scholarly journals De novo variants in MPP5 cause global developmental delay and behavioral changes

2020 ◽  
Vol 29 (20) ◽  
pp. 3388-3401 ◽  
Author(s):  
Noelle Sterling ◽  
Anna R Duncan ◽  
Raehee Park ◽  
David A Koolen ◽  
Jiahai Shi ◽  
...  
Keyword(s):  
Cell Death ◽  
Developmental Delay ◽  
Cell Polarity ◽  
De Novo ◽  
Apoptotic Cell ◽  
Ventricular Zone ◽  
Behavioral Changes ◽  
Ependymal Cells ◽  
Global Developmental Delay ◽  
Apical Surface

Abstract Membrane Protein Palmitoylated 5 (MPP5) is a highly conserved apical complex protein essential for cell polarity, fate and survival. Defects in cell polarity are associated with neurologic disorders including autism and microcephaly. MPP5 is essential for neurogenesis in animal models, but human variants leading to neurologic impairment have not been described. We identified three patients with heterozygous MPP5 de novo variants (DNV) and global developmental delay (GDD) and compared their phenotypes and magnetic resonance imaging (MRI) to ascertain how MPP5 DNV leads to GDD. All three patients with MPP5 DNV experienced GDD with language delay/regression and behavioral changes. MRI ranged from normal to decreased gyral folding and microcephaly. The effects of MPP5 depletion on the developing brain were assessed by creating a heterozygous conditional knock out (het CKO) murine model with central nervous system (CNS)-specific Nestin-Cre drivers. In the het CKO model, Mpp5 depletion led to microcephaly, decreased cerebellar volume and cortical thickness. Het CKO mice had decreased ependymal cells and Mpp5 at the apical surface of cortical ventricular zone compared with wild type. Het CKO mice also failed to maintain progenitor pools essential for neurogenesis. The proportion of cortical cells undergoing apoptotic cell death increased, suggesting that cell death reduces progenitor population and neuron number. Het CKO mice also showed behavioral changes, similar to our patients. To our knowledge, this is the first report to show that variants in MPP5 are associated with GDD, behavioral abnormalities and language regression/delay. Murine modeling shows that neurogenesis is likely altered in these individuals, with cell death and skewed cellular composition playing significant roles.

A novel de novo TMEM63A variant in a patient with severe hypomyelination and global developmental delay

2021 ◽  
Author(s):  
Shinobu Fukumura ◽  
Takuya Hiraide ◽  
Akiyo Yamamoto ◽  
Kousuke Tsuchida ◽  
Kazushi Aoto ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Global Developmental Delay

Presenilin-1 regulates neuronal differentiation during neurogenesis

Development ◽  
2000 ◽  
Vol 127 (12) ◽  
pp. 2593-2606 ◽  
Author(s):  
M. Handler ◽  
X. Yang ◽  
J. Shen
Keyword(s):  
Cell Death ◽  
Progenitor Cells ◽  
Neuronal Differentiation ◽  
Cell Fate ◽  
Neural Progenitor Cells ◽  
Apoptotic Cell ◽  
Ventricular Zone ◽  
Neural Progenitor ◽  
Apoptotic Cell Death ◽  
Presenilin 1

Mutations in Presenilin-1 (PS1) are a major cause of familial Alzheimer's disease. Our previous studies showed that PS1 is required for murine neural development. Here we report that lack of PS1 leads to premature differentiation of neural progenitor cells, indicating a role for PS1 in a cell fate decision between postmitotic neurons and neural progenitor cells. Neural proliferation and apoptotic cell death during neurogenesis are unaltered in PS1(−/−) mice, suggesting that the reduction in the neural progenitor cells observed in the PS1(−/−) brain is due to premature differentiation of progenitor cells, rather than to increased apoptotic cell death or decreased cell proliferation. In addition, the premature neuronal differentiation in the PS1(−/−) brain is associated with aberrant neuronal migration and disorganization of the laminar architecture of the developing cerebral hemisphere. In the ventricular zone of PS1(−/−) mice, expression of the Notch1 downstream effector gene Hes5 is reduced and expression of the Notch1 ligand Dll1 is elevated, whereas expression of Notch1 is unchanged. The level of Dll1 transcripts is also increased in the presomitic mesoderm of PS1(−/−) embryos, while the level of Notch1 transcripts is unchanged, in contrast to a previous report (Wong et al., 1997, Nature 387, 288–292). These results provide direct evidence that PS1 controls neuronal differentiation in association with the downregulation of Notch signalling during neurogenesis.

