Interaction effect between handedness and CNTNAP2 polymorphism (rs7794745 genotype) on voice-specific frontotemporal activity in healthy individuals: an fMRI study

Koeda, Michihiko; Watanabe, Atsushi; Tsuda, Kumiko; Matsumoto, Miwako; Ikeda, Yumiko; Kim, Woochan; Tateno, Amane; Naing, Banyar Than; Karibe, Hiroyuki; Shimada, Takashi; Suzuki, Hidenori; Okubo, Yoshiro

doi:10.3389/fnbeh.2015.00087

Cited by 19 publications

(15 citation statements)

References 62 publications

(104 reference statements)

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“…Further evidence for atypical lateralization for language associated with CNTNAP2 polymorphisms comes from a study of language, voice, and general auditory processing. Koeda et al () reported increased activation in the right middle frontal gyrus during native language listening in Japanese carriers of the nondominant allele for rs7794745. This pattern of increased right hemisphere activation also held for human voice perception (reversed sentences) the right middle frontal gyrus.…”

Section: Developmental Language Disordermentioning

confidence: 99%

Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review

Landi

Perdue

2019

Language and Linguist. Compass

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Developmental disorders of spoken and written language are heterogeneous in nature with impairments observed across various linguistic, cognitive, and sensorimotor domains. These disorders are also associated with characteristic patterns of atypical neural structure and function that are observable early in development, often before formal schooling begins. Established patterns of heritability point toward genetic contributions, and molecular genetics approaches have identified genes that play a role in these disorders. Still, identified genes account for only a limited portion of phenotypic variance in complex developmental disorders, described as the problem of “missing heritability.” The characterization of intermediate phenotypes at the neural level may fill gaps in our understanding of heritability patterns in complex disorders, and the emerging field of neuroimaging genetics offers a promising approach to accomplish this goal. The neuroimaging genetics approach is gaining prevalence in language- and reading-related research as it is well-suited to incorporate behavior, genetics, and neurobiology into coherent etiological models of complex developmental disorders. Here, we review research applying the neuroimaging genetics approach to the study of specific reading disability (SRD) and developmental language disorder (DLD), much of which links genes with known neurodevelopmental function to functional and structural abnormalities in the brain.

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Section: Developmental Language Disordermentioning

confidence: 99%

Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review

Landi

Perdue

2019

Language and Linguist. Compass

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“…Neuroimaging studies have supported the notion that these common variants play a role in psychiatric disorders. SNP rs2710102 has been implicated in brain connectivity in healthy individuals [16, 18, 19], and rs7794745 was implicated in audio-visual speech perception [69], voice-specific brain function [22], and was associated with reduced grey matter volume in left superior occipital gyrus [20, 21]. These studies focused principally on language tasks in general population, given the reported suggestive implications of CNTNAP2 in language impairment traits of ASD or language-related phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, in subsequent studies, rs2710102 was implicated in early language acquisition in the general population [15], and showed functional effects on brain activation in neuroimaging studies [16-19]. Furthermore, genotypes at rs7794745 were associated with reduced grey matter volume in the left superior occipital gyrus in two independent studies [20, 21], and alleles of this SNP were reported to affect voice-specific brain function [22]. Genetic associations with ASD for these, and several other SNPs in CNTNAP2 , have been reported in a number of studies [23-28].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive cross-disorder analyses of CNTNAP2 suggest it is unlikely to be a primary risk gene for psychiatric disorders

