DDIT3), growth arrest and DNA damage-inducible α (GADD45A), caspase-3 (CASP3), and high-temperature requirement protease A2 (HtrA2) were upregulated, and anti-apoptosis genes such as poly(adenosine diphosphate (ADP)-ribose) polymerase family member 3 (PARP3), B-cell lymphoma 2 (Bcl-2), and baculoviral inhibitor of apoptosis protein (IAP) repeat containing 5 (BIRC5) were downregulated. Besides, tumor necrosis factor (TNF) receptor-associated factor 1 (TRAF1), TRAF2, TNF receptor superfamily member 10b (TNFRSF10b), disabled homolog 2 (DAB2)‍-interacting protein (DAB2IP), and inositol 1,4,5-trisphosphate receptor type 3 (ITPR3) were enriched in the upstream of TNF, TNF-related apoptosis-inducing ligand (TRAIL), and endoplasmic reticulum (ER) stress pathways, and TRAIL-receptor 2 (TRAIL-R2) was regarded as an important membrane receptor influenced by T. gondii that had not been previously considered. In conclusion, the T. gondii RH strain could promote and mediate apoptosis through multiple pathways mentioned above in Vero cells. Our findings improve the understanding of the T. gondii infection process through providing new insights into the related cellular apoptosis mechanisms.
Animals ; Apoptosis ; Chlorocebus aethiops ; Gene Expression Profiling ; Humans ; Mammals/genetics* ; Toxoplasma/genetics* ; Toxoplasmosis/pathology* ; Vero Cells ; ras GTPase-Activating Proteins/genetics*

OBJECTIVE: To explore the clinical features and genetic characteristics of a child with 5q14.3 microdeletion syndrome. METHODS: Whole exome sequencing (WES) and low-coverage massively parallel copy number variation sequencing (CNV-seq) were used to determine the potentially pathogenic variants as well as the copy number variations (CNVs). Candidate CNVs were verified by real-time fluorescence quantitative PCR. RESULTS: The patient presented with psychomotor retardation, epilepsy, peculiar face and hypotonia. The results of WES suggested that he has carried a heterozygous deletion for chr5:86 564 268-88 119 605. CNV-seq indicated that the patient carried a heterozygous deletion of 4.76 Mb heterozygous deletion on chromosome 5q14.3. The MEF2C gene and RASA1 gene in the deletion area were verified by real-time fluorescence quantitative PCR. The results showed that the MEF2C geneand RASA1 gene were heterozygous deletion, which was consistent with the sequencing results. CONCLUSION The child was diagnosed with 5q14.3 microdeletion syndrome. Haploinsufficiency of the MEF2C gene may underlie the manifestations of 5q14.3 microdeletion syndrome.
Chromosome Deletion ; Chromosome Disorders ; DNA Copy Number Variations ; Genetic Testing ; Humans ; Male ; Phenotype ; Whole Exome Sequencing ; p120 GTPase Activating Protein

OBJECTIVE: To explore the molecular basis for a Chinese family affected with neurofibromatosis type I. METHODS: Peripheral blood samples were collected from the proband and his parents. Potential mutations of NF1 gene were screened by PCR and Sanger sequencing. Pathogenicity of candidate mutations was analyzed using Polyphen-2 and Provean software. RESULTS: Two mutations of the NF1 gene, including c.702G>A (synonymous mutation) and c.1733T>G (missense mutation), were discovered in the proband. Neither mutation was found in his parents and 50 healthy controls. Bioinformatics analysis indicated that the c.1733T>G mutation (p.Leu578Arg) was probably damaging. The affected codon L578 is highly conserved across various species. CONCLUSION The c.1733T>C mutation of the NF1 gene probably underlies the neurofibromatosis type I in this family.
Asian Continental Ancestry Group ; Genes, Neurofibromatosis 1 ; Humans ; Mutation ; Neurofibromatosis 1 ; genetics ; Neurofibromin 1 ; genetics ; Pedigree

OBJECTIVE: To report on a child with mental retardation caused by SYNGAP1 gene mutation. METHODS: Peripheral blood samples were collected from the proband and her parents. High throughput sequencing (HTS) was employed for screening for potential mutation in the patient. Suspected mutation was validated by Sanger sequencing of the child and her parents. RESULTS: By HTS, a previously unknown mutation [c.1656C>A (p.C552*)] was found in exon 10 of the SYNGAP1 gene in the proband. Sanger sequencing confirmed the heterozygous nature of the mutation and that neither of her parents carried the same mutation. CONCLUSION The dysmorphism and developmental delay of the child were probably due to the pathogenic mutation of the SYNGAP1 gene. HTS can facilitate elucidation of the genetic etiology with efficiency, which has great significance in the diagnosis, treatment and prognosis of the child.
Child ; Exons ; Female ; Heterozygote ; High-Throughput Nucleotide Sequencing ; Humans ; Intellectual Disability ; genetics ; Mutation ; ras GTPase-Activating Proteins ; genetics

Neurofibromatosis type 1 (NF1) is a common neurocutaneous syndrome that presents with multiple café-au-lait spots, skinfold freckling, dermatofibromas, neurofibromas, and Lisch nodules. Mutations of the NF1 gene, encoding the protein neurofibromin, have been identified as the cause of this disease. NF1 can also present with precocious puberty and be associated with optic pathway tumors. Hypothalamic hamartoma as the cause of precocious puberty in patients with NF1 has been rarely described in the literature. Here, we report the findings for a patient with NF1 and precocious puberty associated with a hypothalamic hamartoma who had a newly discovered 14-bp deletion mutation in exon 5 of NF1. To our knowledge, this is the first time this combination is reported in the literature.
Adolescent ; Child* ; Exons ; Genes, Neurofibromatosis 1 ; Hamartoma* ; Histiocytoma, Benign Fibrous ; Humans ; Hypothalamic Diseases ; Neurocutaneous Syndromes ; Neurofibroma ; Neurofibromatoses* ; Neurofibromatosis 1* ; Neurofibromin 1 ; Puberty ; Puberty, Precocious* ; Sequence Deletion

Neurofibromatosis type 1 (NF-1) is an autosomal dominant neurocutaneous syndrome caused by mutations in the neurofibromin gene. NF-1 patients have a high risk of tumors, and optic glioma is the most commonly observed central nervous system tumor in these patients. However, glioblastoma is extremely rare in pediatric NF-1 patients. Here we report the discovery of a novel heterozygous c.6766_6767insAA (p.Ser2256Lysfs*4), pathogenic mutation in the neurofibromin gene in a 17-year-old boy with NF-1-associated glioblastoma.
Adolescent ; Central Nervous System ; Glioblastoma* ; Humans ; Male ; Neurocutaneous Syndromes ; Neurofibromatoses* ; Neurofibromatosis 1 ; Neurofibromin 1* ; Optic Nerve Glioma