Prdm15 acts upstream of Wnt4 signaling in anterior neural development of Xenopus laevis.

Mutations in PRDM15 lead to a syndromic form of holoprosencephaly (HPE) known as the Galloway-Mowat syndrome (GAMOS). While a connection between PRDM15, a zinc finger transcription factor, and WNT/PCP signaling has been established, there is a critical need to delve deeper into their contributions to early development and GAMOS pathogenesis. We used the South African clawed frog Xenopus laevis as the vertebrate model organism and observed that prdm15 was enriched in the tissues and organs affected in GAMOS. Furthermore, we generated a morpholino oligonucleotide-mediated prdm15 knockdown model showing that the depletion of Prdm15 leads to abnormal eye, head, and brain development, effectively recapitulating the anterior neural features in GAMOS. An analysis of the underlying molecular basis revealed a reduced expression of key genes associated with eye, head, and brain development. Notably, this reduction could be rescued by the introduction of wnt4 RNA, particularly during the induction of the respective tissues. Mechanistically, our data demonstrate that Prdm15 acts upstream of both canonical and non-canonical Wnt4 signaling during anterior neural development. Our findings describe severe ocular and anterior neural abnormalities upon Prdm15 depletion and elucidate the role of Prdm15 in canonical and non-canonical Wnt4 signaling.

NECAB2 is an endosomal protein important for striatal function.

Synaptic signaling depends on ATP generated by mitochondria. Dysfunctional mitochondria shift the redox balance towards a more oxidative environment. Due to extensive connectivity, the striatum is especially vulnerable to mitochondrial dysfunction. We found that neuronal calcium-binding protein 2 (NECAB2) plays a role in striatal function and mitochondrial homeostasis. NECAB2 is a predominantly endosomal striatal protein which partially colocalizes with mitochondria. This colocalization is enhanced by mild oxidative stress. Global knockout of Necab2 in the mouse results in increased superoxide levels, increased DNA oxidation and reduced levels of the antioxidant glutathione which correlates with an altered mitochondrial shape and function. Striatal mitochondria from Necab2 knockout mice are more abundant and smaller and characterized by a reduced spare capacity suggestive of intrinsic uncoupling respectively mitochondrial dysfunction. In line with this, we also found an altered stress-induced interaction of endosomes with mitochondria in Necab2 knockout striatal cultures. The predominance of dysfunctional mitochondria and the pro-oxidative redox milieu correlates with a loss of striatal synapses and behavioral changes characteristic of striatal dysfunction like reduced motivation and altered sensory gating. Together this suggests an involvement of NECAB2 in an endosomal pathway of mitochondrial stress response important for striatal function.

Effects of aircraft noise cessation on blood pressure, cardio- and cerebrovascular endothelial function, oxidative stress, and inflammation in an experimental animal model.

Large epidemiological studies have shown that traffic noise promotes the development of cardiometabolic diseases. It remains to be established how long these adverse effects of noise may persist in response to a noise-off period. We investigated the effects of acute aircraft noise exposure (mean sound level of 72 dB(A) applied for 4d) on oxidative stress and inflammation mediating vascular dysfunction and increased blood pressure in male C57BL/6 J mice. 1, 2 or 4d of noise cessation after a 4d continuous noise exposure period completely normalized noise-induced endothelial dysfunction of the aorta (measured by acetylcholine-dependent relaxation) already after a 1d noise pause. Vascular oxidative stress and the increased blood pressure were partially corrected, while markers of inflammation (VCAM-1, IL-6 and leukocyte oxidative burst) showed a normalization within 4d of noise cessation. In contrast, endothelial dysfunction, oxidative stress, and inflammation of the cerebral microvessels of noise-exposed mice did not improve at all. These data demonstrate that the recovery from noise-induced damage is more complex than expected demonstrating a complete restoration of large conductance vessel function but persistent endothelial dysfunction of the microcirculation. These findings also imply that longer noise pauses are required to completely reverse noise-induced vascular dysfunction including the resistance vessels.

Neuroanatomical changes of ionotropic glutamatergic and GABAergic receptor densities in male mice modeling idiopathic and syndromic autism spectrum disorder.

