RESUMO
Rhizomelic chondrodysplasia punctata (RCDP) is a developmental disorder characterized by hypotonia, cataracts, abnormal ossification, impaired motor development, and intellectual disability. The underlying etiology of RCDP is a deficiency in the biosynthesis of ether phospholipids, of which plasmalogens are the most abundant form in nervous tissue and myelin; however, the role of plasmalogens in the peripheral nervous system is poorly defined. Here, we used mouse models of RCDP and analyzed the consequence of plasmalogen deficiency in peripheral nerves. We determined that plasmalogens are crucial for Schwann cell development and differentiation and that plasmalogen defects impaired radial sorting, myelination, and myelin structure. Plasmalogen insufficiency resulted in defective protein kinase B (AKT) phosphorylation and subsequent signaling, causing overt activation of glycogen synthase kinase 3ß (GSK3ß) in nerves of mutant mice. Treatment with GSK3ß inhibitors, lithium, or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) restored Schwann cell defects, effectively bypassing plasmalogen deficiency. Our results demonstrate the requirement of plasmalogens for the correct and timely differentiation of Schwann cells and for the process of myelination. In addition, these studies identify a mechanism by which the lack of a membrane phospholipid causes neuropathology, implicating plasmalogens as regulators of membrane and cell signaling.
Assuntos
Sistema Nervoso Periférico/citologia , Sistema Nervoso Periférico/fisiologia , Plasmalogênios/fisiologia , Células de Schwann/citologia , Células de Schwann/fisiologia , Animais , Diferenciação Celular/fisiologia , Condrodisplasia Punctata Rizomélica/etiologia , Condrodisplasia Punctata Rizomélica/patologia , Condrodisplasia Punctata Rizomélica/fisiopatologia , Feminino , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Mutantes Neurológicos , Modelos Neurológicos , Proteína Básica da Mielina/metabolismo , Bainha de Mielina/fisiologia , Regeneração Nervosa , Receptor 2 de Sinal de Orientação para Peroxissomos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Citoplasmáticos e Nucleares/deficiência , Receptores Citoplasmáticos e Nucleares/genética , Transdução de SinaisRESUMO
Maternal systemic lupus erythematosus and autoimmune diseases have been extremely rarely reported to cause rhizomelic chondrodysplasia punctata. We report on a fetus aborted spontaneously at 21 weeks of gestation due to complications of maternal mixed connective tissue disorder. The fetus had micrognathia, a depressed nasal bridge, flat nose, long philtrum, short columella and rhizomelia. Radiographic study showed stippling of carpal and tarsal bones, short humeri and coronal clefts in the vertebrae. Ossification centers were present at the lower end of the femora and upper end of the tibiae.
Assuntos
Anormalidades Múltiplas/etiologia , Condrodisplasia Punctata Rizomélica/etiologia , Doenças Fetais/etiologia , Doença Mista do Tecido Conjuntivo/complicações , Complicações na Gravidez , Anormalidades Múltiplas/diagnóstico , Aborto Espontâneo , Adulto , Ossos do Carpo/anormalidades , Ossos do Carpo/diagnóstico por imagem , Condrodisplasia Punctata Rizomélica/diagnóstico , Feminino , Doenças Fetais/diagnóstico , Feto , Humanos , Masculino , Micrognatismo/diagnóstico , Micrognatismo/etiologia , Gravidez , Radiografia , Índice de Gravidade de Doença , Ossos do Tarso/anormalidades , Ossos do Tarso/diagnóstico por imagemRESUMO
Chondrodysplasia punctata (CDP) is associated with a number of disorders, including inborn errors of metabolism, involving peroxisomal and cholesterol pathways, embryopathy and chromosomal abnormalities. Several classification systems of the different types of CDP have been suggested earlier. More recently, the biochemical and molecular basis of a number of CDP syndromes has recently been elucidated and a new aetiological classification has emerged. Here we provide an updated version with an overview of the different types of CDP, a discussion of the aetiology and a description of the clinical and radiographic findings. An investigative guideline to help determine the exact diagnosis in new cases is also presented.
