RESUMEN
The article reported the clinical, electrophysiological, renal pathology and gene mutation characteristics of a patient with action myoclonus-renal failure syndrome (AMRF). The patient was a young male who developed epilepsy at the age of 16 and gradually developed tremor, ataxia, and myoclonic seizures. Brain magnetic resonance imaging was normal. The electrophysiological manifestations of the nerve were symmetrical multiple sensory and motor nerve conduction velocity deceleration, especially the easily embedded site of the nerve. Renal pathology showed focal segmental glomerulosclerosis. A new complex heterozygous mutation of SCARB2 gene c.534_537delinsCT (chr4:7710074) and c.358G>T (chr4:7710217) was detected in the patient and verified by his family. The 2 heterozygous mutations were respectively from the patient′s parents. AMRF is a rare type of epilepsy in adolescents. The early manifestations were myoclonus or abnormal renal function, with great clinical heterogeneity and easy to be misdiagnosed and missed diagnosis. The final diagnosis depends on genetic testing.
RESUMEN
<p><b>Background</b>Progressive myoclonus epilepsies (PMEs) comprise a group of rare genetic disorders characterized by action myoclonus, epileptic seizures, and ataxia with progressive neurologic decline. Due to clinical and genetic heterogeneity of PMEs, it is difficult to decide which genes are affected. The aim of this study was to report an action myoclonus with or without renal failure syndrome (EPM4) family and summarize the clinical and genetic characteristics of all reported EPM4 patients.</p><p><b>Methods</b>In the present study, targeted next-generation sequencing (NGS) was applied to screen causative genes in a Chinese PME family. The candidate variant was further confirmed by cosegregation analysis and further functional analysis, including the reverse transcription polymerase chain reaction and Western blot of the proband's muscle. Moreover, literature data on the clinical and mutational features of all reported EPM4 patients were reviewed.</p><p><b>Results</b>The gene analysis revealed a novel homozygous splicing mutation (c.995-1G>A) of the SCARB2 gene in two brothers. Further functional analysis revealed that this mutation led to loss function of the SCARB2 protein. The classification of the candidate variant, according to the American College of Medical Genetics and Genomics standards and guidelines and functional analysis, was pathogenic. Therefore, these two brothers were finally diagnostically confirmed as EPM4.</p><p><b>Conclusions</b>These present results suggest the potential for targeted NGS to conduct a more rapid and precise diagnosis for PME patients. A literature review revealed that mutations in the different functional domains of SCARB2 appear to be associated with the phenotype of EPM4.</p>
RESUMEN
Entero virus 71 (EV71) causes hand, foot, and mouth disease (HFMD) and occasionally leads to severe neurological complications and even death. Scavenger receptor class B member 2 (SCARB2) is a functional receptor for EV71, that mediates viral attachment, internalization, and uncoating. However, the exact binding site of EV71 on SCARB2 is unknown. In this study, we generated a monoclonal antibody (mAb) that binds to human but not mouse SCARB2. It is named JL2, and it can effectively inhibit EV71 infection of target cells. Using a set of chimeras of human and mouse SCARB2, we identified that the region containing residues 77-113 of human SCARB2 contributes significantly to JL2 binding. The structure of the SCARB2-JL2 complex revealed that JL2 binds to the apical region of SCARB2 involving α-helices 2, 5, and 14. Our results provide new insights into the potential binding sites for EV71 on SCARB2 and the molecular mechanism of EV71 entry.
Asunto(s)
Animales , Humanos , Ratones , Secuencia de Aminoácidos , Anticuerpos Monoclonales , Química , Genética , Metabolismo , Sitios de Unión , Línea Celular , Cristalografía por Rayos X , Enterovirus Humano A , Genética , Alergia e Inmunología , Fibroblastos , Virología , Expresión Génica , Células HEK293 , Fragmentos Fab de Inmunoglobulinas , Química , Genética , Metabolismo , Proteínas de Membrana de los Lisosomas , Química , Genética , Alergia e Inmunología , Modelos Moleculares , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Receptores Depuradores , Química , Genética , Alergia e Inmunología , Receptores Virales , Química , Genética , Alergia e Inmunología , Proteínas Recombinantes de Fusión , Química , Genética , Alergia e Inmunología , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Células Sf9 , Spodoptera , TermodinámicaRESUMEN
Purpose To investigate the location and distribution of EV71 receptors scavenger receptor class B member 2 ( SCARB2 ) and human P-selectin glycoprotein ligand-1 (PSGL-1) in lung tissues of fatal hand, foot and mouth disease (HFMD), healthy children and adults. Methods The expression of EV71 receptors SCARB2 and PSGL-1 was detected by using immunohistochemistry in lung tissues of 15 autopsies of HFMD, 3 of healthy children, 8 of healthy adults. Results SCARB2 distributed in bronchial, bronchioli ep-ithelia, alveolar epithelial cells and inflammatory cells among HFMD, healthy children and adults. No significant difference was noted of the positive rates of SCARB2 expression among these three groups (P>0. 05). PSGL-1 distributed in bronchial and bronchioli epi-thelium of adults, but no PSGL-1 expression was found in HFMD and healthy children. The positive rates of PSGL-1 were 100%, 0, 0 in bronchial and bronchioli epithelium among the three groups, respectively (P0. 05). Further, no PSGL-1 expression was observed in alveolar epithelia cells of all groups tested. Conclusions EV71 receptor SCARB2 distributes in bronchial, bronchioli, alveolar epithelial and inflammatory cells of HFMD. Meanwhile, PSGL-1 only distributes in inflammatory cells of HFMD, suggesting that SCARB2 possibly plays a role on HFMD infection.