Autism spectrum disorder (ASD) comprises a wide range of neurodevelopment conditions primarily characterized by impaired social interaction and repetitive behavior, accompanied by a variable degree of neuropsychiatric characteristics. Synaptic dysfunction is undertaken as one of the key underlying mechanisms in understanding the pathophysiology of ASD. The excitatory/inhibitory (E/I) hypothesis is one of the most widely held theories for its pathogenesis. Shifts in E/I balance have been proven in several ASD models. In this study, we investigated three mouse lines recapitulating both idiopathic (the BTBR strain) and genetic (Fmr1 and Shank3 mutants) forms of ASD at late infancy and early adulthood. Using receptor autoradiography for ionotropic excitatory (AMPA and NMDA) and inhibitory (GABAA) receptors, we mapped the receptor binding densities in brain regions known to be associated with ASD such as prefrontal cortex, dorsal and ventral striatum, dorsal hippocampus, and cerebellum. The individual mouse lines investigated show specific alterations in excitatory ionotropic receptor density, which might be accounted as specific hallmark of each individual line. Across all the models investigated, we found an increased binding density to GABAA receptors at adulthood in the dorsal hippocampus. Interestingly, reduction in the GABAA receptor binding density was observed in the cerebellum. Altogether, our findings suggest that E/I disbalance individually affects several brain regions in ASD mouse models and that alterations in GABAergic transmission might be accounted as unifying factor.

Fixation and staining methods for macroscopical investigation of the brain.

The proper preservation of human brain tissue is an indispensable requirement for post-mortem investigations. Neuroanatomical teaching, neuropathological examination, neurosurgical training, basic and clinical neuroscientific research are some of the possible downstream applications of brain specimens and, although much apart from one another, proper tissue fixation and preservation is a common denominator to all of them. In this review, the most relevant procedures to fixate brain tissue are described. In situ and immersion fixation approaches have been so far the most widespread ways to deliver the fixatives inside the skull. Although most of them rely on the use of formalin, alternative fixative solutions containing lower amounts of this compound mixed with other preservative agents, have been attempted. The combination of fixation and freezing paved the way for fiber dissection, particularly relevant for the neurosurgical practice and clinical neuroscience. Moreover, special techniques have been developed in neuropathology to tackle extraordinary problems, such as the examination of highly infective specimens, as in the case of the Creutzfeldt-Jakob encephalopathy, or fetal brains. Fixation is a fundamental prerequisite for further staining of brain specimens. Although several staining techniques have been developed for the microscopical investigation of the central nervous system, numerous approaches are also available for staining macroscopic brain specimens. They are mostly relevant for neuroanatomical and neuropathological teaching and can be divided in white and gray matter staining techniques. Altogether, brain fixation and staining techniques are rooted in the origins of neuroscience and continue to arouse interest in both preclinical and clinical neuroscientists also nowadays.

Striatal increase of dopamine receptor 2 density in idiopathic and syndromic mouse models of autism spectrum disorder.

Autism spectrum disorder (ASD) comprises a wide range of neurodevelopmental phenotypes united by impaired social interaction and repetitive behavior. Environmental and genetic factors are associated with the pathogenesis of ASD, while other cases are classified as idiopathic. The dopaminergic system has a profound impact in the modulation of motor and reward-motivated behaviors, and defects in dopaminergic circuits are implicated in ASD. In our study, we compare three well-established mouse models of ASD, one idiopathic, the BTBR strain, and two syndromic, Fmr1 and Shank3 mutants. In these models, and in humans with ASD, alterations in dopaminergic metabolism and neurotransmission were highlighted. Still, accurate knowledge about the distribution of dopamine receptor densities in the basal ganglia is lacking. Using receptor autoradiography, we describe the neuroanatomical distribution of D1 and D2 receptors in dorsal and ventral striatum at late infancy and adulthood in the above-mentioned models. We show that D1 receptor binding density is different among the models irrespective of the region. A significant convergence in increased D2 receptor binding density in the ventral striatum at adulthood becomes apparent in BTBR and Shank3 lines, and a similar trend was observed in the Fmr1 line. Altogether, our results confirm the involvement of the dopaminergic system, showing defined alterations in dopamine receptor binding density in three well-established ASD lines, which may provide a plausible explanation to some of the prevalent traits of ASD. Moreover, our study provides a neuroanatomical framework to explain the utilization of D2-acting drugs such as Risperidone and Aripiprazole in ASD.

