CYFIP1 Research Articles

Impaired oxysterol-liver X receptor signaling underlies aberrant cortical neurogenesis in a stem cell model of neurodevelopmental disorder

The mechanisms by which genomic risks contribute to the onset of neuropsychiatric conditions remain a key challenge and a prerequisite for successful development of effective therapies. 15q11.2 copy number variation (CNV) containing the CYFIP1 gene is associated with autism and schizophrenia. Using stem cell models, we show that 15q11.2 deletion (15q11.2del) and CYFIP1 loss of function (CYFIP1-LoF) lead to premature neuronal differentiation, while CYFIP1 gain of function (CYFIP1-GoF) favors neural progenitor maintenance. CYFIP1 dosage changes led to dysregulated cholesterol metabolism and altered levels of 24S,25-epoxycholesterol, which can mimic the 15q11.2del and CYFIP1-LoF phenotypes by promoting cortical neuronal differentiation and can restore the impaired neuronal differentiation of CYFIP1-GoF neural progenitors. Moreover, the neurogenic activity of 24S,25-epoxycholesterol is lost following genetic deletion of liver X receptor (LXRβ), while compound deletion of LXRβ in CYFIP1-/- background rescued their premature neurogenesis. This work delineates LXR-mediated oxysterol regulation of neurogenesis as a pathological mechanism in neural cells carrying 15q11.2 CNV and provides a potential target for therapeutic strategies for associated disorders.

Loss of Function in the Neurodevelopmental Disease and Schizophrenia-Associated Gene CYFIP1 in Human Microglia-like Cells Supports a Functional Role in Synaptic Engulfment

BackgroundThe CYFIP1 gene, located in the neurodevelopmental risk locus 15q11.2, is highly expressed in microglia, but its role in human microglial function as it relates to neurodevelopment is not well understood. MethodsWe generated multiple CRISPR (clustered regularly interspaced short palindromic repeat) knockouts of CYFIP1 in patient-derived models of microglia to characterize function and phenotype. Using microglia-like cells reprogrammed from peripheral blood mononuclear cells, we quantified phagocytosis of synaptosomes (isolated and purified synaptic vesicles) from human induced pluripotent stem cell (iPSC)–derived neuronal cultures as an in vitro model of synaptic pruning. We repeated these analyses in human iPSC-derived microglia-like cells derived from 3 isogenic wild-type/knockout line pairs derived from 2 donors and further characterized microglial development and function through morphology and motility. ResultsCYFIP1 knockout using orthogonal CRISPR constructs in multiple patient-derived cell lines was associated with a statistically significant decrease in synaptic vesicle phagocytosis in microglia-like cell models derived from both peripheral blood mononuclear cells and iPSCs. Morphology was also shifted toward a more ramified profile, and motility was significantly reduced. However, iPSC-CYFIP1 knockout lines retained the ability to differentiate to functional microglia. ConclusionsThe changes in microglial phenotype and function due to the loss of function of CYFIP1 observed in this study implicate a potential impact on processes such as synaptic pruning that may contribute to CYFIP1-related neurodevelopmental disorders. Investigating risk genes in a range of central nervous system cell types, not solely neurons, may be required to fully understand the way in which common and rare variants intersect to yield neuropsychiatric disorders.

Prader-Willi Syndrome and Chromosome 15q11.2 BP1-BP2 Region: A Review.

Prader-Willi syndrome (PWS) is a complex genetic disorder with three PWS molecular genetic classes and presents as severe hypotonia, failure to thrive, hypogonadism/hypogenitalism and developmental delay during infancy. Hyperphagia, obesity, learning and behavioral problems, short stature with growth and other hormone deficiencies are identified during childhood. Those with the larger 15q11-q13 Type I deletion with the absence of four non-imprinted genes (NIPA1, NIPA2, CYFIP1, TUBGCP5) from the 15q11.2 BP1-BP2 region are more severely affected compared with those with PWS having a smaller Type II deletion. NIPA1 and NIPA2 genes encode magnesium and cation transporters, supporting brain and muscle development and function, glucose and insulin metabolism and neurobehavioral outcomes. Lower magnesium levels are reported in those with Type I deletions. The CYFIP1 gene encodes a protein associated with fragile X syndrome. The TUBGCP5 gene is associated with attention-deficit hyperactivity disorder (ADHD) and compulsions, more commonly seen in PWS with the Type I deletion. When the 15q11.2 BP1-BP2 region alone is deleted, neurodevelopment, motor, learning and behavioral problems including seizures, ADHD, obsessive-compulsive disorder (OCD) and autism may occur with other clinical findings recognized as Burnside-Butler syndrome. The genes in the 15q11.2 BP1-BP2 region may contribute to more clinical involvement and comorbidities in those with PWS and Type I deletions.

