Schaaf CP


Full name : Schaaf Christian P

First name : Christian

Mail : Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States\; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX

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Country : USA

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References (8)

Title : Mecp2 Deletion from Cholinergic Neurons Selectively Impairs Recognition Memory and Disrupts Cholinergic Modulation of the Perirhinal Cortex - Ballinger_2019_eNeuro_6_
Author(s) : Ballinger EC , Schaaf CP , Patel AJ , De Maio A , Tao H , Talmage DA , Zoghbi HY , Role LW
Ref : eNeuro , 6 : , 2019
Abstract : Rett Syndrome is a neurological disorder caused by mutations in the gene encoding methyl CpG binding protein 2 (MeCP2) and characterized by severe intellectual disability. The cholinergic system is a critical modulator of cognitive ability and is affected in patients with Rett Syndrome. To better understand the importance of MeCP2 function in cholinergic neurons, we studied the effect of selective Mecp2 deletion from cholinergic neurons in mice. Mice with Mecp2 deletion from cholinergic neurons were selectively impaired in assays of recognition memory, a cognitive task largely mediated by the perirhinal cortex (PRH). Deletion of Mecp2 from cholinergic neurons resulted in profound alterations in baseline firing of L5/6 neurons and eliminated the responses of these neurons to optogenetic stimulation of cholinergic input to PRH. Both the behavioral and the electrophysiological deficits of cholinergic Mecp2 deletion were rescued by inhibiting ACh breakdown with donepezil treatment.
ESTHER : Ballinger_2019_eNeuro_6_
PubMedSearch : Ballinger_2019_eNeuro_6_
PubMedID: 31562178

Title : The human clinical phenotypes of altered CHRNA7 copy number - Gillentine_2015_Biochem.Pharmacol_97(4)_352
Author(s) : Gillentine MA , Schaaf CP
Ref : Biochemical Pharmacology , 97 :352 , 2015
Abstract : Copy number variants (CNVs) have been implicated in multiple neuropsychiatric conditions, including autism spectrum disorder (ASD), schizophrenia, and intellectual disability (ID). Chromosome 15q13 is a hotspot for such CNVs due to the presence of low copy repeat (LCR) elements, which facilitate non-allelic homologous recombination (NAHR). Several of these CNVs have been overrepresented in individuals with neuropsychiatric disorders; yet variable expressivity and incomplete penetrance are commonly seen. Dosage sensitivity of the CHRNA7 gene, which encodes for the alpha7 nicotinic acetylcholine receptor in the human brain, has been proposed to have a major contribution to the observed cognitive and behavioral phenotypes, as it represents the smallest region of overlap to all the 15q13.3 deletions and duplications. Individuals with zero to four copies of CHRNA7 have been reported in the literature, and represent a range of clinical severity, with deletions causing generally more severe and more highly penetrant phenotypes. Potential mechanisms to account for the variable expressivity within each group of 15q13.3 CNVs will be discussed.
ESTHER : Gillentine_2015_Biochem.Pharmacol_97(4)_352
PubMedSearch : Gillentine_2015_Biochem.Pharmacol_97(4)_352
PubMedID: 26095975

Title : Nicotinic acetylcholine receptors in human genetic disease - Schaaf_2014_Genet.Med_16_649
Author(s) : Schaaf CP
Ref : Genet Med , 16 :649 , 2014
Abstract : Nicotinic acetylcholine receptors represent a family of ligand-gated ion channels that are widely expressed in the central and peripheral nervous systems. To date, 16 genes encoding subunits of mammalian nicotinic acetylcholine receptors have been identified. The various subunits form homomeric or heteromeric receptor proteins, allowing for a complex and adaptable system of nicotinic neurotransmission. Mutations of nicotinic receptor genes can cause Mendelian disorders, most importantly congenital myasthenic syndromes, multiple pterygium syndromes, and nocturnal frontal lobe epilepsies. Haploinsufficiency of CHRNA7 predisposes to neuropsychiatric phenotypes in 15q13.3 deletion syndrome. The role of various nicotinic receptor genes is also discussed for complex disorders such as addiction, schizophrenia, Alzheimer disease, and Parkinson disease.
ESTHER : Schaaf_2014_Genet.Med_16_649
PubMedSearch : Schaaf_2014_Genet.Med_16_649
PubMedID: 24556925