Mouse models, antibodies, and neuroimaging: Current knowledge and future perspectives in neuropsychiatric systemic lupus erythematosus (NPSLE).

As a chronic autoimmune disease systemic lupus erythematosus (SLE) can also affect the central and the peripheral nervous system causing symptoms which are summed up as neuropsychiatric systemic lupus erythematosus (NPSLE). These symptoms are heterogenous including cognitive impairment, seizures, and fatigue, leading to morbidity or even mortality. At present, little is known about the pathophysiological processes involved in NPSLE. This review focuses on the current knowledge of the pathogenesis of NPSLE gained from the investigation of animal models, autoantibodies, and neuroimaging techniques. The antibodies investigated the most are anti-ribosomal P protein antibodies (Anti-rib P) and anti-N-Methyl-D-Aspartic Acid Receptor 2 antibodies (Anti-NR2), which represent a subpopulation of anti-dsDNA autoantibodies. Experimental data demonstrates that Anti-rib P and Anti-NR2 cause different neurological pathologies when applied intravenously (i.v.), intrathecally or intracerebrally in mice. Moreover, the investigation of lupus-prone mice, such as the MRL/MpJ-Fas lpr/lpr strain (MRL/lpr) and the New Zealand black/New Zealand white mice (NZB × NZW F1) showed that circulating systemic antibodies cause different neuropsychiatric symptoms compared to intrathecally produced antibodies. Furthermore, neuroimaging techniques including magnetic resonance imaging (MRI) and positron emission tomography (PET) are commonly used tools to investigate structural and functional abnormalities in NPSLE patients. Current research suggests that the pathogenesis of NPSLE is heterogenous, complex and not yet fully understood. However, it demonstrates that further investigation is needed to develop individual therapy in NPSLE.

A morphometric analysis of the circumolivary fiber bundle of the human brainstem.

The circumolivary fiber bundle (CFB) is considered to be an anatomical variation, which can be found on the surface of the human medulla oblongata. The macroscopical fiber bundle runs downwards from either the anterior median fissure, the pyramid, or both, around the inferior pole of the olive and turns upwards to reach the restiform body of the inferior cerebellar peduncle. Multiple fiber systems feed the constitution of the CFB (collateral corticospinal fibers, fibers connecting to the reticular formation, anterior external arcuate fibers). With this examination we provide a systematic analysis of the frequency of occurrence (6.14%), size, and laterality of the CFB. Including all three fiber bundle parts (descending part, genu, and ascending part), the left-sided sizes were increased. Likewise, the appearance of an unilateral left-sided CFB could be detected in more than 60% of our cases. Our morphometrical analysis currently covers the largest sample of investigated brainstem sides (n = 489) so far. This investigation should widen the perspective on how anatomists, neuroradiologists, and neurosurgeons expect the anterolateral surface of the human medulla oblongata.

Functional characterization of a novel TP53RK mutation identified in a family with Galloway-Mowat syndrome.

Galloway-Mowat syndrome (GAMOS) is a very rare condition characterized by early-onset nephrotic syndrome and microcephaly with variable neurologic features. While considerable genetic heterogeneity of GAMOS has been identified, the majority of cases are caused by pathogenic variants in genes encoding the four components of the Kinase, endopeptidase, and other proteins of small size (KEOPS) complex, one of which is TP53RK. Here we describe a 3-year-old male with progressive microcephaly, neurodevelopmental deficits, and glomerular proteinuria. He was found to carry a novel homozygous TP53RK missense variant, c.163C>G (p.Arg55Gly), which was considered as potentially disease-causing. We generated a morpholino tp53rk knockdown model in Xenopus laevis showing that the depletion of endogenous Tp53rk caused abnormal eye and head development. This phenotype could be rescued by the expression of human wildtype TP53RK but not by the c.163C>G mutant nor by another previously described GAMOS-associated mutant c.125G>A (p.Gly42Asp). These findings support the pathogenic role of the novel TP53RK variant.

Chronic social stress disrupts the intracellular redistribution of brain hexokinase 3 induced by shifts in peripheral glucose levels.