Toma

Pierce

Shaw

et al. 2018

Preprint

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max=300 words): 283 28 Article body: 3,950 ABSTRACT 34The contactin-associated protein-like 2 (CNTNAP2) gene is a member of the neurexin 35 superfamily. CNTNAP2 was implicated in the cortical dysplasia-focal epilepsy (CDFE) 36 syndrome, a recessive disease characterized by intellectual disability, epilepsy, language 37 4 58 AUTHOR SUMMARY 59 Genetic mutations that disrupt both copies of the CNTNAP2 gene lead to severe disease, 60 characterized by profound intellectual disability, epilepsy, language difficulties and autistic 61 traits. Researchers hypothesized that this gene may also be involved in autism given some 62 overlapping clinical features with this disease. Indeed, several large DNA deletions affecting 63 one of the two copies of CNTNAP2 were found in some patients with autism, and later also in 64 patients with schizophrenia, bipolar disorder, ADHD and epilepsy, suggesting that this gene 65 was involved in several psychiatric or neurologic diseases. Other studies considered genetic 66 sequence variations that are common in the general population, and suggested that two such 67 sequence variations in CNTNAP2 predispose to psychiatric diseases by influencing the 68 functionality and connectivity of the brain. In the current study, we report the deletion of one 69 copy of CNTNAP2 in a patient with bipolar disorder from an extended family where five 70 relatives were affected with this condition. To better understand the involvement of CNTNAP2 71 in risk of mental illness, we performed several genetic analyses using a series of large publically 72 available or in-house datasets, comprising many thousands of patients and controls. Despite 73 the previous consideration of CNTNAP2 as a strong candidate gene for autism or schizophrenia, 74 we show that neither common, deletion nor ultra-rare variants in CNTNAP2 are likely to play 75 a major role in risk of psychiatric diseases. 76 77 78 79 80 81 82 5 83 84The contactin-associated protein-like 2 (CNTNAP2) is located on chromosome 7q35-36.1, and 85 consists of 24 exons spanning 2.3Mb, making it one of the largest protein coding genes in the 86 human genome. This gene encodes the CASPR2 protein, related to the neurexin superfamily, 87 which localises with potassium channels at the juxtaparanodal regions of the Ravier nodes in 88 myelinated axons, playing a crucial role in the clustering of potassium channels required for 89 conduction of axon potentials [1]. CNTNAP2 is expressed in the spinal cord, prefrontal and 90 frontal cortex, striatum, thalamus and amygdala; this pattern of expression is preserved 91 throughout the development and adulthood [2, 3]. Its function is related to neuronal migration, 92 dendritic arborisation and synaptic transmission [4]. The crucial role of CNTNAP2 in the 93 human brain became clear when Strauss et al, reported homozygous mutations in Old Order 94 Amish families segregating with a severe Mendelian condition, described as cortical dysplasia-95 focal epilepsy (CDFE) syndrome (OMIM 610042) [5]. In 2009, additional patie...

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“…3 ), association studies may help to narrow down and to better circumscribe the phenotypic scope of CNTNAP2 function. For instance, CNTNAP2 polymorphisms may affect neural development as related to vocal communication and language processing [Koeda et al, 2015]. The genotype of SNP rs7794745 (A/A or A/T) in intron 2 significantly affects voice-specific brain function in the right middle frontal gyrus and in the bilateral superior temporal gyrus in healthy individuals [Koeda et al, 2015].…”

Section: The Phenotypic Scope Of Cntnap2 Deletion Disordersmentioning

confidence: 99%

“…For instance, CNTNAP2 polymorphisms may affect neural development as related to vocal communication and language processing [Koeda et al, 2015]. The genotype of SNP rs7794745 (A/A or A/T) in intron 2 significantly affects voice-specific brain function in the right middle frontal gyrus and in the bilateral superior temporal gyrus in healthy individuals [Koeda et al, 2015]. The SNP rs2710102 in intron 13 of CNTNAP2 associates with impaired language development, specific language impairment, delayed oral and written language skills, dyslexia, age of first words as well as speech and sound disorder ( Fig.…”

Section: The Phenotypic Scope Of Cntnap2 Deletion Disordersmentioning

confidence: 99%

Intragenic CNTNAP2 Deletions: A Bridge Too Far

Poot¹

2017

Mol Syndromol

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Intragenic deletions of the contactin-associated protein-like 2 gene (CNTNAP2) have been found in patients with Gilles de la Tourette syndrome, intellectual disability (ID), obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, stuttering, and attention deficit hyperactivity disorder. A variety of molecular mechanisms, such as loss of transcription factor binding sites and perturbation of penetrance and expressivity, have been proposed to account for the phenotypic variability resulting from CNTNAP2 mutations. Deletions of both CNTNAP2 alleles produced truncated proteins lacking the transmembrane or some of the extracellular domains, or no protein at all. This observation can be extended to heterozygous intragenic deletions by assuming that such deletion-containing alleles lead to expression of a Caspr2 protein lacking one or several extracellular domains. Such altered forms of Capr2 proteins will lack the ability to bridge the intercellular space between neurons by binding to partners, such as CNTN1, CNTN2, DLG1, and DLG4. This presumed effect of intragenic deletions of CNTNAP2, and possibly other genes involved in connecting neuronal cells, represents a molecular basis for the postulated neuronal hypoconnectivity in autism and probably other neurodevelopmental disorders, including epilepsy, ID, language impairments and schizophrenia. Thus, CNTNAP2 may represent a paradigmatic case of a gene functioning as a node in a genetic and cellular network governing brain development and acquisition of higher cognitive functions.

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Interaction effect between handedness and CNTNAP2 polymorphism (rs7794745 genotype) on voice-specific frontotemporal activity in healthy individuals: an fMRI study

Cited by 19 publications

References 62 publications

Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review

Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review

Comprehensive cross-disorder analyses of CNTNAP2 suggest it is unlikely to be a primary risk gene for psychiatric disorders

Intragenic CNTNAP2 Deletions: A Bridge Too Far

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