Title : CHRNA7 triplication associated with cognitive impairment and neuropsychiatric phenotypes in a three-generation pedigree - Soler-Alfonso_2014_Eur.J.Hum.Genet_22_1071
Author(s) : Soler-Alfonso C , Carvalho CM , Ge J , Roney EK , Bader PI , Kolodziejska KE , Miller RM , Lupski JR , Stankiewicz P , Cheung SW , Bi W , Schaaf CP
Ref : Eur J Hum Genet , 22 :1071 , 2014
Abstract : Although deletions of CHRNA7 have been associated with intellectual disability (ID), seizures and neuropsychiatric phenotypes, the pathogenicity of CHRNA7 duplications has been uncertain. We present the first report of CHRNA7 triplication. Three generations of a family affected with various neuropsychiatric phenotypes, including anxiety, bipolar disorder, developmental delay and ID, were studied with array comparative genomic hybridization (aCGH). High-resolution aCGH revealed a 650-kb triplication at chromosome 15q13.3 encompassing the CHRNA7 gene, which encodes the alpha7 subunit of the neuronal nicotinic acetylcholine receptor. A small duplication precedes the triplication at the proximal breakpoint junction, and analysis of the breakpoint indicates that the triplicated segment is in an inverted orientation with respect to the duplication. CHRNA7 triplication appears to occur by a replication-based mechanism that produces inverted triplications embedded within duplications. Co-segregation of the CHRNA7 triplication with neuropsychiatric and cognitive phenotypes provides further evidence for dosage sensitivity of CHRNA7.
ESTHER : Soler-Alfonso_2014_Eur.J.Hum.Genet_22_1071
PubMedSearch : Soler-Alfonso_2014_Eur.J.Hum.Genet_22_1071
PubMedID: 24424125

Title : SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties - Han_2013_Nature_503_72
Author(s) : Han K , Holder JL, Jr. , Schaaf CP , Lu H , Chen H , Kang H , Tang J , Wu Z , Hao S , Cheung SW , Yu P , Sun H , Breman AM , Patel A , Lu HC , Zoghbi HY
Ref : Nature , 503 :72 , 2013
Abstract : Mutations in SHANK3 and large duplications of the region spanning SHANK3 both cause a spectrum of neuropsychiatric disorders, indicating that proper SHANK3 dosage is critical for normal brain function. However, SHANK3 overexpression per se has not been established as a cause of human disorders because 22q13 duplications involve several genes. Here we report that Shank3 transgenic mice modelling a human SHANK3 duplication exhibit manic-like behaviour and seizures consistent with synaptic excitatory/inhibitory imbalance. We also identified two patients with hyperkinetic disorders carrying the smallest SHANK3-spanning duplications reported so far. These findings indicate that SHANK3 overexpression causes a hyperkinetic neuropsychiatric disorder. To probe the mechanism underlying the phenotype, we generated a Shank3 in vivo interactome and found that Shank3 directly interacts with the Arp2/3 complex to increase F-actin levels in Shank3 transgenic mice. The mood-stabilizing drug valproate, but not lithium, rescues the manic-like behaviour of Shank3 transgenic mice raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile.
ESTHER : Han_2013_Nature_503_72
PubMedSearch : Han_2013_Nature_503_72
PubMedID: 24153177

Title : The genetics of Autism Spectrum Disorders--a guide for clinicians - Heil_2013_Curr.Psychiatry.Rep_15_334
Author(s) : Heil KM , Schaaf CP
Ref : Curr Psychiatry Rep , 15 :334 , 2013
Abstract : Recent advances in genetic testing technology have made chromosome microarray analysis (CMA) a first-tier clinical diagnostic test for Autism Spectrum Disorders (ASDs). Two main types of microarrays are available, single nucleotide polymorphism (SNP) arrays and array comparative genomic hybridization (aCGH), each with its own advantages and disadvantages in ASDs testing. Rare genetic variants, and copy number variants (CNVs) in particular, have been shown to play a major role in ASDs. More than 200 autism susceptibility genes have been identified to date, and complex patterns of inheritance, such as oligogenic heterozygosity, appear to contribute to the etiopathogenesis of ASDs. Incomplete penetrance and variable expressivity represent particular challenges in the interpretation of CMA testing of autistic individuals. This review aims to provide an overview of autism genetics for the practicing physician and gives hands-on advice on how to follow-up on abnormal CMA findings in individuals with neuropsychiatric disorders.
ESTHER : Heil_2013_Curr.Psychiatry.Rep_15_334
PubMedSearch : Heil_2013_Curr.Psychiatry.Rep_15_334
PubMedID: 23250815

