Publications by authors named "John Neidhardt"

With almost a quadrillion individuals, the Antarctic krill processes five million tons of organic carbon every day during austral summer. This high carbon flux requires a broad range of hydrolytic enzymes to decompose the diverse food-derived biopolymers. While krill itself possesses numerous such enzymes, it is unclear, to what extent the endogenous microbiota contribute to the hydrolytic potential of the gut environment.

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Aromatic compounds are globally abundant organic molecules with a multitude of natural and anthropogenic sources, underpinning the relevance of their biodegradation. EbN1 is a well-studied environmental betaproteobacterium specialized on the anaerobic degradation of aromatic compounds. The here studied responsiveness toward phenol in conjunction with the apparent high ligand selectivity (non-promiscuity) of its PheR sensor and those of the related -cresol (PcrS) and -ethylphenol (EtpR) sensors are in accord with the substrate-specificity and biochemical distinctiveness of the associated degradation pathways.

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Splicing of transcripts is catalyzed by the spliceosome, a mega-complex consisting of hundreds of proteins and five snRNAs, which employs direct interactions. When U1 snRNA forms high-affinity binding, namely more than eight base pairs, with the 5'SS, the result is usually a suppressing effect on the splicing activity. This likely occurs due to the inefficient unwinding of U1/5'SS base-pairing or other regulatory obstructions.

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Progressive degeneration of rod and cone photoreceptors frequently is caused by mutations in the X-chromosomal gene Retinitis Pigmentosa GTPase Regulator (). Males hemizygous for a mutation often are affected by Retinitis Pigmentosa (RP), whereas female mutation carriers only occasionally present with severe RP phenotypes. The underlying pathomechanism leading to RP in female carriers is not well understood.

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Article Synopsis
  • The study evaluated a gene therapy using engineered U1 snRNA to fix splice defects in a mutant mouse model.
  • The treatment successfully increased wild-type transcripts and Opa1 protein levels in the retina, showing effective results.
  • No negative side effects or off-target gene alterations were observed, suggesting the therapy is safe and has potential for wider applications in treating inherited retinal diseases.
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TARP syndrome (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistence of the left superior vena cava) is a rare genetic condition, caused by developmental defects during embryogenesis. The phenotypic spectrum of TARP shows high clinical variability with patients either missing cardinal features or having additional clinical traits. Initially, TARP was considered a lethal syndrome, but patients with milder symptoms were recently described.

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Variants in the X-linked retinitis pigmentosa GTPase regulator gene ( and, specifically, in its retinal opening reading frame-15 isoform () may cause rod-cone (RCD), cone, and cone-rod dystrophies (CDs and CRDs). While -related RCDs have been frequently evaluated, the characteristics and progression of -related CD/CRDs are largely unknown. Therefore, the goal of our work was to perform genotype-phenotype correlations specifically in -related CD/CRDs.

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Autosomal dominant optic atrophy (ADOA) is frequently caused by mutations in the optic atrophy 1 () gene, with haploinsufficiency being the major genetic pathomechanism. Almost 30% of the -associated cases suffer from splice defects. We identified a novel mutation, c.

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Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy.

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Background: Plasticity-related genes (Prgs/PRGs) or lipid phosphate phosphatase-related proteins (LPPRs) comprise five known members, which have been linked to neuronal differentiation processes, such as neurite outgrowth, axonal branching, or dendritic spine formation. PRGs are highly brain-specific and belong to the lipid phosphate phosphatases (LPPs) superfamily, which influence lipid metabolism by dephosphorylation of bioactive lipids. PRGs, however, do not possess enzymatic activity, but modify lipid metabolism in a way that is still under investigation.

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Retinal dystrophies (RD) are clinically and genetically heterogenous disorders showing mutations in over 270 disease-associated genes. Several millions of people worldwide are affected with different types of RD. Studying the relevance of disease-associated sequence alterations will assist in understanding disorders and may lead to the development of therapeutic approaches.

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Heterotopia is a brain malformation caused by a failed migration of cortical neurons during development. Clinical symptoms of heterotopia vary in severity of intellectual disability and may be associated with epileptic disorders. Abnormal neuronal migration is known to be associated with mutations in the doublecortin gene (DCX), the platelet-activating factor acetylhydrolase gene (PAFAH1B1), or tubulin alpha-1A gene (TUBA1A).

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X-linked retinitis pigmentosa (XLRP) is frequently caused by mutations in the () gene. A complex splicing process acts on the gene resulting in three major isoforms: , and . We characterized the widely expressed, alternatively spliced transcript lacking exons 14 and 15.

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Purpose: The purpose of this study was to perform a detailed longitudinal phenotyping of X-linked retinitis pigmentosa (RP) caused by mutations in the RPGR gene during a long follow-up period.

Methods: An Italian cohort of 48 male patients (from 31 unrelated families) with RPGR-associated RP was clinically assessed at a single center (mean follow-up = 6.5 years), including measurements of best-corrected visual acuity (BCVA), Goldmann visual field (GVF), optical coherence tomography (OCT), fundus autofluorescence (FAF), microperimetry, and full-field electroretinography (ERG).

