The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.

• MeSH
• ageneze corpus callosum diagnostické zobrazování   genetika   MeSH
• dítě MeSH
• dospělí MeSH
• hydrolasy chemie   genetika   MeSH
• lidé MeSH
• mentální retardace diagnostické zobrazování   genetika   MeSH
• missense mutace genetika   MeSH
• mladý dospělý MeSH
• molekulární modely MeSH
• mozeček abnormality   diagnostické zobrazování   MeSH
• neurovývojové poruchy diagnostické zobrazování   genetika   MeSH
• předškolní dítě MeSH
• proteiny asociované s mikrotubuly chemie   genetika   metabolismus   MeSH
• tubulin metabolismus   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Regulation of axon guidance and pruning of inappropriate synapses by class 3 semaphorins are key to the development of neural circuits. Collapsin response mediator protein 2 (CRMP2) has been shown to regulate axon guidance by mediating semaphorin 3A (Sema3A) signaling; however, nothing is known about its role in synapse pruning. Here, using newly generated crmp2-/- mice we demonstrate that CRMP2 has a moderate effect on Sema3A-dependent axon guidance in vivo, and its deficiency leads to a mild defect in axon guidance in peripheral nerves and the corpus callosum. Surprisingly, crmp2-/- mice display prominent defects in stereotyped axon pruning in hippocampus and visual cortex and altered dendritic spine remodeling, which is consistent with impaired Sema3F signaling and with models of autism spectrum disorder (ASD). We demonstrate that CRMP2 mediates Sema3F signaling in primary neurons and that crmp2-/- mice display ASD-related social behavior changes in the early postnatal period as well as in adults. Together, we demonstrate that CRMP2 mediates Sema3F-dependent synapse pruning and its dysfunction shares histological and behavioral features of ASD.

• MeSH
• dendritické trny MeSH
• membránové proteiny fyziologie   MeSH
• mezibuněčné signální peptidy a proteiny genetika   MeSH
• myši knockoutované MeSH
• myši MeSH
• neurony MeSH
• neuroplasticita MeSH
• poruchy autistického spektra * MeSH
• proteiny nervové tkáně genetika   fyziologie   MeSH
• semaforiny * MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIMS: Hypotension can be a symptom of paraneoplastic autonomic neuropathy (PAN). Onconeural antibodies (OA) provide strong evidence for the paraneoplastic origin of neurological syndromes. Our goal was to assess the frequency of PAN among patients with advanced malignancies and hypotension using OA. METHODS: Patients with advanced malignancies and hypotension were screened and enrolled as per protocol. Plasma levels of six classical OAs were assessed in these patients. We prospectively evaluated other symptoms of PAN in these patients. RESULTS: 31 patients out of 740 screened met the criteria of this cross-sectional study. OAs were present in 4 patients (12.9%). Anti-amphiphysin was found in 1 patient (3.23%), anti- CV2 (anti-CRPM5, anti- collapsin- response mediator protein) was present in 1 patient (3.23%), 1 patient (3.23%) was positive for anti-Hu and anti-Ma2 was present in 1 patient (3.23%). No patient was positive for 2 or more OAs. Normalization of blood pressure in concordance with partial remission occurred in 5 patients. The most used criteria for PAN were fulfilled in 9 patients. CONCLUSION: The frequency of PAN may be underestimated in a busy oncology clinic. Assessing OAs may aid in the differential diagnosis of hypotension of unknown origin.

