Polymorphisms in the TMEM132D region are associated with panic disorder in HLA-DRB1*13:02-negative individuals of a Japanese population

Shimada-Sugimoto, Mihoko; Otowa, Takeshi; Miyagawa, Taku; Khor, Seik‐Soon; Omae, Yosuke; Toyo-Oka, Licht; Sugaya, Nagisa; Kawamura, Yoshiya; Umekage, Tadashi; Miyashita, Akinori; Kuwano, Ryozo; Kaiya, Hisanobu; Kasai, Kiyoto; Tanii, Hisashi; Okazaki, Yuji; Tokunaga, Katsushi; Sasaki, Tsukasa

doi:10.1038/hgv.2016.1

Cited by 11 publications

(11 citation statements)

References 19 publications

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“…A homozygous missense mutation in human TMEM132E (Arg420Gln) was confirmed using a zebrafish model to cause autosomal-recessive nonsyndromic hearing loss ( Li et al , 2015 ). Common variants within the TMEM132E gene are associated with insomnia symptoms ( Lane et al , 2017 ); common and rare variants near TMEM132D gene are robustly associated with panic disorder ( Erhardt et al , 2011 , 2012 ; Hodgson et al , 2016 ; Howe et al , 2016 ; Inoue et al , 2015 ; Quast et al , 2012 ; Shimada-Sugimoto et al , 2016 ; Wang et al , 2016 ); and variants near TMEM132B are associated with excessive daytime sleepiness ( Lane et al , 2017 ). In healthy individuals, some of the TMEM132D non-coding variants exhibit higher anxiety scores and larger volumetric estimates of the amygdala and hippocampus, key neural structures associated with fear and anxiety ( Haaker et al , 2014 ).…”

Section: Introductionmentioning

confidence: 99%

TMEM132: an ancient architecture of cohesin and immunoglobulin domains define a new family of neural adhesion molecules

Sánchez‐Pulido

Ponting

2017

Bioinformatics

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SummaryThe molecular functions of TMEM132 genes remain poorly understood and under-investigated despite their mutations associated with non-syndromic hearing loss, panic disorder and cancer. Here we show the full domain architecture of human TMEM132 family proteins solved using in-depth sequence and structural analysis. We reveal them to be five previously unappreciated cell adhesion molecules whose domain architecture has an early holozoan origin prior to the emergence of choanoflagellates and metazoa. The extra-cellular portions of TMEM132 proteins contain five conserved domains including three tandem immunoglobulin domains, and a cohesin domain homologue, the first such domain found in animals. These findings strongly predict a cellular adhesion function for TMEM132 family, connecting the extracellular medium with the intracellular actin cytoskeleton.Supplementary information Supplementary data are available at Bioinformatics online.

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Section: Introductionmentioning

confidence: 99%

TMEM132: an ancient architecture of cohesin and immunoglobulin domains define a new family of neural adhesion molecules

Sánchez‐Pulido

Ponting

2017

Bioinformatics

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“…TMEM132 family of transmembrane proteins have been associated with a variety of neurological, respiratory and circulatory disorders, as well as embryonic development and cancer [ 6 – 9 , 11 , 13 , 14 , 23 , 24 ], thus understanding the function of these proteins is of great value to human health. Unfortunately, the presence of five highly homologous Tmem132 genes in the mouse and human genomes suggests potential functional redundancy between paralogues, making it challenging to reveal the full requirement for these proteins in vivo.…”

Section: Resultsmentioning

confidence: 99%

“…Such genome-wide association studies have recently implicated four out of five members of the transmembrane 132 (TMEM132) family of single-pass membrane proteins in a plethora of human disease conditions. TMEM132B and TMEM132D have been linked to intracranial aneurysms and anxiety/panic disorders, respectively [ 5 – 11 ]. With probable involvement in colorectal cancer, TMEM132C was among one of four genes of a cancer-associated locus [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Efficient multiplexed genome engineering with a polycistronic tRNA and CRISPR guide-RNA reveals an important role of detonator in reproduction of Drosophila melanogaster

Chon

Matsui

et al. 2021

PLoS ONE

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Genome association studies in human and genetic studies in mouse implicated members of the transmembrane protein 132 (TMEM132) family in multiple conditions including panic disorder, hearing loss, limb and kidney malformation. However, the presence of five TMEM132 paralogs in mammalian genomes makes it extremely challenging to reveal the full requirement for these proteins in vivo. In contrast, there is only one TMEM132 homolog, detonator (dtn), in the genome of fruit fly Drosophila melanogaster, enabling straightforward research into its in vivo function. In the current study, we generate multiple loss-of-function dtn mutant fly strains through a polycistronic tRNA-gRNA approach, and show that most embryos lacking both maternal and paternal dtn fail to hatch into larvae, indicating an essential role of dtn in Drosophila reproduction.

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“…This family encodes single-pass transmembrane proteins present in metazoans but remains functionally uncharacterized in any organisms. The human genome encodes 5 paralogs ( TMEM132A-E ), genetic variants of which have been identified as risk alleles of many human diseases, including those associated with panic disorder and anxiety severity in TMEM132D [ 6 – 12 ]. Risk variants of TMEM132D have been shown to correlate with altered mRNA levels of TMEM132D in anxiety-related brain regions and psychiatric syndromes [ 6 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

The C. elegans homolog of human panic-disorder risk gene TMEM132D orchestrates neuronal morphogenesis through the WAVE-regulatory complex

et al. 2021

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TMEM132D is a human gene identified with multiple risk alleles for panic disorders, anxiety and major depressive disorders. Defining a conserved family of transmembrane proteins, TMEM132D and its homologs are still of unknown molecular functions. By generating loss-of-function mutants of the sole TMEM132 ortholog in C. elegans, we identify abnormal morphologic phenotypes in the dopaminergic PDE neurons. Using a yeast two-hybrid screen, we find that NAP1 directly interacts with the cytoplasmic domain of human TMEM132D, and mutations in C. elegans tmem-132 that disrupt interaction with NAP1 cause similar morphologic defects in the PDE neurons. NAP1 is a component of the WAVE regulatory complex (WRC) that controls F-actin cytoskeletal dynamics. Decreasing activity of WRC rescues the PDE defects in tmem-132 mutants, whereas gain-of-function of TMEM132D in mammalian cells inhibits WRC, leading to decreased abundance of select WRC components, impaired actin nucleation and cell motility. We propose that metazoan TMEM132 family proteins play evolutionarily conserved roles in regulating NAP1 protein homologs to restrict inappropriate WRC activity, cytoskeletal and morphologic changes in the cell.

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Polymorphisms in the TMEM132D region are associated with panic disorder in HLA-DRB1*13:02-negative individuals of a Japanese population

Cited by 11 publications

References 19 publications

TMEM132: an ancient architecture of cohesin and immunoglobulin domains define a new family of neural adhesion molecules

TMEM132: an ancient architecture of cohesin and immunoglobulin domains define a new family of neural adhesion molecules

Efficient multiplexed genome engineering with a polycistronic tRNA and CRISPR guide-RNA reveals an important role of detonator in reproduction of Drosophila melanogaster

The C. elegans homolog of human panic-disorder risk gene TMEM132D orchestrates neuronal morphogenesis through the WAVE-regulatory complex

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