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Synaptotagmin-1 (Syt1) is a presynaptic calcium sensor with two calcium binding domains, C2A and C2B, that triggers action potential-induced synchronous neurotransmitter release, while suppressing asynchronous and spontaneous release. We identified a de novo missense mutation (P401L) in the C2B domain in a patient with developmental delay and autistic symptoms. Expressing the orthologous mouse mutant (P400L) in cultured Syt1 null mutant neurons revealed a reduction in dendrite outgrowth with a proportional reduction in synapses. This was not observed in single Syt1 PL -rescued neurons that received normal synaptic input when cultured in a control network. Patch-clamp recordings showed that spontaneous miniature release events per synapse were increased more than 500% in Syt1 PL -rescued neurons, even beyond the increased rates in Syt1 KO neurons. Furthermore, action potential-induced asynchronous release was increased more than 100%, while synchronous release was unaffected. A similar shift to more asynchronous release was observed during train stimulations. These cellular phenotypes were also observed when Syt1 PL was overexpressed in wild type neurons. Our findings show that Syt1 PL desynchronizes neurotransmission by increasing the readily releasable pool for asynchronous release and reducing the suppression of spontaneous and asynchronous release. Neurons respond to this by shortening their dendrites, possibly to counteract the increased synaptic input. Syt1 PL acts in a dominant-negative manner supporting a causative role for the mutation in the heterozygous patient. We propose that the substitution of a rigid proline to a more flexible leucine at the bottom of the C2B domain impairs clamping of release by interfering with Syt1’s primary interface with the SNARE complex. This is a novel cellular phenotype, distinct from what was previously found for other SYT1 disease variants, and points to a role for spontaneous and asynchronous release in SYT1 -associated neurodevelopmental disorder.

Background: Duodenal obstruction (DO) is a congenital anomaly that is highly associated with other anomalies, such as cardiac anomalies and trisomy 21. However, an overview of additional anomalies and patient-specific risk factors for cardiac anomalies is lacking. Potential association with the vertebral, anorectal, cardiac, trachea-esophageal, renal and limb anomalies (VACTERL) spectrum remains unknown. Therefore, we aim to examine the incidence of associated anomalies, a VACTERL-spectrum association and patient-specific risk factors for cardiac anomalies in patients with DO. Methods: A retrospective cohort study was performed between 1996 and 2021. Outcomes were the presence of any additional anomalies. Risk factors for cardiac anomalies were analyzed using multivariate logistic regression. Results: Of 112 neonates with DO, 47% (N = 53/112) had one associated anomaly and 38% (N = 20/53) had multiple anomalies. Cardiac anomalies (N = 35/112) and trisomy 21 (N = 35/112) were present in 31%. In four patients, VACTERL-spectrum was discovered, all with cardiac anomalies. Trisomy 21 was found to be a risk factor for cardiac anomalies (OR:6.5; CI-95%2.6–16.1). Conclusion: Associated anomalies were present in half of patients with DO, of which cardiac anomalies and trisomy 21 occurred most often, and the VACTERL-spectrum was present in four patients. Trisomy 21 was a significant risk factor for cardiac anomalies. Therefore, we recommend a preoperative echocardiogram in patients with DO. In case a cardiac anomaly is found without trisomy 21, VACTERL-screening should be performed.

KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients’ neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mRNA decay. Although we demonstrate that Kif21b haploinsufficiency leads to an impaired neuronal positioning, the duplication variant might not be pathogenic. Altogether, our data indicate that impaired KIF21B autoregulation and function play a critical role in the pathogenicity of human neurodevelopmental disorder. Kinesins regulate intracellular transport and microtubule dynamics. Here, the authors show that KIF21B variants in humans associate with corpus callosum agenesis and microcephaly. Using mice and zebrafish, they showed the cellular mechanisms altered by the missense KIF21B variants.

In spite of antibiotic treatment, pneumococcal meningitis continues to be associated with significant morbidity and mortality. The complement system is a key component of innate immunity against invading pathogens. However, activation of complement is also involved in tissue damage, and complement inhibition by C1 inhibitor (C1-inh) is beneficial in animal models of endotoxemia and sepsis. In the present study, we demonstrate classical pathway complement activation during pneumococcal meningitis in rats. We also evaluate the effect of C1-inh treatment on clinical illness, bacterial clearance, and inflammatory responses in rats and mice with pneumococcal meningitis. C1-inh treatment was associated with reduced clinical illness, a lesspronounced inflammatory infiltrate around the meninges, and lower brain levels of proinflammatory cytokines and chemokines. C1-inh treatment increased bacterial clearance, possibly through an up-regulation of CR3. Hence, C1-inh may be a useful agent in the treatment of pneumococcal meningitis.

We present six patients from five unrelated families with a condition originally described by Van Maldergem et al and provide follow-up studies of the original patient. The phenotype comprises a distinctive facial appearance that includes blepharophimosis, maxillary hypoplasia, telecanthus, microtia and atresia of the external auditory meatus, intellectual disability, digital contractures and skeletal anomalies together with subependymal and subcortical neuronal heterotopia. Affected patients typically have neonatal hypotonia, chronic feeding difficulties and respiratory problems. In our cohort, we have observed one instance of sibling recurrence and parental consanguinity in three of the families, indicating that autosomal recessive inheritance is likely.

