Altered expression of DENND5B in patients with epilepsy and its regulation of seizures in mice

Feather pecking (FP) is a damaging non-aggressive behavior in laying hens with a heritable component. Its occurrence has been linked to the immune system, the circadian clock, and foraging behavior. Furthermore, dysregulation of miRNA biogenesis, disturbance of the gamma-aminobutyric acid (GABAergic) system, as well as neurodevelopmental deficiencies are currently under debate as factors influencing the propensity for FP behavior. Past studies, which focused on the dissection of the genetic factors involved in FP, relied on single nucleotide polymorphisms (SNPs) and short insertions and deletions < 50 bp (InDels). These variant classes only represent a certain fraction of the genetic variation of an organism. Hence, we re-analyzed whole genome sequencing data from two experimental populations, which have been divergently selected for FP behavior for over more than 15 generations, and performed variant calling for structural variants (SVs) as well as tandem repeats (TRs) and jointly analyzed the data with SNPs and InDels. Genotype imputation and subsequent genome-wide association studies in combination with expression quantitative trait loci analysis led to the discovery of multiple variants influencing the GABAergic system. These include a significantly associated TR downstream of the GABA receptor subunit beta-3 (GABRB3) gene, two micro RNAs targeting several GABA receptor genes, and dystrophin (DMD), a direct regulator of GABA receptor clustering. Furthermore, we found the transcription factor ETV1 to be associated with differential expression of 23 genes, which points towards a role of ETV1, together with SMAD4 and KLF14, in the disturbed neurodevelopment of high feather pecking chickens.

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“…DENN domain-containing protein 5B Altered expression in patients with epilepsy and regulation of seizures in mice [72].…”

Section: Dennd5bmentioning

confidence: 99%

Structural variation and eQTL analysis in two experimental populations of chickens divergently selected for feather pecking behavior

Falker‐Gieske

Bennewitz

Tetens

2022

Preprint

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“…DENND5B (MIM: 617279) is located on chromosome 12 (12p11.21) and encodes a 1,274-amino-acid protein with a molecular weight of 145 kDa. 7 , 8 DENND5B, also known as Rab6-interacting Protein 1B-like protein (R6IP1B or R6IP1-like), is one of the two members of the DENND5 protein subfamily, the other being DENND5A (also known as R6IP1A or R6IP1). 7 , 8 These related DENN proteins interact with functionally relevant Rab proteins, such as RAB6, RAB11, and RAB39.…”

Section: Introductionmentioning

confidence: 99%

“… 7 , 8 DENND5B, also known as Rab6-interacting Protein 1B-like protein (R6IP1B or R6IP1-like), is one of the two members of the DENND5 protein subfamily, the other being DENND5A (also known as R6IP1A or R6IP1). 7 , 8 These related DENN proteins interact with functionally relevant Rab proteins, such as RAB6, RAB11, and RAB39. As such, DENND5 proteins have been suggested to contribute to synaptic plasticity through the modulation of synaptic vesicle axonal trafficking and neurotransmitter release.…”

Section: Introductionmentioning

confidence: 99%

“…As such, DENND5 proteins have been suggested to contribute to synaptic plasticity through the modulation of synaptic vesicle axonal trafficking and neurotransmitter release. 7 , 8 DENND5A and DENND5B contain six distinct functional domains. The DENN domain is encircled on both sides by more divergent domains, known as uDENN (upstream DENN) and dDENN (downstream DENN), forming the tripartite DENN domain.…”

Section: Introductionmentioning

confidence: 99%

“… 16 In mice, Dennd5b expression is mainly restricted to neurons and is especially enriched in the hippocampus. 7 In the human brain, DENND5B is preferentially expressed in the cerebral cortex, basal ganglia, cerebellum, and hippocampus ( https://www.proteinatlas.org/ENSG00000170456-DENND5B/tissue ). Additionally, the expression of DENND5B was recently reported to be significantly decreased in the brains of individuals with temporal lobe epilepsy and chronic epileptic mouse models.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

De novo variants in DENND5B cause a neurodevelopmental disorder

Scala,

Tomati,

Ferla

et al. 2024

The American Journal of Human Genetics

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Structural variation and eQTL analysis in two experimental populations of chickens divergently selected for feather-pecking behavior

2022

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Feather pecking (FP) is a damaging nonaggressive behavior in laying hens with a heritable component. Its occurrence has been linked to the immune system, the circadian clock, and foraging behavior. Furthermore, dysregulation of miRNA biogenesis, disturbance of the gamma-aminobutyric acid (GABAergic) system, as well as neurodevelopmental deficiencies are currently under debate as factors influencing the propensity for FP behavior. Past studies, which focused on the dissection of the genetic factors involved in FP, relied on single nucleotide polymorphisms (SNPs) and short insertions and deletions < 50 bp (InDels). These variant classes only represent a certain fraction of the genetic variation of an organism. Hence, we reanalyzed whole-genome sequencing data from two experimental populations, which have been divergently selected for FP behavior for over more than 15 generations, performed variant calling for structural variants (SVs) as well as tandem repeats (TRs), and jointly analyzed the data with SNPs and InDels. Genotype imputation and subsequent genome-wide association studies, in combination with expression quantitative trait loci analysis, led to the discovery of multiple variants influencing the GABAergic system. These include a significantly associated TR downstream of the GABA receptor subunit beta-3 (GABRB3) gene, two microRNAs targeting several GABA receptor genes, and dystrophin (DMD), a direct regulator of GABA receptor clustering. Furthermore, we found the transcription factor ETV1 to be associated with the differential expression of 23 genes, which points toward a role of ETV1, together with SMAD4 and KLF14, in the disturbed neurodevelopment of high-feather pecking chickens.

show abstract

Altered expression of DENND5B in patients with epilepsy and its regulation of seizures in mice

Cited by 4 publications

References 36 publications

Structural variation and eQTL analysis in two experimental populations of chickens divergently selected for feather pecking behavior

Structural variation and eQTL analysis in two experimental populations of chickens divergently selected for feather pecking behavior

De novo variants in DENND5B cause a neurodevelopmental disorder

Structural variation and eQTL analysis in two experimental populations of chickens divergently selected for feather-pecking behavior

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