Chronic stress has the potential to impair health and may increase the vulnerability for psychiatric disorders. Emerging evidence suggests that specific neurometabolic dysfunctions play a role herein. In mice, chronic social defeat (CSD) stress reduces cerebral glucose uptake despite hyperglycemia. We hypothesized that this metabolic decoupling would be reflected by changes in contact sites between mitochondria and the endoplasmic reticulum, important intracellular nutrient sensors, and signaling hubs. We thus analyzed the proteome of their biochemical counterparts, mitochondria-associated membranes (MAMs) from whole brain tissue obtained from CSD and control mice. This revealed a lack of the glucose-metabolizing enzyme hexokinase 3 (HK3) in MAMs from CSD mice. In controls, HK3 protein abundance in MAMs and also in striatal synaptosomes correlated positively with peripheral blood glucose levels, but this connection was lost in CSD. We conclude that the ability of HK3 to traffic to sites of need, such as MAMs or synapses, is abolished upon CSD and surmise that this contributes to a cellular dysfunction instigated by chronic stress. KEY MESSAGES : Chronic social defeat (CSD) alters brain glucose metabolism CSD depletes hexokinase 3 (HK3) from mitochondria-associated membranes (MAMs) CSD results in loss of positive correlation between blood glucose and HK3 in MAMs and synaptosomes.

TMBIM5 loss of function alters mitochondrial matrix ion homeostasis and causes a skeletal myopathy.

Ion fluxes across the inner mitochondrial membrane control mitochondrial volume, energy production, and apoptosis. TMBIM5, a highly conserved protein with homology to putative pH-dependent ion channels, is involved in the maintenance of mitochondrial cristae architecture, ATP production, and apoptosis. Here, we demonstrate that overexpressed TMBIM5 can mediate mitochondrial calcium uptake. Under steady-state conditions, loss of TMBIM5 results in increased potassium and reduced proton levels in the mitochondrial matrix caused by attenuated exchange of these ions. To identify the in vivo consequences of TMBIM5 dysfunction, we generated mice carrying a mutation in the channel pore. These mutant mice display increased embryonic or perinatal lethality and a skeletal myopathy which strongly correlates with tissue-specific disruption of cristae architecture, early opening of the mitochondrial permeability transition pore, reduced calcium uptake capability, and mitochondrial swelling. Our results demonstrate that TMBIM5 is an essential and important part of the mitochondrial ion transport system machinery with particular importance for embryonic development and muscle function.

The Sexual Dimorphic Synapse: From Spine Density to Molecular Composition.

A synaptic sexual dimorphism is relevant in the context of multiple neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. Many of these disorders show a different prevalence and progression in woman and man. A similar variance is also present in corresponding animal models. To understand and characterize this dimorphism in pathologies it is important to first understand sex differences in unaffected individuals. Therefore, sexual differences have been studied since 1788, first focusing on brain weight, size, and volume. But as these measures are not directly related to brain function, the investigation of sexual dimorphism also expanded to other organizational levels of the brain. This review is focused on sexual dimorphism at the synaptic level, as these specialized structures are the smallest functional units of the brain, determining cell communication, connectivity, and plasticity. Multiple differences between males and females can be found on the levels of spine density, synaptic morphology, and molecular synapse composition. These differences support the importance of sex-disaggregated data. The specificity of changes to a particular brain region or circuit might support the idea of a mosaic brain, in which each tile individually lies on a continuum from masculinization to feminization. Moreover, synapses can be seen as the smallest tiles of the mosaic determining the classification of larger areas.

The K63 deubiquitinase CYLD modulates autism-like behaviors and hippocampal plasticity by regulating autophagy and mTOR signaling.

Nondegradative ubiquitin chains attached to specific targets via Lysine 63 (K63) residues have emerged to play a fundamental role in synaptic function. The K63-specific deubiquitinase CYLD has been widely studied in immune cells and lately also in neurons. To better understand if CYLD plays a role in brain and synapse homeostasis, we analyzed the behavioral profile of CYLD-deficient mice. We found that the loss of CYLD results in major autism-like phenotypes including impaired social communication, increased repetitive behavior, and cognitive dysfunction. Furthermore, the absence of CYLD leads to a reduction in hippocampal network excitability, long-term potentiation, and pyramidal neuron spine numbers. By providing evidence that CYLD can modulate mechanistic target of rapamycin (mTOR) signaling and autophagy at the synapse, we propose that synaptic K63-linked ubiquitination processes could be fundamental in understanding the pathomechanisms underlying autism spectrum disorder.

Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment.

Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms. Less well studied are the neuropsychiatric symptoms such as ASD. Here, we assess the relevance of these signalopathies in ASD reviewing genetic, human cell model, rodent studies and clinical trials. We conclude that signalopathies have an increased liability for ASD and that, in particular, ASD individuals with dysmorphic features and intellectual disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related genes. Studies on rodent and human cell models confirm aberrant neuronal development as the underlying pathology. Human studies further suggest that multiple hits are necessary to induce the respective phenotypes. Recent clinical trials do only report improvements for comorbid conditions such as epilepsy or cancer but not for behavioral aspects. Animal models show that treatment during early development can rescue behavioral phenotypes. Taken together, we suggest investigating the differential roles of mTOR and RAS signaling in both human and rodent models, and to test drug treatment both during and after neuronal development in the available model systems.

Galloway-Mowat syndrome: New insights from bioinformatics and expression during Xenopus embryogenesis.

Galloway-Mowat syndrome (GAMOS) is a rare developmental disease. Patients suffer from congenital brain anomalies combined with renal abnormalities often resulting in an early-onset steroid-resistant nephrotic syndrome. The etiology of GAMOS has a heterogeneous genetic contribution. Mutations in more than 10 different genes have been reported in GAMOS patients. Among these are mutations in four genes encoding members of the human KEOPS (kinase, endopeptidase and other proteins of small size) complex, including OSGEP, TP53RK, TPRKB and LAGE3. Until now, these components have been functionally mainly investigated in bacteria, eukarya and archaea and in humans in the context of the discovery of its role in GAMOS, but the KEOPS complex members' expression and function during embryogenesis in vertebrates is still unknown. In this study, in silico analysis showed that both gene localization and the protein sequences of the three core KEOPS complex members Osgep, Tp53rk and Tprkb are highly conserved across different species including Xenopus laevis. In addition, we examined the spatio-temporal expression pattern of osgep, tp53rk and tprkb using RT-PCR and whole mount in situ hybridization approaches during early Xenopus development. We observed that all three genes were expressed during early embryogenesis and enriched in tissues and organs affected in GAMOS. More precisely, KEOPS complex genes are expressed in the pronephros, but also in neural tissue such as the developing brain, eye and cranial cartilage. These findings suggest that the KEOPS complex plays an important role during vertebrate embryonic development.

Criss-crossing autism spectrum disorder and adult neurogenesis.

Autism spectrum disorder (ASD) comprises a group of multifactorial neurodevelopmental disorders primarily characterized by deficits in social interaction and repetitive behavior. Although the onset is typically in early childhood, ASD poses a lifelong challenge for both patients and caretakers. Adult neurogenesis (AN) is the process by which new functional neurons are created from neural stem cells existing in the post-natal brain. The entire event is based on a sequence of cellular processes, such as proliferation, specification of cell fate, maturation, and ultimately, synaptic integration into the existing neural circuits. Hence, AN is implicated in structural and functional brain plasticity throughout life. Accumulating evidence shows that impaired AN may underlie some of the abnormal behavioral phenotypes seen in ASD. In this review, we approach the interconnections between the molecular pathways related to AN and ASD. We also discuss existing therapeutic approaches targeting such pathways both in preclinical and clinical studies. A deeper understanding of how ASD and AN reciprocally affect one another could reveal important converging pathways leading to the emergence of psychiatric disorders.

Early life adversity targets the transcriptional signature of hippocampal NG2+ glia and affects voltage gated sodium (Nav) channels properties.

The precise mechanisms underlying the detrimental effects of early life adversity (ELA) on adult mental health remain still elusive. To date, most studies have exclusively targeted neuronal populations and not considered neuron-glia crosstalk as a crucially important element for the integrity of stress-related brain function. Here, we have investigated the impact of ELA, in the form of a limited bedding and nesting material (LBN) paradigm, on a glial subpopulation with unique properties in brain homeostasis, the NG2+ cells. First, we have established a link between maternal behavior, activation of the offspring's stress response and heterogeneity in the outcome to LBN manipulation. We further showed that LBN targets the hippocampal NG2+ transcriptome with glucocorticoids being an important mediator of the LBN-induced molecular changes. LBN altered the NG2+ transcriptome and these transcriptional effects were correlated with glucocorticoids levels. The functional relevance of one LBN-induced candidate gene, Scn7a, could be confirmed by an increase in the density of voltage-gated sodium (Nav) channel activated currents in hippocampal NG2+ cells. Scn7a remained upregulated until adulthood in LBN animals, which displayed impaired cognitive performance. Considering that Nav channels are important for NG2+ cell-to-neuron communication, our findings provide novel insights into the disruption of this process in LBN mice.