scholarly journals Nucleotide Biosynthesis Links Glutathione Metabolism to Ferroptosis Sensitivity

2021 ◽  
Author(s):  
Amy Tarangelo ◽  
Joon Tae Kim ◽  
Jonathan Z Long ◽  
Scott J Dixon
Keyword(s):  
Cell Death ◽  
De Novo ◽  
Apoptotic Cell ◽  
Lipid Peroxides ◽  
Nucleotide Metabolism ◽  
Apoptotic Cell Death ◽  
Death Process ◽  
Glutathione Metabolism ◽  
Dependent Manner ◽  
Nucleotide Synthesis

Nucleotide synthesis is a metabolically demanding process essential for cell division. Several anti-cancer drugs that inhibit nucleotide metabolism induce apoptosis. How inhibition of nucleotide metabolism impacts non-apoptotic cell death is less clear. Here, we report that inhibition of nucleotide metabolism by the p53 pathway is sufficient to suppress the non-apoptotic cell death process of ferroptosis. Mechanistically, stabilization of wild-type p53 and induction of the p53 target gene CDKN1A (p21) leads to decreased expression of the ribonucleotide reductase (RNR) subunits RRM1 and RRM2. RNR is the rate-limiting enzyme of de novo nucleotide synthesis that reduces ribonucleotides to deoxyribonucleotides in a glutathione-dependent manner. Direct inhibition of RNR conserves glutathione which can then be used to limit the accumulation of toxic lipid peroxides, preventing the onset of ferroptosis. These results support a mechanism linking p53-dependent regulation of nucleotide metabolism to non-apoptotic cell death.

Identification of de novo CSNK2A1 and CSNK2B variants in cases of global developmental delay with seizures

2019 ◽  
Vol 64 (4) ◽  
pp. 313-322 ◽  
Author(s):  
Mitsuko Nakashima ◽  
Jun Tohyama ◽  
Eiji Nakagawa ◽  
Yoshihiro Watanabe ◽  
Ch’ng Gaik Siew ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Global Developmental Delay

16p11.2 de novo microdeletion encompassing SRCAP gene in a patient with speech impairment, global developmental delay and behavioural problems

2014 ◽  
Vol 57 (11-12) ◽  
pp. 649-653 ◽  
Author(s):  
Francesca Gerundino ◽  
Giuseppina Marseglia ◽  
Chiara Pescucci ◽  
Elisabetta Pelo ◽  
Matteo Benelli ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Behavioural Problems ◽  
Global Developmental Delay ◽  
Speech Impairment

scholarly journals KCNQ2 mutations: genotype-phenotype association beyond epilepsy

2015 ◽  
Vol 42 (S1) ◽  
pp. S8-S8
Author(s):  
SE Buerki ◽  
GA Horwath ◽  
MI Van Allen ◽  
A Datta ◽  
C Boelman ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Autonomic Dysfunction ◽  
De Novo ◽  
Focal Epilepsy ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
High Signal ◽  
Brain Volume Loss ◽  
Hyperkinetic Movement Disorder

Background: KCNQ2 abnormalities were described in infants with benign familial neonatal seizures (BFNS) and epileptic encephalopathy (EE). Associated features possibly include abnormal neuroimaging findings such as hypomyelination and/or T2 high signal of basal ganglia. Methods: This report describes 4 infants carrying different heterozygous KCNQ2 variants and 2 infants with 20q13.33 deletions encompassing KCNQ2 gene. Results: The different KCNQ2 mutations led to EE in 3 patients and included a novel de novo missense variant, p.Arg201Cys/c.601C>T, in an infant with severe EE and global developmental delay, hyperkinetic movement disorder, autonomic dysfunction with chronic hypoventilation, apnea, low GABA levels in CSF, and hypomyelination. She died at age 3 years of respiratory failure. One patient with BFNS and normal MRI has a previously reported c.508delG frame shift mutation in KCNQ2. Of the two de novo 22q13.33 deletions (1.2Mb versus 254.1 Kb) the larger caused a more severe phenotype, including focal epilepsy from infancy until 4 years, moderate developmental delay and diffuse brain volume loss. Conclusions: Along with varied epilepsy phenotypes and neuroimaging findings KCNQ abnormalities were associated with severe autonomic dysfunction and reduced CSF GABA levels. This might have further treatment implications, besides that the altered potassium channel function itself presents a therapeutic target.

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