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Dominant optic atrophy (DOA) is an inherited mitochondrial disease leading to specific degeneration of retinal ganglion cells (RGCs), thus compromising transmission of visual information from the retina to the brain. Usually, DOA starts during childhood and evolves to poor vision or legal blindness, affecting the central vision, whilst sparing the peripheral visual field. In 20% of cases, DOA presents as syndromic disorder, with secondary symptoms affecting neuronal and muscular functions.

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X-chromosomal retinitis pigmentosa (RP) frequently is caused by mutations in the retinitis pigmentosa GTPase regulator () gene. We evaluated the potential of PTC124 (Ataluren, Translama) treatment to promote ribosomal read-through of premature termination codons (PTC) in . Expression constructs in HEK293T cells showed that the efficacy of read-through reagents is higher for UGA than UAA PTCs.

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Intellectual disability syndrome (IDS) associated with a hereditary persistence of fetal haemoglobin (HbF), also known as Dias-Logan syndrome, is commonly characterised by psychomotor developmental delay, intelectual disability, language delay, strabismus, thin upper lip, abnormalities of external ears, microcephaly, downslanting palpebral fissures. Sporadically, autism spectrum disorders and blue sclerae in infancy have been reported in IDS. Rarely, IDS-affected patients present with epilepsy and/or epileptic syndromes.

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Niemann-Pick type C1 (NPC1) is a lysosomal storage disorder, inherited as an autosomal-recessive trait. Mutations in the gene result in malfunction of the NPC1 protein, leading to an accumulation of unesterified cholesterol and glycosphingolipids. Beside visceral symptoms like hepatosplenomegaly, severe neurological symptoms such as ataxia occur.

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Background: Epilepsy belongs to a group of chronic and highly heterogeneous brain disorders. Many types of epilepsy and epileptic syndromes are caused by genetic factors. The neural amino acid y-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the mammalian central nervous system.

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Background: Retinitis pigmentosa (RP) is one of the most common form of inherited retinal dystrophies. Identification of disease-causing mutations is a prerequisite for applying targeted therapeutic approaches. The present study aimed to identify disease-associated mutations in a large Serbian family, in which two brothers have suffered from RP starting in the first decade of their lives.

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Anaerobic degradation of -cresol (4-methylphenol) by the denitrifying betaproteobacterium EbN1 is regulated with high substrate specificity, presumed to be mediated by the predicted σ-dependent two-component system PcrSR. An unmarked, in-frame Δ deletion mutant showed reduced expression of the genes (21-fold) and (8-fold) that encode the two enzymes for initial oxidation of -cresol to -hydroxybenzoate compared to their expression in the wild type. The expression of and was restored by in complementation with in the Δ background to even higher levels than in the wild type.

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Manipulation of pre-mRNA processing is a promising approach toward overcoming disease-causing mutations and treating human diseases. We show that a combined treatment applying two splice-manipulating technologies improves therapeutic efficacies to correct mutation-induced splice defects. Previously, we identified a family affected by retinitis pigmentosa caused by the homozygous BBS1 splice donor site mutation c.

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Hartsfield syndrome is a rare clinical entity characterized by holoprosencephaly and ectrodactyly with the variable feature of cleft lip/palate. In addition to these symptoms patients with Hartsfield syndrome can show developmental delay of variable severity, isolated hypogonadotropic hypogonadism, central diabetes insipidus, vertebral anomalies, eye anomalies, and cardiac malformations. Pathogenic variants in FGFR1 have been described to cause phenotypically different FGFR1-related disorders such as Hartsfield syndrome, hypogonadotropic hypogonadism with or without anosmia, Jackson-Weiss syndrome, osteoglophonic dysplasia, Pfeiffer syndrome, and trigonocephaly Type 1.

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Inherited white matter disorders of the central nervous system frequently are degenerative and progressive clinical entities. They are classified into myelin disorders, including hypomyelination, dysmyelination, demyelination, and myelin vacuolization, but also astrocytopathies, leuko-axonopathies, microgliopathies, and leuko-vasculopathies. Hypomyelinating leukodystrophy is the main feature of Pelizaeus-Merzbacher disease (PMD) and Pelizaeus-Merzbacher-like disease (PMLD1).

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Article Synopsis
  • Niemann-Pick disease type C1 (NPC1) is a rare genetic disorder causing spleen dysfunction and lipid metabolism issues, impacting approximately 1 in 120,000 births.
  • Researchers utilized an NPC1 mouse model to test the effects of treatments like miglustat, 2-hydroxypropyl-ß-cyclodextrin, and allopregnanolone, which improved both spleen health and lipid metabolism.
  • The study found that these treatments stabilized spleen structure, normalized immune cell populations, and halted disease progression at a molecular level, although they did change the ratios of different T cell types.
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