The Fizzy‐related protein 1 (Fzr1) gene encodes Cdh1 protein, a coactivator of the E3 ubiquitin ligase anaphase‐promoting complex/cyclosome (APC/C). Previously, we found that genetic ablation of Fzr1 ...promotes the death of neural progenitor cells leading to neurogenesis impairment and microcephaly in mouse. To ascertain the possible translation of these findings in humans, we searched for mutations in the Fzr1 gene in 390 whole exomes sequenced in trio in individuals showing neurodevelopmental disorders compatible with a genetic origin. We found a novel missense (p.Asp187Gly) Fzr1 gene mutation (c.560A>G) in a heterozygous state in a 4‐year‐old boy, born from non‐consanguineous Spanish parents, who presents with severe antenatal microcephaly, psychomotor retardation, and refractory epilepsy. Cdh1 protein levels in leucocytes isolated from the patient were significantly lower than those found in his parents. Expression of the Asp187Gly mutant form of Cdh1 in human embryonic kidney 293T cells produced less Cdh1 protein and APC/C activity, resulting in altered cell cycle distribution when compared with cells expressing wild‐type Cdh1. Furthermore, ectopic expression of the Asp187Gly mutant form of Cdh1 in cortical progenitor cells in primary culture failed to abolish the enlargement of the replicative phase caused by knockout of endogenous Cdh1. These results indicate that the loss of function of APC/C‐Cdh1 caused by Cdh1 Asp187Gly mutation is a new cause of prenatal microcephaly, psychomotor retardation, and severe epilepsy.
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We previously found that the anaphase promoting complex/cyclosome (APC/C) inactivation, by deletion of its activator Cdh1, promotes microcephaly in mouse. Here, we describe a de novo Cdh1 mutation (p.Asp187Gly) in a 4‐year‐old boy with prenatal microcephaly, psychomotor retardation, and epilepsy. Functional studies in the patient leukocytes, in a human cell line and in mouse neural precursor cells reveal that the Asp187Gly mutation results in decreased Cdh1 protein abundance, likely due to nuclear degradation, leading to APC/C inactivation. Thus, Cdh1 Asp187Gly mutation is herein identified as a novel cause of APC/C‐Cdh1 inactivation triggering prenatal microcephaly, psychomotor retardation, and severe epilepsy in human.
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Although progress has been made in elucidating the behavioral and neural development of global stopping across the lifespan, little is known about the development of selective stopping. This more ...complex form of inhibitory control is required in real‐world situations where ongoing responses must be inhibited to certain stimuli but not others, and can be assessed in laboratory settings using a stimulus selective stopping task. Here we used this task to investigate the qualitative and quantitative developmental changes in selective stopping in a large‐scale cross‐sectional study with three different age groups (children, preadolescents, and young adults). We found that the ability to stop a response selectively to some stimuli (i.e., use a selective strategy) rather than non‐selectively to all presented stimuli (i.e., use a global, non‐selective strategy) is fully mature by early preadolescence, and remains stable afterwards at least until young adulthood. By contrast, the efficiency or speed of stopping (indexed by a shorter stop‐signal reaction time or SSRT) continues to mature throughout adolescence until young adulthood, both for global and selective implementations of stopping. We also provide some preliminary findings regarding which other task variables beyond the strategy and SSRT predicted age group status. Premature responding (an index of “waiting impulsivity”) and post‐ignore slowing (an index of cognitive control) were among the most relevant predictors in discriminating between developmental age groups. Although present results need to be confirmed and extended in longitudinal studies, they provide new insights into the development of a relevant form of inhibitory control.
Tatton‐Brown–Rahman syndrome (TBRS) or DNMT3A‐overgrowth syndrome is characterized by overgrowth and intellectual disability associated with minor dysmorphic features, obesity, and behavioral ...problems. It is caused by variants of the DNMT3A gene. We report four patients with this syndrome due to de novo DNMT3A pathogenic variants, contributing to a deeper understanding of the genetic basis and pathophysiology of this autosomal dominant syndrome. Clinical and magnetic resonance imaging assessments were also performed. All patients showed corpus callosum anomalies, small posterior fossa, and a deep left Sylvian fissure; as well as asymmetry of the uncinate and arcuate fascicles and marked increased cortical thickness. These results suggest that structural neuroimaging anomalies have been previously overlooked, where corpus callosum and brain tract alterations might be unrecognized neuroimaging traits of TBRS syndrome caused by DNMT3A variants.