Effective laboratory animal models of bacterial meningitis are needed to unravel the pathophysiology of this disease. Previous models have failed to simulate human meningitis by using a directly intracerebral route of infection. Hyaluronidase is a virulence factor of Streptococcus pneumoniae. In this study, a novel model of murine meningitis is described. Intranasal administration of S. pneumoniae with hyaluronidase induced meningitis in 50% of inoculated mice, as defined by a positive cerebrospinal fluid (CSF) culture and an inflammatory infiltrate in the meninges. None of the mice inoculated without hyaluronidase developed meningitis. Hyaluronidase was found to facilitate pneumococcal invasion of the bloodstream after colonization of the upper respiratory tract. Meningitis was characterized by pleocytosis of CSF and the induction of proinflammatory cytokines and CXC chemokines in brain tissue. These results indicate that this murine model mimics important features of human disease and allow for the use of this model for studying issues related to the pathophysiology and the treatment of pneumococcal meningitis

Anterior segment dysgenesis (ASD) encompasses a broad spectrum of developmental conditions affecting anterior ocular structures and associated with an increased risk for glaucoma. Various systemic anomalies are often observed in ASD conditions such as Axenfeld-Rieger syndrome (ARS) and De Hauwere syndrome. We report DNA sequencing and copy number analysis of PITX2 and FOXC1 in 76 patients with syndromic or isolated ASD and related conditions. PITX2 mutations and deletions were found in 24 patients with dental and/or umbilical anomalies seen in all. Seven PITX2-mutant alleles were novel including c.708_730del, the most C-terminal mutation reported to date. A second case of deletion of the distant upstream but not coding region of PITX2 was identified, highlighting the importance of this recently discovered mechanism for ARS. FOXC1 deletions were observed in four cases, three of which demonstrated hearing and/or heart defects, including a patient with De Hauwere syndrome; no nucleotide mutations in FOXC1 were identified. Review of the literature identified several other patients with 6p25 deletions and features of De Hauwere syndrome. The 1.3-Mb deletion of 6p25 presented here defines the critical region for this phenotype and includes the FOXC1, FOXF2, and FOXQ1 genes. In summary, PITX2 or FOXC1 disruptions explained 63% of ARS and 6% of other ASD in our cohort; all affected patients demonstrated additional systemic defects with PITX2 mutations showing a strong association with dental and/or umbilical anomalies and FOXC1 with heart and hearing defects. FOXC1 deletion was also found to be associated with De Hauwere syndrome.

Magdalena Götz, Stephen Robertson and colleagues show that biallelic mutations in DCHS1 and FAT4 cause a multisystem disorder that includes periventricular neuronal heterotopia. They further show that reducing expression of Dchs1 and Fat4 in mouse embryonic neuroepithelium causes an increase in progenitor cell numbers and reduced neuronal differentiation, resulting in heterotopic accumulation of cells below the neuronal layers in the neocortex. The regulated proliferation and differentiation of neural stem cells before the generation and migration of neurons in the cerebral cortex are central aspects of mammalian development. Periventricular neuronal heterotopia, a specific form of mislocalization of cortical neurons, can arise from neuronal progenitors that fail to negotiate aspects of these developmental processes. Here we show that mutations in genes encoding the receptor-ligand cadherin pair DCHS1 and FAT4 lead to a recessive syndrome in humans that includes periventricular neuronal heterotopia. Reducing the expression of Dchs1 or Fat4 within mouse embryonic neuroepithelium increased progenitor cell numbers and reduced their differentiation into neurons, resulting in the heterotopic accumulation of cells below the neuronal layers in the neocortex, reminiscent of the human phenotype. These effects were countered by concurrent knockdown of Yap, a transcriptional effector of the Hippo signaling pathway. These findings implicate Dchs1 and Fat4 upstream of Yap as key regulators of mammalian neurogenesis.

Copy number variations associate with different developmental phenotypes and represent a major cause of congenital anomalies of the kidney and urinary tract (CAKUT). Because rare pathogenic copy number variations are often large and contain multiple genes, identification of the underlying genetic drivers has proven to be difficult. Here we studied the role of rare copy number variations in 80 patients from the KIMONO study cohort for which pathogenic mutations in three genes commonly implicated in CAKUT were excluded. In total, 13 known or novel genomic imbalances in 11 of 80 patients were absent or extremely rare in 23,362 population controls. To identify the most likely genetic drivers for the CAKUT phenotype underlying these rare copy number variations, we used a systematic in silico approach based on frequency in a large data set of controls, annotation with publicly available databases for developmental diseases, tolerance and haploinsufficiency scores, and gene expression profile in the developing kidney and urinary tract. Five novel candidate genes for CAKUT were identified that showed specific expression in the human and mouse developing urinary tract. Among these genes, DLG1 and KIF12 are likely novel susceptibility genes for CAKUT in humans. Thus, there is a significant role of genomic imbalance in the determination of kidney developmental phenotypes. Additionally, we defined a systematic strategy to identify genetic drivers underlying rare copy number variations.