Title : Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions - Schaaf_2012_Eur.J.Hum.Genet_20_1240
Author(s) : Schaaf CP , Boone PM , Sampath S , Williams C , Bader PI , Mueller JM , Shchelochkov OA , Brown CW , Crawford HP , Phalen JA , Tartaglia NR , Evans P , Campbell WM , Tsai AC , Parsley L , Grayson SW , Scheuerle A , Luzzi CD , Thomas SK , Eng PA , Kang SH , Patel A , Stankiewicz P , Cheung SW
Ref : Eur J Hum Genet , 20 :1240 , 2012
Abstract : Copy number variants (CNVs) and intragenic rearrangements of the NRXN1 (neurexin 1) gene are associated with a wide spectrum of developmental and neuropsychiatric disorders, including intellectual disability, speech delay, autism spectrum disorders (ASDs), hypotonia and schizophrenia. We performed a detailed clinical and molecular characterization of 24 patients who underwent clinical microarray analysis and had intragenic deletions of NRXN1. Seventeen of these deletions involved exons of NRXN1, whereas seven deleted intronic sequences only. The patients with exonic deletions manifested developmental delay/intellectual disability (93%), infantile hypotonia (59%) and ASDs (56%). Congenital malformations and dysmorphic features appeared infrequently and inconsistently among this population of patients with NRXN1 deletions. The more C-terminal deletions, including those affecting the beta isoform of neurexin 1, manifested increased head size and a high frequency of seizure disorder (88%) when compared with N-terminal deletions of NRXN1.
ESTHER : Schaaf_2012_Eur.J.Hum.Genet_20_1240
PubMedSearch : Schaaf_2012_Eur.J.Hum.Genet_20_1240
PubMedID: 22617343

Title : Structures and molecular mechanisms for common 15q13.3 microduplications involving CHRNA7: benign or pathological? - Szafranski_2010_Hum.Mutat_31_840
Author(s) : Szafranski P , Schaaf CP , Person RE , Gibson IB , Xia Z , Mahadevan S , Wiszniewska J , Bacino CA , Lalani S , Potocki L , Kang SH , Patel A , Cheung SW , Probst FJ , Graham BH , Shinawi M , Beaudet AL , Stankiewicz P
Ref : Hum Mutat , 31 :840 , 2010
Abstract : We have investigated four approximately 1.6-Mb microduplications and 55 smaller 350-680-kb microduplications at 15q13.2-q13.3 involving the CHRNA7 gene that were detected by clinical microarray analysis. Applying high-resolution array-CGH, we mapped all 118 chromosomal breakpoints of these microduplications. We also sequenced 26 small microduplication breakpoints that were clustering at hotspots of nonallelic homologous recombination (NAHR). All four large microduplications likely arose by NAHR between BP4 and BP5 LCRs, and 54 small microduplications arose by NAHR between two CHRNA7-LCR copies. We identified two classes of approximately 1.6-Mb microduplications and five classes of small microduplications differing in duplication size, and show that they duplicate the entire CHRNA7. We propose that size differences among small microduplications result from preexisting heterogeneity of the common BP4-BP5 inversion. Clinical data and family histories of 11 patients with small microduplications involving CHRNA7 suggest that these microduplications might be associated with developmental delay/mental retardation, muscular hypotonia, and a variety of neuropsychiatric disorders. However, we conclude that these microduplications and their associated potential for increased dosage of the CHRNA7-encoded alpha 7 subunit of nicotinic acetylcholine receptors are of uncertain clinical significance at present. Nevertheless, if they prove to have a pathological effects, their high frequency could make them a common risk factor for many neurobehavioral disorders.
ESTHER : Szafranski_2010_Hum.Mutat_31_840
PubMedSearch : Szafranski_2010_Hum.Mutat_31_840
PubMedID: 20506139