Truncation of the Down Syndrome Candidate Gene DYRK1A in Two Unrelated Patients with Microcephaly

Møller, Rikke S.; Kübart, Sabine; Hoeltzenbein, Maria; Heye, Babett; Vogel, Ida; Hansen, Christian Pilebæk; Menzel, Corinna; Ullmann, Reinhard; Tommerup, Niels; Ropers, Hans‐Hilger; Tümer, Zeynep; Kalscheuer, Vera M.

doi:10.1016/j.ajhg.2008.03.001

Cited by 153 publications

(154 citation statements)

References 23 publications

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“…There were some strikingly similar features between members of our cohort and the features of previously reported individuals with a similar genotype, [10][11][12][13][14][15][16][17] indicating that this is a recognizable syndrome. Microcephaly, IUGR, brain abnormalities consistent with cerebral hypomyelination, global DD, ID, severe speech delay, seizures, broadbased gait, short stature, minor skeletal anomalies, and distinct facial gestalt were the most commonly shared features.…”

Section: Resultssupporting

confidence: 85%

“…[10][11][12][13][14][15][16] These are included in Supplementary Table S1. Specific evidence supporting the role of DYRK1A individuals includes the deletion of the non-coding 5′-UTR (NM_130436.3) in one published case, 11 as well as the disruption of DYRK1A by translocation in two cases reported by Moller et al 10 Furthermore, in the Database of Genomic Variants, there are only two self-reported phenotypically normal individuals with exonic losses of DYRK1A (8 Kb and 181 Kb). There are no segmental duplications flanking the deletion breakpoints.…”

Section: Resultsmentioning

confidence: 99%

“…A clinical geneticist provided phenotypic information for all patients. The clinical features of our cohort (n = 14, Table 1) are summarized and were assessed for both overlap and divergence among the cohort and compared with the 13 individuals in published reports, [10][11][12][13][14][15][16][17] as shown in Supplementary Table S1.…”

Section: Phenotypic Analysismentioning

confidence: 99%

“…5,6 Furthermore, data from both animal models and humans have suggested that decreased DYRK1A expression is also pathogenic. [7][8][9] Pathogenic variants in DYRK1A resulting in haploinsufficiency of the gene have recently been proposed to cause intellectual disability (ID), mental retardation autosomal dominant type 7 (MIM 614104) in individuals with translocations, 10 single-nucleotide variants (SNVs), 11,12 and intragenic microdeletions 11,[13][14][15][16][17] disrupting only DYRK1A.…”

Section: Introductionmentioning

confidence: 99%

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DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

et al. 2015

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Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from − 2 SD to − 5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broadbased gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.

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Section: Resultssupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Section: Phenotypic Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

et al. 2015

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“…Higher expression of DYRK1A was also found in a subset of oligodendroglioma patient samples (40), raising a possibility that DYRK1A may suppress Cic activity in human cells, much like Mnb does in Drosophila. A connection between DYRK1A and Cic in controlling brain development may extend even deeper, because both proteins have been implicated in neurodegenerative diseases (9,(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Minibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua

Liu

Paul

Trieu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The transcriptional repressor Capicua (Cic) controls tissue patterning and restricts organ growth, and has been recently implicated in several cancers. Cic has emerged as a primary sensor of signaling downstream of the receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway, but how Cic activity is regulated in different cellular contexts remains poorly understood. We found that the kinase Minibrain (Mnb, ortholog of mammalian DYRK1A), acting through the adaptor protein Wings apart (Wap), physically interacts with and phosphorylates the Cic protein. Mnb and Wap inhibit Cic function by limiting its transcriptional repressor activity. Down-regulation of Cic by Mnb/Wap is necessary for promoting the growth of multiple organs, including the wings, eyes, and the brain, and for proper tissue patterning in the wing. We have thus uncovered a previously unknown mechanism of down-regulation of Cic activity by Mnb and Wap, which operates independently from the ERK-mediated control of Cic. Therefore, Cic functions as an integrator of upstream signals that are essential for tissue patterning and organ growth. Finally, because DYRK1A and CIC exhibit, respectively, prooncogenic vs. tumor suppressor activities in human oligodendroglioma, our results raise the possibility that DYRK1A may also down-regulate CIC in human cells.

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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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Truncation of the Down Syndrome Candidate Gene DYRK1A in Two Unrelated Patients with Microcephaly

Cited by 153 publications

References 23 publications

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

Minibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua

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

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