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Science Class

Articoli accademici


Man mano che troviamo articoli di ricerca interessanti, li presenteremo qui nella nostra sezione di ricerca in primo piano. Grazie aLa dottoressa Genevieve Konopka per aver dedicato del tempo a riassumere alcune delle ricerche che lei e il suo team stanno svolgendo presso l'Università di  Texas – Sud-ovest.

Questi documenti sono selezionati da una biblioteca letteraria più ampia gestita dalla Fondazione.

Fai clic qui per vedere il biblioteca completa.



Individuals with FOXP1 syndrome present with a complex neurobehavioral profile with high rates of ADHD, anxiety, repetitive behaviors, and sensory symptoms

M. Pilar Trelles, Tess Levy, Bonnie Lerman, Paige Siper, Reymundo Lozano, Danielle Halpern, Hannah Walker, Jessica Zweifach, Yitzchak Frank, Jennifer Foss-Feig, Alexander Kolevzon & Joseph Buxbaum

These findings have important implications for the treatment and care of individuals with FOXP1 syndrome. Notably, standardized testing for ASD showed high sensitivity, but low specificity, when compared to expert consensus diagnosis. Furthermore, many individuals in our cohort who received diagnoses of attention-deficit/hyperactivity disorder or anxiety disorder were not being treated for these symptoms; therefore, our findings suggest that there may be immediate areas for improvements in treatment for some individuals.



Severe speech impairment is a distinguishing feature of FOXP1-related disorder

Ruth O Braden, David J Amori, Simon E Fisher, Cristina Mei,
Candace T Muers, Heather Mefford, DeepakGill, Siddharth Srivastava,
Lindsay C Swanson, Himanshu Goel, Ingrid E Scheffer, Angela T Morgan

This study delineates the speech and language phenotype of a cohort of individuals with FOXP1-related disorder. Individuals were given standardized tests to examine speech and oral motor function, receptive and expressive language, non-verbal cognition, and adaptive behaviour. Clinical history and cognitive assessments were analysed together with speech and language findings. The interpretation of the results is FOXP1-related disorder is characterized by a complex speech and language phenotype with prominent dysarthria, broader motor planning and programming deficits, and linguistic-based phonological errors. Diagnosis of the speech phenotype associated with FOXP1-related dysfunction will inform early targeted therapy.



FOXP1 negatively regulates intrinsic excitability in D2 striatal projection neurons by promoting inwardly rectifying and leak potassium currents

Nitin Khandelwal, Sheridan Cavalier, Volodymyr Rybalchenko, Ashwinikumar Kulkarni, Ashley G Anderson, Genevieve Konopka, Jay R Gibson

This study describes the possible cause of hyperexcitability of specific neurons in the striatum due to the absence of FOXP1. The striatum is composed of two major neuronal subtypes - D1 and D2 neurons that are involved in regulating motor activities by acting on two opposite pathways. FOXP1 is highly expressed in striatal D1 and D2 neurons. The authors used mice with deletion of the Foxp1 gene in either D1 or D2 neurons and studied the electrical properties of these neurons. Deletion of Foxp1 increases the electrical resistance of these neurons leading to their hyperexcitability. Remarkably, these effects are more prominent in D2 neurons than in D1 neurons. The firing pattern of a neuron is determined by several factors including the ion channels and receptors present on its membrane. The authors then conducted the neuronal recordings in the presence of blockers of specific potassium channels and identified two major categories of potassium channels, leak and inwardly rectifying, regulated by FOXP1. Finally, all of these effects are either absent or minimal in D1 neurons as compared to D2 neurons, which suggests a cell-type specific role of FOXP1 in the striatum.



Single-Cell Analysis of Foxp1-Driven Mechanisms Essential for Striatal Development

Ashley G Anderson, Ashwinikumar Kulkarni, Matthew Harper, Genevieve Konopka

The striatum is a brain region that receives a neurochemical called dopamine from other brain regions to control behavior. Using mice with loss of Foxp1 specifically in the striatum, the authors found that Foxp1 regulates the structure of the striatum by altering the types of dopamine-receiving cells that develop and disrupting the connections these cells make with other parts of the brain. Interestingly, these changes only occur when Foxp1 is deleted from one subset of striatal cells. In addition, different motor and social behavioral deficits occur in these mice when Foxp1 is removed from specific cell types. Taken together, this study highlights that Foxp1 has distinct functions in the brain depending on which cells express it.



Whole exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene

Mir Reza Bekheirnia, MD, FACMG (2018)

This study used whole exome sequencing (WES) in identifying gene mutations related to congenital anomalies (birth defects) of the kidney and urinary tract. The researchers identified six of the eight individuals with FOXP1 variants as having urinary tract defects. This implicates the FOXP1 gene in the development of the urinary tract.