Acitretin reverses early functional network degradation in a mouse model of familial Alzheimer's disease.

Aberrant activity of local functional networks underlies memory and cognition deficits in Alzheimer's disease (AD). Hyperactivity was observed in microcircuits of mice AD-models showing plaques, and also recently in early stage AD mutants prior to amyloid deposition. However, early functional effects of AD on cortical microcircuits remain unresolved. Using two-photon calcium imaging, we found altered temporal distributions (burstiness) in the spontaneous activity of layer II/III visual cortex neurons, in a mouse model of familial Alzheimer's disease (5xFAD), before plaque formation. Graph theory (GT) measures revealed a distinct network topology of 5xFAD microcircuits, as compared to healthy controls, suggesting degradation of parameters related to network robustness. After treatment with acitretin, we observed a re-balancing of those network measures in 5xFAD mice; particularly in the mean degree distribution, related to network development and resilience, and post-treatment values resembled those of age-matched controls. Further, behavioral deficits, and the increase of excitatory synapse numbers in layer II/III were reversed after treatment. GT is widely applied for whole-brain network analysis in human neuroimaging, we here demonstrate the translational value of GT as a multi-level tool, to probe networks at different levels in order to assess treatments, explore mechanisms, and contribute to early diagnosis.

Carl Toldt Centennial, Surgeon and Anatomist.

Carl Florian Toldt was an Austrian anatomist who made meaningful contributions worldwide and defined what is one of the most important surgical landmarks in abdominal surgery. Through his research studies, the embryologic dissection plane known as the "White Line of Toldt" represents an important anatomical landmark that helps to mobilize either the ascending or descending colon. His career spanned over 45 years, beginning in Verona and continuing to Prague and Vienna. He was an author of several innovative books and scientific articles regarding micro- and macroscopic anatomy. In addition, he received numerous recognitions and prizes for his work, making him an essential figure in the medical scientific community. Even a street in Vienna, Karl-Toldt-Weg, is named in his honor. The purpose of this historical article is to celebrate and honor Toldt 100 years following his death, remembering his scientific contributions to the medical and surgical fields and giving thanks for his numerous accomplishments. This article brings light to the man behind the eponym.

Mutations in PRDM15 Are a Novel Cause of Galloway-Mowat Syndrome.

BACKGROUND: Galloway-Mowat syndrome (GAMOS) is characterized by neurodevelopmental defects and a progressive nephropathy, which typically manifests as steroid-resistant nephrotic syndrome. The prognosis of GAMOS is poor, and the majority of children progress to renal failure. The discovery of monogenic causes of GAMOS has uncovered molecular pathways involved in the pathogenesis of disease. METHODS: Homozygosity mapping, whole-exome sequencing, and linkage analysis were used to identify mutations in four families with a GAMOS-like phenotype, and high-throughput PCR technology was applied to 91 individuals with GAMOS and 816 individuals with isolated nephrotic syndrome. In vitro and in vivo studies determined the functional significance of the mutations identified. RESULTS: Three biallelic variants of the transcriptional regulator PRDM15 were detected in six families with proteinuric kidney disease. Four families with a variant in the protein's zinc-finger (ZNF) domain have additional GAMOS-like features, including brain anomalies, cardiac defects, and skeletal defects. All variants destabilize the PRDM15 protein, and the ZNF variant additionally interferes with transcriptional activation. Morpholino oligonucleotide-mediated knockdown of Prdm15 in Xenopus embryos disrupted pronephric development. Human wild-type PRDM15 RNA rescued the disruption, but the three PRDM15 variants did not. Finally, CRISPR-mediated knockout of PRDM15 in human podocytes led to dysregulation of several renal developmental genes. CONCLUSIONS: Variants in PRDM15 can cause either isolated nephrotic syndrome or a GAMOS-type syndrome on an allelic basis. PRDM15 regulates multiple developmental kidney genes, and is likely to play an essential role in renal development in humans.