Endocannabinoids; CYFIP1 gene; postsynaptic density development

Endocannabinoids; CYFIP1 gene; postsynaptic density development

Association between the rs8028440 polymorphism of CYFIP 1 gene in autism patients

Demonstrated no association between ASD and rs8028440 polymorphism of the CYFIP1 gene, which needs further studies in a larger population of ASD subjects to find the contribution of rs8028440 polymorphism in CYFIP1 gene with ASD in Iranian patients. Introduction: Given the importance of the Cytoplasmic FMR1 Interacting Protein 1 (CYFIP1 gene) in relation to neurodevelopmental abnormalities such as autism spectrum disorder (ASD), recognizing the interaction between single nucleotide polymorphisms (SNPs) of this gene in autism cases is important. In this study, we evaluated the probable association of rs8028440 polymorphism of the CYFIP1 gene with ASD disorder in Iranian subjects. Methods and patients: The CYFIP1 gene were amplified with specific primers and the PCR products were digested with RsaI restriction enzyme to obtain the rs8028440 polymorphism in 100 ASD patients and 100 healthy control cases. Finally, the samples were genotyped using direct sequencing to identify CC, CT, and TT genotypes. Results: The Hardy-Weinberg equilibrium showed no significant deviation in the subjected population. According to our results, the frequency of the C allele was higher in ASD groups than in the control group. The full length of PCR was 662 bp and through RFLP‐PCR, normal genotype (C/C), heterozygote genotype (T/C), and homozygous genotype (T/T) was detected. Ten PCR products were sequenced and the corresponded alleles A/T and Y (C or T) were determined. It was revealed no significant difference was found between ASD subjects and controls with respect to the frequency of the rs8028440 gene allele

Is There a Hemispheric Disconnect in Neurodevelopmental Disorders?

The CYFIP1 gene has been linked to autism and schizophrenia and, while there is a noted heterogeneity, both have been characterized to be disorders of connectivity. Recent studies by Dominquez-Iturza etal. and Silva etal. provide direct evidence for CYFIP1 in functional and structural connectivity in the brain.

The autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour

Copy-number variants of the CYFIP1 gene in humans have been linked to autism spectrum disorders (ASD) and schizophrenia (SCZ), two neuropsychiatric disorders characterized by defects in brain connectivity. Here, we show that CYFIP1 plays an important role in brain functional connectivity and callosal functions. We find that Cyfip1-heterozygous mice have reduced functional connectivity and defects in white matter architecture, similar to phenotypes found in patients with ASD, SCZ and other neuropsychiatric disorders. Cyfip1-deficient mice also present decreased myelination in the callosal axons, altered presynaptic function, and impaired bilateral connectivity. Finally, Cyfip1 deficiency leads to abnormalities in motor coordination, sensorimotor gating and sensory perception, which are also known neuropsychiatric disorder-related symptoms. These results show that Cyfip1 haploinsufficiency compromises brain connectivity and function, which might explain its genetic association to neuropsychiatric disorders.

Expression Analysis of CYFIP1 and CAMKK2 Genes in the Blood of Epileptic and Schizophrenic Patients.

Schizophrenia and epilepsy are two prevalent neurological disorders with high global burden to the society. Genome-wide studies have identified potential underlying causes for these neurological diseases. In the present case-control study, we have assessed expression of CYFIP1 and CAMKK2 genes in the blood samples of epileptic and schizophrenic patients compared with healthy subjects. A total of 180 subjects including 40 epileptic patients, 50 schizophrenic patients, and 90 healthy individuals participated in the study. Expression of the mentioned genes was measured using TaqMan real-time PCR. The results demonstrated a significant upregulation of CYFIP1 gene expression in epileptic patients (P = 0.029). CAMKK2 was downregulated in female schizophrenic patients compared with female healthy individuals (P = 0.048). These results may provide new insight into the pathogenesis of epilepsy and schizophrenia and suggest these genes as potential therapeutic targets for these neurological disorders. Future studies should evaluate these results in larger cohorts of patients.

Pathogenic copy number variants (pCNVs) in individuals diagnosed on the autism spectrum disorder (ASD): A closer look at candidate genes


 
 
 Introduction: The genetic basis for autism spectrum disorders (Asds) is well established and its heterogenetic nature provides us with substantial evidence for the many chromosomal aberrations associated with this complex disorder (5). however, little is known about the genes that occupy the different chromosomal regions and the gene networks they participate in as they relate to phenotypes associated with Asds. Methods: here, the author reports pathogenic copy number variants (pcnVs) validated through array-comparative genomic hybridization (cgh) and the candidate genes found on these affected regions that may be implicated in the observed clinical phenotypes in 9 patients diagnosed with an Asd. formal clinical assessments, which include a full physical examination, a medical history report, and a family history, were administered by a clinical geneticist unaware of the array-cgh results. results: The author’s findings suggest a number of genes involved in neurodevelopment as well as craniofacial and systemic features that may account for the observed phenotypes in the nine affected patients. discussion: Among the candidate genes found, the CYFIP1 gene, which is involved in maturation and maintenance of dendrites, the gamma acid receptor family (GABA) which exhibit linkage disequilibrium with autistic disorders, and the PHF8 and WNK3 genes, which have been shown to be associated with X-linked mental retardation (XlMr), present the most interesting findings as they may account for most of the neurodevelopmental pathogenesis observed in the affected patients. future studies need to be conducted in order to precisely determine the networks these genes participate in and how they are regulated to gain a deeper understanding in the roles they play in the clinical presentations of affected individuals with Asds.