Case report of novel DYRK1A mutations in 2 individuals with syndromic intellectual disability and a review of the literature

Luco, Stephanie M.; Pohl, Daniela; Sell, Erick; Wagner, Justin D.; Dyment, David A.; Daoud, Hussein

doi:10.1186/s12881-016-0276-4

Cited by 46 publications

(43 citation statements)

References 25 publications

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“…Thirty-two previously published cases of DYRK1A disruptive SNVs (Pub-SNV group) included 31 de novo cases and 1 non-maternal case [ 13 , 15 , 21 , 22 , 30 – 32 ] with available medical history, physical features, and diagnoses.…”

Section: Methodsmentioning

confidence: 99%

Clinical phenotype of ASD-associated DYRK1A haploinsufficiency

et al. 2017

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Background DYRK1A is a gene recurrently disrupted in 0.1–0.5% of the ASD population. A growing number of case reports with DYRK1A haploinsufficiency exhibit common phenotypic features including microcephaly, intellectual disability, speech delay, and facial dysmorphisms.MethodsPhenotypic information from previously published DYRK1A cases (n = 51) and participants in an ongoing study at the University of Washington (UW, n = 10) were compiled. Frequencies of recurrent phenotypic features in this population were compared to features observed in a large sample with idiopathic ASD from the Simons Simplex Collection (n = 1981). UW DYRK1A cases were further characterized quantitatively and compared to a randomly subsampled set of idiopathic ASD cases matched on age and gender (n = 10) and to cases with an ASD-associated disruptive mutation to CHD8 (n = 12). Contribution of familial genetic background to clinical heterogeneity was assessed by comparing head circumference, IQ, and ASD-related symptoms of UW DYRK1A cases to their unaffected parents.Results DYRK1A haploinsufficiency results in a common phenotypic profile including intellectual disability, speech and motor difficulties, microcephaly, feeding difficulties, and vision abnormalities. Eighty-nine percent of DYRK1A cases ascertained for ASD presented with a constellation of five or more of these symptoms. When compared quantitatively, DYRK1A cases presented with significantly lower IQ and adaptive functioning compared to idiopathic cases and significantly smaller head size compared to both idiopathic and CHD8 cases. Phenotypic variability in parental head circumference, IQ, and ASD-related symptoms corresponded to observed variability in affected child phenotype.ConclusionsResults confirm a core clinical phenotype for DYRK1A disruptions, with a combination of features that is distinct from idiopathic ASD. Cases with DYRK1A mutations are also distinguishable from disruptive mutations to CHD8 by head size. Measurable, quantitative characterization of DYRK1A haploinsufficiency illuminates clinical variability, which may be, in part, due to familial genetic background.Electronic supplementary materialThe online version of this article (10.1186/s13229-017-0173-5) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Clinical phenotype of ASD-associated DYRK1A haploinsufficiency

et al. 2017

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“…The DYRK1a gene is located in the Down syndrome critical region on chromosome 21, which results in a 1.5‐fold increase of Dyrk1a protein levels (Tejedor & Hammerle, ). Dyrk1a levels are tightly regulated, as both overexpression and lack of Dyrk1a activity are associated with mental retardation (Luco et al ., ). Dyrk1a can directly phosphorylate tau on numerous serine and threonine residues (Ryoo et al ., ; Azorsa et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Dyrk1 inhibition improves Alzheimer's disease‐like pathology

et al. 2017

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SummaryThere is an urgent need for the development of new therapeutic strategies for Alzheimer's disease (AD). The dual‐specificity tyrosine phosphorylation‐regulated kinase‐1A (Dyrk1a) is a protein kinase that phosphorylates the amyloid precursor protein (APP) and tau and thus represents a link between two key proteins involved in AD pathogenesis. Furthermore, Dyrk1a is upregulated in postmortem human brains, and high levels of Dyrk1a are associated with mental retardation. Here, we sought to determine the effects of Dyrk1 inhibition on AD‐like pathology developed by 3xTg‐AD mice, a widely used animal model of AD. We dosed 10‐month‐old 3xTg‐AD and nontransgenic (NonTg) mice with a Dyrk1 inhibitor (Dyrk1‐inh) or vehicle for eight weeks. During the last three weeks of treatment, we tested the mice in a battery of behavioral tests. The brains were then analyzed for the pathological markers of AD. We found that chronic Dyrk1 inhibition reversed cognitive deficits in 3xTg‐AD mice. These effects were associated with a reduction in amyloid‐β (Aβ) and tau pathology. Mechanistically, Dyrk1 inhibition reduced APP and insoluble tau phosphorylation. The reduction in APP phosphorylation increased its turnover and decreased Aβ levels. These results suggest that targeting Dyrk1 could represent a new viable therapeutic approach for AD.

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“…In addition, 5 individuals with activated STAT3 mutations were reported, and all individuals showed short stature (<2.0 SDS) in contrast to individuals with Hyper Ig E syndrome caused by inactivated STAT3 mutation 27. DYRK1A is a protein kinase located in the Down syndrome critical region of chromosome 21, and DYRK1A haploinsufficiency has recently been regarded as a cause of novel syndromic disorder 28. Eventually, this subject was determined to carry a nonsense mutation of DYRK1A (MIM 600855).…”

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confidence: 99%