RESUMO
Neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative disorders caused by mutations in fourteen distinct ceroid lipofuscinoses, neuronal (CLN) genes described with various severe symptoms such as seizures, visual failure, motor decline, and progressive cognitive deterioration. The current research represents novel CLN5 (c.741G > A) and CLN8 (c.565delT) mutations in two different Iranian families with late-infantile NCL (LINCL) and their relatives by using whole-exome sequencing (WES). The first family had a 10-year-old male with consanguineous parents and severe NCL symptoms, including motor clumsiness, telangiectasia, and cerebellar atrophy. The second family with a child who suffered from nystagmus rotation, motor difficulties, and seizure was a 5-year-old male with consanguineous parent. WES of probands 1 and 2 revealed homozygotic mutations in exon 4 of CLN5 (c.741G > A, p.W247X) and deletion in exon 3 (c.565delT, p.F189fs) of CLN8, respectively. Both patients' parents were heterozygous for these alterations. In concordance with previous studies, our results indicate that pathogenic mutations in CLN genes, especially CLN5 and 8, are a main cause of LINCL; these results also suggest that LINCL is not a regionally or nationally dependent disorder and can occur in any ethnic group despite the fact that some populations may be more at risk. Consequently, CLN gene screening for patients with typical signs of LINCL is recommended.
Assuntos
Mutação com Perda de Função , Proteínas de Membrana Lisossomal/genética , Lisossomos/fisiologia , Proteínas de Membrana/genética , Lipofuscinoses Ceroides Neuronais/genética , Criança , Pré-Escolar , Códon sem Sentido , Consanguinidade , Éxons/genética , Feminino , Genótipo , Humanos , Irã (Geográfico) , Proteínas de Membrana Lisossomal/fisiologia , Imageamento por Ressonância Magnética , Masculino , Proteínas de Membrana/fisiologia , Modelos Moleculares , Neuroimagem , Lipofuscinoses Ceroides Neuronais/diagnóstico por imagem , Lipofuscinoses Ceroides Neuronais/patologia , Linhagem , Processamento de Proteína Pós-Traducional , Deleção de Sequência , Sequenciamento do ExomaRESUMO
Alzheimer's disease (AD) is a heterogeneous disorder with multiple patterns of clinical manifestations. Recently, due to the advance of linkage studies, next-generation sequencing and genome-wide association studies, a large number of putative risk genes for AD have been identified using acquired genome mega data. The genetic association between three causal genes, including amyloid precursor protein, presenilin1, and presenilin2 in early-onset AD (EOAD), was discovered over the past few decades. These discoveries showed that there should be additional genetic risk factors for both EOAD and late-onset AD (LOAD) to help fully explain the leading molecular mechanisms in a single pathophysiological entity. This study reviews the clinical features and genetic etiology of LOAD and discusses a variety of AD-mediated genes that are involved in cholesterol and lipid metabolism, endocytosis, and immune response according to their mutations for more efficient selection of functional candidate genes for LOAD. New mechanisms and pathways have been identified as a result.
