<scp><i>DYRK1B</i></scp> haploinsufficiency in a family with metabolic syndrome and abnormal cognition

Orenstein, Naama; Gofin, Yoel; Shomron, Noam; Ruhrman‐Shahar, Noa; Magal, Nurit; Hagari, Ofir; Azulay, Noy; Bazak, Lily; Goldberg, Yael; Basel‐Salmon, Lina

doi:10.1111/cge.14084

Cited by 6 publications

(7 citation statements)

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“…Dyrk1b (−2.2) (which encodes dual-specificity tyrosine phosphorylation regulated kinase 1B) is a mediator of double-stranded DNA break repair 50 and regulates hedgehog signaling by activating the mTor/AKT pathway 51 , 52 . Dyrk1b has been linked to metabolic syndrome and autism 53 . The 55% reduction in Dyrk1b expression induced by VPA could contribute to autistic-like behavior by dysregulating hedgehog or mTor/AKT signaling.…”

Section: Discussionmentioning

confidence: 99%

Rapid effects of valproic acid on the fetal brain transcriptome: Implications for brain development and autism

Krueger,

Dorsey,

Mocci

et al. 2024

Preprint

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There is an increased incidence of autism among the children of women who take the anti-epileptic, mood-stabilizing drug, valproic acid (VPA) during pregnancy; moreover, exposure to VPA in utero causes autistic-like symptoms in rodents and non-human primates. Analysis of RNA-seq data obtained from E12.5 fetal mouse brains 3 hours after VPA administration to the pregnant dam revealed that VPA rapidly and significantly increased or decreased the expression of approximately 7,300 genes. No significant sex differences in VPA-induced gene expression were observed. Expression of 399 autism risk genes was significantly altered by VPA as was expression of 255 genes that have been reported to play fundamental roles in fetal brain development but are not otherwise linked to autism. Expression of genes associated with intracellular signaling pathways, neurogenesis, and excitation-inhibition balance as well as synaptogenesis, neuronal fate determination, axon and dendritic development, neuroinflammation, circadian rhythms, and epigenetic modulation of gene expression was dysregulated by VPA. The goal of this study was to identify mouse genes that are: (a) significantly up- or down-regulated by VPA in the fetal brain and (b) known to be associated with autism and/or to play a role in embryonic neurodevelopmental processes, perturbation of which has the potential to alter brain connectivity and, consequently behavior, in the adult. The set of genes meeting these criteria provides potential targets for future hypothesis-driven studies to elucidate the proximal causes of errors in brain connectivity underlying neurodevelopmental disorders such as autism.

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Section: Discussionmentioning

confidence: 99%

Rapid effects of valproic acid on the fetal brain transcriptome: Implications for brain development and autism

Krueger,

Dorsey,

Mocci

et al. 2024

Preprint

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“…In humans, DYRK1B has been associated with abdominal obesity‐metabolic syndrome 3 (OMIM #615812) when caused by dominant missense variants (Keramati et al, 2014; Mendoza‐Caamal et al, 2021). More recently, a familiar case of abnormal cognition and metabolic syndrome was associated with a dominant splicing variant predicted to lead to LOF (Orenstein et al, 2022). The authors suggested that it is possible that LOF variants in DYRK1B contribute to the abnormal neurologic phenotype (Orenstein et al, 2022).…”

Section: Figurementioning

confidence: 99%

“…More recently, a familiar case of abnormal cognition and metabolic syndrome was associated with a dominant splicing variant predicted to lead to LOF (Orenstein et al, 2022). The authors suggested that it is possible that LOF variants in DYRK1B contribute to the abnormal neurologic phenotype (Orenstein et al, 2022). In addition, recent large‐scale data from human genome sequencing studies presented in the Genome Aggregation Database (gnomAD) (Karczewski et al, 2020) showed that the probability of a LOF intolerance score for DYRK1B was 0.97, meaning that this gene falls into the class of haploinsufficient LOF genes.…”

