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Vertebrates stabilize gaze using a neural circuit that transforms sensed instability into compensatory counter-rotation of the eyes. Sensory feedback tunes this vestibulo-ocular reflex throughout life. Gaze stabilization matures progressively, either due to similar tuning, or to a slowly developing circuit component. Here we studied the functional development of vestibulo-ocular reflex circuit components in the larval zebrafish, with and without sensation. Blind fish stabilize gaze normally, and neural responses to body tilts mature before behavior. Instead, synapses between motor neurons and the eye muscles mature with a timecourse similar to behavioral maturation. Larvae without vestibular sensory experience, but whose neuromuscular junction was mature, had a strong vestibulo-ocular reflex. Development of the neuromuscular junction, and not sensory experience, determines the rate of maturation of an ancient behavior.

Background: Beta-lactam (BL)-antibiotics are the most frequent reason for drug-induced hypersensitivity reactions. Because they are more efficient, less toxic, and less costly than other antibiotics, confirmation or exclusion of BL allergy is worthwhile. However, allergy tests for drug allergies are often false-negative., Objectives: To evaluate the components of a stepwise diagnostic algorithm for immediate BL hypersensitivity with regard to sensitivity (SENS)., Methods: Consecutive patients with suspected allergy to BL antibiotics were retrospectively analyzed with regard to increasing sensitivity (plausible history of immediate BL hypersensitivity serving as external criterion) of (i) skin prick test (SPT) by adding a second reading (n = 746), (ii) BL-specific IgE-determination in vitro at two cut-offs (n = 539), and (iii) adding in vivo testing of minor and major BL determinants (n = 288)., Results: In the history-based population indicative of immediate BL hypersensitivity (n = 457), SPT with a sole 20-minute reading identified 99 (SENS: 0.21) and SPT with 20- and 40-minute-reading identified 133 cases (SENS: 0.29). in vitro specific IgE-examination identified 31 positives at a cut-off ≥0.35 kUA/L (5.8% of tested) and 99 at cut-off ≥0.11 kUA/L (18.4% of tested). In 203 SPT-negative individuals, immediate BL hypersensitivity was identified by additional tests: in 79 by specific IgE (cut-off ≥0.11 kUA/L) (thereof 53 identified solely by this test) and in 150 by in vivo testing of BL determinants in combination with Penicillin and Ampicillin intradermally (thereof 124 solely by this test); in 26 individuals both additional tests were positive. The combination of the three outpatient-based test modalities-(i) optimized SPT, (ii) specific IgE at optimized cut-off, and (iii) in vivo testing of BL determinants/Penicillin/Ampicillin-identified altogether 336/457 individuals with immediate BL-hypersensitivity (SENS: 0.73), whereas the combination of the two (i) + (ii) identified 212/457 (SENS: 0.46); (i) + (iii) 283/457 (SENS: 0.61)., Conclusions: To overcome the low sensitivity of allergological tests, optimized reading times of the SPT of BL, a lower cut-off for in vitro detection of BL-specific IgE, and intradermal testing of Penicillin, Ampicillin, and BL-determinants contribute to overall sensitivity under real life conditions to diagnose immediate BL-hypersensitivity., (© 2020 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Background: Transport protein particle (TRAPP) is a multisubunit complex that regulates membrane trafficking through the Golgi apparatus. The clinical phenotype associated with mutations in various TRAPP subunits has allowed elucidation of their functions in specific tissues. The role of some subunits in human disease, however, has not been fully established, and their functions remain uncertain., Objective: We aimed to expand the range of neurodevelopmental disorders associated with mutations in TRAPP subunits by exome sequencing of consanguineous families., Methods: Linkage and homozygosity mapping and candidate gene analysis were used to identify homozygous mutations in families. Patient fibroblasts were used to study splicing defect and zebrafish to model the disease., Results: We identified six individuals from three unrelated families with a founder homozygous splice mutation in TRAPPC6B , encoding a core subunit of the complex TRAPP I. Patients manifested a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features, and showed splicing defect. Zebrafish trappc6b morphants replicated the human phenotype, displaying decreased head size and neuronal hyperexcitability, leading to a lower seizure threshold., Conclusion: This study provides clinical and functional evidence of the role of TRAPPC6B in brain development and function., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Pontocerebellar hypoplasia (PCH) represents a group of recessive developmental disorders characterized by impaired growth of the pons and cerebellum, which frequently follows a degenerative course. Currently, there are 10 partially overlapping clinical subtypes and 13 genes known mutated in PCH. Here, we report biallelic TBC1D23 mutations in six individuals from four unrelated families manifesting a non-degenerative form of PCH. In addition to reduced volume of pons and cerebellum, affected individuals had microcephaly, psychomotor delay, and ataxia. In zebrafish, tbc1d23 morphants replicated the human phenotype showing hindbrain volume loss. TBC1D23 localized at the trans-Golgi and was regulated by the small GTPases Arl1 and Arl8, suggesting a role in trans-Golgi membrane trafficking. Altogether, this study provides a causative link between TBC1D23 mutations and PCH and suggests a less severe clinical course than other PCH subtypes., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg 2+ -dependent 3'-end RNases with substrate specificity that is mostly unknown. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase. toe1-morphant zebrafish displayed midbrain and hindbrain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found that TOE1 associated with small nuclear RNAs (snRNAs) incompletely processed spliceosomal. These pre-snRNAs contained 3' genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3'-end-extended pre-snRNAs, and the immunoisolated TOE1 complex was sufficient for 3'-end maturation of snRNAs. Our findings identify the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in the processing of snRNA 3' ends.

