Molecular causes of primary microcephaly and related diseases: a report from the UNIA Workshop

Stracker, Travis H.; Morrison, Ciarán; Gergely, Fanni

doi:10.1007/s00412-020-00737-6

Cited by 5 publications

(4 citation statements)

References 60 publications

(60 reference statements)

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“…Together, the results suggest that they are potentially valuable models for understanding the etiology of the disease( 3 ). DNA damage, p53 activation and defects in cilia function, that we observed following ADSL depletion, have all been implicated in neurodevelopmental disorders associated with microcephaly( 20 ). One prominent example is Seckel Syndrome.…”

Section: Discussionmentioning

confidence: 79%

SAICAr-dependent and independent effects of ADSL deficiency on neurodevelopment

Dutto

Gerhards

Herrera

et al. 2020

Preprint

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Adenylosuccinate Lyase (ADSL) functions in the de novo purine biosynthesis pathway. ADSL deficiency (ADSLD) causes numerous neurodevelopmental pathologies, including microcephaly and autism spectrum disorder. ADSLD patients have normal purine nucleotide levels but exhibit accumulation of the dephosphorylated ADSL substrates SAICAr and S-Ado. SAICAr was implicated in the neurotoxic effects of ADSLD, although its role remains unknown. We examined the effects of ADSL depletion in human cells and found increased DNA damage signaling, that was rescued by nucleosides, and impaired primary ciliogenesis, that was rescued by reducing SAICAr. By analyzing ADSL deficient chicken and zebrafish embryos we observed impaired neurogenesis and microcephaly, and neuroprogenitor attrition in zebrafish was rescued by reducing SAICAr. Zebrafish embryos also displayed phenotypes commonly linked to ciliopathies. Our results suggest that both reduced purine levels and SAICAr accumulation contribute to neurodevelopmental pathology in ADSLD and defective ciliogenesis may influence the ADSLD phenotypic spectrum.

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Section: Discussionmentioning

confidence: 79%

SAICAr-dependent and independent effects of ADSL deficiency on neurodevelopment

Dutto

Gerhards

Herrera

et al. 2020

Preprint

Self Cite

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“…Together, the results suggest that they are potentially valuable models for understanding the etiology of microcephaly in ADSLD ( Jurecka et al, 2015 ). DNA damage, p53 activation, and defects in cilia function, which we observed following ADSL depletion, have all been implicated in neurodevelopmental disorders, such as Seckel syndrome, which is associated with microcephaly ( Stracker et al, 2020 ). In Seckel syndrome mice expressing hypomorphic, humanized alleles of Atr , replication stress and DNA damage preceded neuroprogenitor cell death ( O’Driscoll et al, 2003 ; Murga et al, 2009 ).…”

Section: Discussionmentioning

confidence: 85%

Pathway-specific effects of ADSL deficiency on neurodevelopment

Dutto

Gerhards

Herrera

et al. 2022

eLife

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Adenylosuccinate Lyase (ADSL) functions in de novo purine biosynthesis (DNPS) and the purine nucleotide cycle. ADSL deficiency (ADSLD) causes numerous neurodevelopmental pathologies, including microcephaly and autism spectrum disorder. ADSLD patients have normal serum purine nucleotide levels but exhibit accumulation of dephosphorylated ADSL substrates, S-Ado and SAICAr, the latter being implicated in neurotoxic effects through unknown mechanisms. We examined the phenotypic effects of ADSL depletion in human cells and their relation to phenotypic outcomes. Using specific interventions to compensate for reduced purine levels or modulate SAICAr accumulation, we found that diminished AMP levels resulted in increased DNA damage signaling and cell cycle delays, while primary ciliogenesis was impaired specifically by loss of ADSL or administration of SAICAr. ADSL deficient chicken and zebrafish embryos displayed impaired neurogenesis and microcephaly. Neuroprogenitor attrition in zebrafish embryos was rescued by pharmacological inhibition of DNPS, but not increased nucleotide concentration. Zebrafish also displayed phenotypes commonly linked to ciliopathies. Our results suggest that both reduced purine levels and impaired DNPS contribute to neurodevelopmental pathology in ADSLD and that defective ciliogenesis may influence the ADSLD phenotypic spectrum.

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“…In particular, ARHGEF10 is involved in neuronal morphogenesis and DECIPHER Patient 368323, which carries an ARHGEF10 SNV, presents microcephaly; CSMD1 and KBTBD11 are brain-specific expressed genes, and CSMD1 is also dosage-sensitive. The strict connection between brain genes and microcephaly is well-documented in the literature [ 51 , 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature

Catusi

Garzo

Capra

et al. 2021

Genes

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To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which FBXO25, DLGAP2, CLN8, ARHGEF10 and MYOM2 are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only DLGAP2, CLN8 and ARHGEF10 genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that DLGAP2 is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of DLGAP2 and better define how the two contiguous genes, ARHGEF10 and CLN8, might contribute to the clinical phenotype.

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Molecular causes of primary microcephaly and related diseases: a report from the UNIA Workshop

Cited by 5 publications

References 60 publications

SAICAr-dependent and independent effects of ADSL deficiency on neurodevelopment

SAICAr-dependent and independent effects of ADSL deficiency on neurodevelopment

Pathway-specific effects of ADSL deficiency on neurodevelopment

8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature

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