• MeSH
• autonomní nervový systém patofyziologie   MeSH
• autoprotilátky krev   MeSH
• dospělí MeSH
• hypotenze etiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů patofyziologie   MeSH
• nádorové biomarkery krev   MeSH
• nádory komplikace   patofyziologie   MeSH
• nemoci nervového systému etiologie   MeSH
• průřezové studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Poruchy autistického spektra (PAS) jsou heterogenní skupinou neurovývojových poruch charakterizovanou narušením sociálních interakcí, komunikace a stereotypními, opakujícími se vzorci chování, zájmů a aktivit. Příčiny vzniku a rizikové faktory PAS nejsou dosud plně objasněny, etiologie je komplexní se zastoupením jak genetických faktorů, tak faktorů vnějšího prostředí. V posledních dvou dekádách je stále více zkoumán vliv imunitního systému na vyvíjející se nervovou soustavu během prenatálního období. Dysregulace maternálního imunitního systému během gestace může vést k neurovývojovým změnám a vzniku neurovývojového onemocnění jako je PAS. Jedním z potenciálních etiologických imunologických faktorů ve vztahu k PAS jsou maternální autoprotilátky reaktivní vůči proteinům fetálního mozku. Pro takto podmíněný typ PAS používají výzkumné studie pojem MAR autism (maternal autoantibody related autism, autismus související s maternálními autoprotilátkami). Spojení bylo prokázáno jak klinickými studiemi, tak zvířecími modely. Je známo několik proteinů, proti kterým jsou namířeny maternální autoprotilátky ve vztahu k PAS. V článku se zaměříme na collapsin response mediator protein 2 (CRMP2), který hraje důležitou roli v regulaci růstu a navádění axonů v průběhu vývoje mozku, a roli autoprotilátek proti CRMP2 při vzniku PAS. Závěrem ještě krátce zmíníme hypotetickou možnost léčby PAS spojených s maternálními autoprotilátkami.

Autism spectrum disorders (ASD) are heterogeneous group of neurodevelopmental disorders characterized by impairments in social interaction, communication and stereotyped, repetitive patterns of behavior, interests and activities. The causes and risk factors of ASD are largely unknown with a complex etiology combining genetic as well as environmental factors. In the last two decades it has been well established that an important role in the prenatal brain development is played by the immune system. Deregulation of the immune system during embryonic development may lead to neurodevelopmental changes resulting in ASD and one of the potential etiologic factors in the development of ASD has been identified as presence of maternal autoantibodies targeting the fetal brain proteins. The type of ASD associated with the presence of maternal autoantibodies has been referred to as MAR autism (maternal antibodies related autism). The link between the maternal autoantibodies and ASD has been demonstrated in both clinical studies and animal models. Several protein targets of ASD-related maternal autoantibodies have been identified. In this article we focus on Collapsin response mediator protein 2 (CRMP2), which has been previously shown to play an important role in regulation of axon growth and guidance during brain development. In addition, we discuss the potential effect of CRMP2 targeting by maternal antibodies in ASD pathogenesis and future possibilities of MAR ASD treatment.

• Klíčová slova
• CRMP2, maternální autoprotilátky,
• MeSH
• autoprotilátky * MeSH
• fosfoproteiny MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• mozek růst a vývoj   MeSH
• poruchy autistického spektra * genetika   MeSH
• vývoj plodu MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

AIMS: Hypotension can be a symptom of paraneoplastic autonomic neuropathy (PAN). Onconeural antibodies (OA) provide strong evidence for the paraneoplastic origin of neurological syndromes. Our goal was to assess the frequency of PAN among patients with advanced malignancies and hypotension using OA. METHODS: Patients with advanced malignancies and hypotension were screened and enrolled as per protocol. Plasma levels of six classical OAs were assessed in these patients. We prospectively evaluated other symptoms of PAN in these patients. RESULTS: 31 patients out of 740 screened met the criteria of this cross-sectional study. OAs were present in 4 patients (12.9%). Anti-amphiphysin was found in 1 patient (3.23%), anti- CV2 (anti-CRPM5, anti- collapsin- response mediator protein) was present in 1 patient (3.23%), 1 patient (3.23%) was positive for anti-Hu and anti-Ma2 was present in 1 patient (3.23%). No patient was positive for 2 or more OAs. Normalization of blood pressure in concordance with partial remission occurred in 5 patients. The most used criteria for PAN were fulfilled in 9 patients. CONCLUSION: The frequency of PAN may be underestimated in a busy oncology clinic. Assessing OAs may aid in the differential diagnosis of hypotension of unknown origin.

• Publikační typ
• časopisecké články MeSH