Joubert Syndrome (JS) is an inherited ciliopathy associated with mutations in genes essential in primary cilium function. Whole exome sequencing in a multiplex consanguineous family from India revealed a KIAA0556 homozygous single base pair deletion mutation (c.4420del; p.Met1474Cysfs*11). Knockdown of the gene in zebrafish resulted in a ciliopathy phenotype, rescued by co-injection of wildtype cDNA. Affected siblings present a mild and classical form of Joubert syndrome allowing for further delineation of the JS associated genotypic spectrum.

Galloway-Mowat syndrome is a rare autosomal-recessive disorder classically described as the combination of microcephaly and nephrotic syndrome. Recently, homozygous truncating mutations in WDR73 (WD repeat domain 73) were described in two of 31 unrelated families with Galloway-Mowat syndrome which was followed by a report of two sibs in an Egyptian consanguineous family. In this report, seven affecteds from four families showing biallelic missense mutations in WDR73 were identified by exome sequencing and confirmed to follow a recessive model of inheritance. Three-dimensional modeling predicted conformational alterations as a result of the mutation, supporting pathogenicity. An additional 13 families with microcephaly and renal phenotype were negative for WDR73 mutations. Missense mutations in the WDR73 gene are reported for the first time in Galloway-Mowat syndrome. A detailed phenotypic comparison of all reported WDR73-linked Galloway-Mowat syndrome patients with WDR73 negative patients showed that WDR73 mutations are limited to those with classical Galloway-Mowat syndrome features, in addition to cerebellar atrophy, thin corpus callosum, brain stem hypoplasia, occasional coarse face, late-onset and mostly slow progressive nephrotic syndrome, and frequent epilepsy., Competing Interests: The authors declare that they have no conflict of interest., (© 2016 Wiley Periodicals, Inc.)

Docosahexanoic acid (DHA) is the most abundant omega-3 fatty acid in brain, and, although it is considered essential, deficiency has not been linked to disease. Despite the large mass of DHA in phospholipids, the brain does not synthesize it. DHA is imported across the blood-brain barrier (BBB) through the major facilitator superfamily domain-containing 2a (MFSD2A) protein. MFSD2A transports DHA as well as other fatty acids in the form of lysophosphatidylcholine (LPC). We identify two families displaying MFSD2A mutations in conserved residues. Affected individuals exhibited a lethal microcephaly syndrome linked to inadequate uptake of LPC lipids. The MFSD2A mutations impaired transport activity in a cell-based assay. Moreover, when expressed in mfsd2aa-morphant zebrafish, mutants failed to rescue microcephaly, BBB breakdown and lethality. Our results establish a link between transport of DHA and LPCs by MFSD2A and human brain growth and function, presenting the first evidence of monogenic disease related to transport of DHA in humans.

Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain-containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction.

Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.

Joubert syndrome and related disorders (JSRDs) are genetically heterogeneous and characterized by a distinctive mid-hindbrain malformation. Causative mutations lead to primary cilia dysfunction, which often results in variable involvement of other organs such as the liver, retina, and kidney. We identified predicted null mutations in CSPP1 in six individuals affected by classical JSRDs. CSPP1 encodes a protein localized to centrosomes and spindle poles, as well as to the primary cilium. Despite the known interaction between CSPP1 and nephronophthisis-associated proteins, none of the affected individuals in our cohort presented with kidney disease, and further, screening of a large cohort of individuals with nephronophthisis demonstrated no mutations. CSPP1 is broadly expressed in neural tissue, and its encoded protein localizes to the primary cilium in an in vitro model of human neurogenesis. Here, we show abrogated protein levels and ciliogenesis in affected fibroblasts. Our data thus suggest that CSPP1 is involved in neural-specific functions of primary cilia., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Cobblestone brain malformation (COB) is a neuronal migration disorder characterized by protrusions of neurons beyond the first cortical layer at the pial surface of the brain. It is usually seen in association with dystroglycanopathy types of congenital muscular dystrophies (CMDs) and ocular abnormalities termed muscle-eye-brain disease. Here we report homozygous deleterious mutations in LAMB1, encoding laminin subunit beta-1, in two families with autosomal-recessive COB. Affected individuals displayed a constellation of brain malformations including cortical gyral and white-matter signal abnormalities, severe cerebellar dysplasia, brainstem hypoplasia, and occipital encephalocele, but they had less apparent ocular or muscular abnormalities than are typically observed in COB. LAMB1 is localized to the pial basement membrane, suggesting that defective connection between radial glial cells and the pial surface mediated by LAMB1 leads to this malformation., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)