FOXP1-related intellectual disability syndrome: a recognizable entity

Ilse Meerschaut , Daniel Rochefort, Nicole Revençu, Justine Pètre, Christina Corsello,Guy A Rouleau (2017)

This study correlates clinical and genetic data of forty-eight individuals with a FOXP1 variant. The data demonstrates I.D. (intellectual disability), SLI (specific language impairment), and NMD (neuromotor delay) and recurrent facial features are noted. Autistic and other behavioral features are noted. Various organ system malformations are associated with the mutation. Hearing loss and feeding difficulties are also indicated in the data. The wide clinical spectrum and frequent systemic involvement identified in these forty-eight patients will help in the evaluation and clinical management of individuals with FOXP1 Syndrome.



Foxp1 in Forebrain Pyramidal Neurons Controls Gene Expression Required for Spatial Learning and Synaptic Plasticity

Daniel J Araujo, Kazuya Toriumi , Christine O Escamilla, Ashwinikumar Kulkarni, Ashley G Anderson, Matthew Harper, Noriyoshi Usui, Jacob Ellegood, Jason P Lerch, Shari G Birnbaum, Haley O Tucker, Craig M Powell, Genevieve Konopka

To understand the function of FOXP1 in specific brain regions, in this paper, the authors used a mouse model where Foxp1 is removed from the neocortex, the outermost layer of the brain, and the hippocampus, a brain region important for memory. The authors then studied these mice in adulthood and found that the mice had simpler, less complex communications. The authors also report that these mutant mice have reduced social interactions, hyperactivity, and anxiety-like behaviors. Though the mice had no change in general learning ability, they had difficulties in spatial learning, or remembering the location of where objects are or where an event occurred. The volume of the hippocampus was also decreased. Finally, the authors measured how loss of Foxp1 affects overall gene expression and found that many genes important for brain development are altered as well as genes already implicated in ASD. Different genes were regulated by Foxp1 in either the hippocampus or neocortex. Together, these data suggest that Foxp1 has specific functions in different regions of the brain.



Foxp1 regulation of neonatal vocalizations via cortical development

Noriyoshi Usui, Daniel J Araujo, Ashwinikumar Kulkarni, Marissa Co, Jacob Ellegood, Matthew Harper, Kazuya Toriumi, Jason P Lerch, Genevieve Konopka

To understand the function of FOXP1 in specific brain regions, in this paper, the authors again used a mouse model where Foxp1 is removed from the neocortex, the outermost layer of the brain, and the hippocampus, a brain region important for memory. The authors find that these mutant mice do not call out to their mothers as much, the usual organization of cells in the neocortex is changed, and the neocortex is overall smaller. Since the function of Foxp1 is to regulate how much other genes are expressed, the authors examined how loss of Foxp1 affects overall gene expression in the neocortex or hippocampus. They found that genes regulated by Foxp1 are relevant for the birth of neurons or for how neurons get to their destination in the brain. Indeed, when an altered version of Foxp1 is introduced to these mice, the neurons of these mice are not always able to reach their appropriate final location. The volume of the cortex and hippocampus was also reduced in these mice lacking Foxp1.



Prospective Investigation of FOXP1 Syndrome

Siper ET AL (2017)

This study identifies nine children, between the ages of 5-12 years old, who have been identified as having FOXP1 Syndrome. Evaluations were compiled by teams of clinicians including medical, neurological, dysmorphic, and neuro-psychological. An extensive battery of clinical assessments were administered to evaluate autism spectrum disorder symptomatology, intellectual functioning, adaptive behavior, receptive and expressive language, fine and gross motor skills, visual-motor integration, and psychiatric features. Charts are included in the study to see the results.



FoxP1 orchestration of ASD-relevant signaling pathways in the striatum

Daniel J Araujo, Ashley G Anderson, Stefano Berto, Wesley Runnels, Matthew Harper, Simon Ammanuel, Michael A Rieger, Hung-Chung Huang, Kacey Rajkovich, Kristofer W Loerwald, Joseph D Dekker, Haley O Tucker, Joseph D Dougherty, Jay R Gibson, Genevieve Konopka

The function of FOXP1 is to turn on and off the expression of other genes. In this study, the authors sought to understand which genes FOXP1 regulates in the brain. Both human brain cells and mice with FoxP1 mutations were used, and the authors found that FoxP1 regulates other genes that are known to be implicated in autism. Furthermore, Foxp1 mutations in mice increase the activity of a subset of neurons in a region of the brain called the striatum. FoxP1 also regulates the expression of autism genes in these striatal neurons. Taken together, this study showed an important role for FoxP1 in regulating other known autism genes in the striatum, a brain region important for behaviors associated with autism.

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