Pathogenic variants in the X‐linked gene ZC4H2, which encodes a zinc‐finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and ...peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from nine families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the nine carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, four were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense, and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo‐/akinesia and/or (neurogenic) AMC.
Overview of newly identified likely pathogenic variants in the X‐linked gene ZC4H2 leading to ZC4H2‐Associated Rare Disorders (ZARD) in affected males and females. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense and partial ZC4H2 deletions in affected females.
Giant ankyrin-G (gAnkG) coordinates assembly of axon initial segments (AISs), which are sites of action potential generation located in proximal axons of most vertebrate neurons. Here, we identify a ...mechanism required for normal neural development in humans that ensures ordered recruitment of gAnkG and β4-spectrin to the AIS. We identified 3 human neurodevelopmental missense mutations located in the neurospecific domain of gAnkG that prevent recruitment of β4-spectrin, resulting in a lower density and more elongated pattern for gAnkG and its partners than in the mature AIS. We found that these mutations inhibit transition of gAnkG from a closed configuration with close apposition of N- and C-terminal domains to an extended state that is required for binding and recruitment of β4-spectrin, and normally occurs early in development of the AIS. We further found that the neurospecific domain is highly phosphorylated in mouse brain, and that phosphorylation at 2 sites (S1982 and S2619) is required for the conformational change and for recruitment of β4-spectrin. Together, these findings resolve a discrete intermediate stage in formation of the AIS that is regulated through phosphorylation of the neurospecific domain of gAnkG.
Tenorio syndrome (TNORS) (OMIM #616260) is a relatively recent disorder with very few cases described so far. Clinical features included macrocephaly, intellectual disability, hypotonia, enlarged ...ventricles and autoimmune diseases. Molecular underlying mechanism demonstrated missense variants and a large deletion encompassing RNF125, a gene that encodes for an U3 ubiquitin ligase protein. Since the initial description of the disorder in six patients from four families, several new patients were diagnosed, adding more evidence to the clinical spectrum. In this article, we described 14 additional cases with deep phenotyping and make an overall review of all the cases with pathogenic variants in RNF125. Not all patients presented with overgrowth, but instead, most patients showed a common pattern of neurodevelopmental disease, macrocephaly and/or large forehead. Segregation analysis showed that, though the variant was inherited in some patients from an apparently asymptomatic parent, deep phenotyping suggested a mild form of the disease in some of them. The mechanism underlying the development of this disease is not well understood yet and the report of further cases will help to a better understanding and clinical characterization of the syndrome.
SMARCA4 encodes a central ATPase subunit in the BRG1‐/BRM‐associated factors (BAF) or polybromo‐associated BAF (PBAF) complex in humans, which is responsible in part for chromatin remodeling and ...transcriptional regulation. Variants in this and other genes encoding BAF/PBAF complexes have been implicated in Coffin–Siris Syndrome, a multiple congenital anomaly syndrome classically characterized by learning and developmental differences, coarse facial features, hypertrichosis, and underdevelopment of the fifth digits/nails of the hands and feet. Individuals with SMARCA4 variants have been previously reported and appear to display a variable phenotype. We describe here a cohort of 15 unrelated individuals with SMARCA4 variants from the Coffin–Siris syndrome/BAF pathway disorders registry who further display variability in severity and degrees of learning impairment and health issues. Within this cohort, we also report two individuals with novel nonsense variants who appear to have a phenotype of milder learning/behavioral differences and no organ‐system involvement.