Section: Figurementioning

confidence: 99%

DYRK1B haploinsufficiency in a Holstein cattle with epilepsy

et al. 2023

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In this study, epilepsy with focal seizures progressing to generalized seizures was diagnosed in a 6‐month‐old Holstein heifer. The seizures were characterized by a brief pre‐ictal phase with depression and vocalization. During the ictal phase eyelid spasms, tongue contractions, nodding and abundant salivation were observed, rapidly followed by a convulsive phase with bilateral tonic, clonic or tonic–clonic activity and loss of consciousness. Finally, during the postictal phase the heifer was obtunded and disorientated, unable to perceive obstacles and hypermetric, and pressed its head against objects. In the inter‐seizure phase, the heifer was clinically normal. Neuropathology revealed axonal degeneration in the brainstem and diffuse astrocytic hypertrophic gliosis. Whole genome sequencing of the affected heifer identified a private heterozygous splice‐site variant in DYRK1B (NM_001081515.1: c.‐101‐1G>A), most likely resulting in haploinsufficiency owing to loss‐of‐function. This represents a report of a DYRK1B‐associated disease in cattle and adds DYRK1B to the candidate genes for epilepsy.

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“…Importantly, altered DYRK1A protein levels appear to be causative based on murine models, as artificially reducing DYRK1A expression is sufficient to rescue major aspects of motor impairment and hypoactive behaviour in transgenic DYRK1A overexpression animals [ 269 ]. Although most research has focussed on DYRK1A, there is also a recent report of DYRK1B haploinsufficiency in a family with mild and severe intellectual disability, seizures, autism, obesity, and other symptoms [ 270 ]. Additionally, a transcriptomic and functional enrichment analysis of resected tissue from a subset of patients with epilepsy has associated downregulation of DYRK2 with an epileptic and neuronal apoptotic gene network [ 271 ].…”

Section: Dysregulation Of Srpk Clk ...mentioning

confidence: 99%

“…For example, DYRK2 has pleotropic roles in cancer [ 272 , 291 ] and can act as an apoptotic kinase [ 135 ], whilst DYRK1A/1B/3 are protective against apoptosis [ 320 , 321 ] and important during interphase of the cell cycle [ 322 ]. In contrast, in other intellectual disabilities, such as DYRK1A‐related haploinsufficiency syndrome with DYRK1A/1B mutations and/or deletions, downstream signalling is likely impaired in ways that are not yet well understood [ 265 , 266 , 267 , 270 ]. However, there are indications that it may be beneficial to restore activity to correct for imbalanced neuronal signalling and reduced GABAergic neurotransmission [ 268 ].…”

Section: Therapeutic Potential Of Srpk ...mentioning

confidence: 99%

Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders

Hogg,

Findlay

2023

FEBS Letters

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Human developmental disorders encompass a wide range of debilitating physical conditions and intellectual disabilities. Perturbation of protein kinase signalling underlies the development of some of these disorders. For example, disrupted SRPK signalling is associated with intellectual disabilities, and the gene dosage of DYRKs can dictate the pathology of disorders including Down's syndrome. Here, we review the emerging roles of the CMGC kinase families SRPK, CLK, DYRK, and sub‐family HIPK during embryonic development and in developmental disorders. In particular, SRPK, CLK, and DYRK kinase families have key roles in developmental signalling and stem cell regulation, and can co‐ordinate neuronal development and function. Genetic studies in model organisms reveal critical phenotypes including embryonic lethality, sterility, musculoskeletal errors, and most notably, altered neurological behaviours arising from defects of the neuroectoderm and altered neuronal signalling. Further unpicking the mechanisms of specific kinases using human stem cell models of neuronal differentiation and function will improve our understanding of human developmental disorders and may provide avenues for therapeutic strategies.

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DYRK1B haploinsufficiency in a family with metabolic syndrome and abnormal cognition

Cited by 6 publications

References 6 publications

Rapid effects of valproic acid on the fetal brain transcriptome: Implications for brain development and autism

Rapid effects of valproic acid on the fetal brain transcriptome: Implications for brain development and autism

DYRK1B haploinsufficiency in a Holstein cattle with epilepsy

Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders

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