Anoctamin 3 (ANO3) belongs to a family of transmembrane proteins that form phospholipid scramblases and ion channels. A large number of ANO3 variants were identified as the cause of craniocervical ...dystonia, but the underlying pathogenic mechanisms remain obscure. It was suggested that ANO3 variants may dysregulate intracellular Ca2+ signalling, as variants in other Ca2+ regulating proteins like hippocalcin were also identified as a cause of dystonia. In this study, we conducted a comprehensive evaluation of the clinical, radiological and molecular characteristics of four individuals from four families who carried heterozygous variants in ANO3. The median age at follow-up was 6.6 years (ranging from 3.8 to 8.7 years). Three individuals presented with hypotonia and motor developmental delay. Two patients exhibited generalized progressive dystonia, while one patient presented with paroxysmal dystonia. Additionally, another patient exhibited early dyskinetic encephalopathy. One patient underwent bipallidal deep brain stimulation (DBS) and showed a mild but noteworthy response, while another patient is currently being considered for DBS treatment. Neuroimaging analysis of brain MRI studies did not reveal any specific abnormalities. The molecular spectrum included two novel ANO3 variants (V561L and S116L) and two previously reported ANO3 variants (A599D and S651N). As anoctamins are suggested to affect intracellular Ca2+ signals, we compared Ca2+ signalling and activation of ion channels in cells expressing wild-type ANO3 and cells expressing anoctamin variants. Novel V561L and S116L variants were compared with previously reported A599D and S651N variants and with wild-type ANO3 expressed in fibroblasts isolated from patients or when overexpressed in HEK293 cells. We identified ANO3 as a Ca2+-activated phospholipid scramblase that also conducts ions. Impaired Ca2+ signalling and compromised activation of Ca2+-dependent K+ channels were detected in cells expressing ANO3 variants. In the brain striatal cells of affected patients, impaired activation of KCa3.1 channels due to compromised Ca2+ signals may lead to depolarized membrane voltage and neuronal hyperexcitability and may also lead to reduced cellular viability, as shown in the present study. In conclusion, our study reveals the association between ANO3 variants and paroxysmal dystonia, representing the first reported link between these variants and this specific dystonic phenotype. We demonstrate that ANO3 functions as a Ca2+-activated phospholipid scramblase and ion channel; cells expressing ANO3 variants exhibit impaired Ca2+ signalling and compromised activation of Ca2+-dependent K+ channels. These findings provide a mechanism for the observed clinical manifestations and highlight the importance of ANO3 for neuronal excitability and cellular viability.
We describe a 7-year-old male with high functioning autism spectrum disorder (ASD) and maternally-inherited rare missense variant of Synaptotagmin-like protein 4 (
gene (Xq22.1; c.835C>T; ...p.Arg279Cys) and an unknown missense variant of Transmembrane protein 187 (
) gene (Xq28; c.708G>T; p. Gln236His). Multiple in-silico predictions described in our study indicate a potentially damaging status for both X-linked genes. Analysis of predicted atomic threading models of the mutant and the native SYTL4 proteins suggest a potential structural change induced by the R279C variant which eliminates the stabilizing Arg279-Asp60 salt bridge in the N-terminal half of the SYTL4, affecting the functionality of the protein's critical RAB-Binding Domain. In the European (Non-Finnish) population, the allele frequency for this variant is 0.00042. The
gene is known to directly interact with several members of the RAB family of genes, such as,
and
which are known autism spectrum disorder genes. The
gene also directly interacts with three known autism genes:
,
and
Through a literature-based analytical approach, we identified three of five (60%) autism-associated serum microRNAs (miRs) with high predictive power among the total of 298 mouse Sytl4 associated/predicted microRNA interactions. Five of 13 (38%) miRs were differentially expressed in serum from ASD individuals which were predicted to interact with the mouse equivalent
4 gene.
gene, like
, is a protein-coding gene that belongs to a group of genes which host microRNA genes in their introns or exons. The novel Q236H amino acid variant in the TMEM187 in our patient is near the terminal end region of the protein which is represented by multiple sequence alignments and hidden Markov models, preventing comparative structural analysis of the variant harboring region. Like
, the
gene is expressed in the brain and interacts with four known ASD genes, namely,
; and
is in linkage with
, which is a well-known determinant of brain structure and size and is a well-known autism gene. Other members of the
gene family,
and
genes are associated with bipolar and panic disorders, respectively, while
is a known syndromic autism gene. Together,
and
genes directly interact with recognized important ASD genes, and their mRNAs are found in extracellular vesicles in the nervous system and stimulate target cells to translate into active protein. Our evidence shows that both these genes should be considered as candidate genes for autism. Additional biological testing is warranted to further determine the pathogenicity of these gene variants in the causation of autism.
Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late ...developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies.
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