RESUMO
Cohen syndrome is an autosomal recessive disorder caused by VPS13B (COH1) gene mutations. This syndrome is significantly underdiagnosed and is characterized by intellectual disability, microcephaly, autistic symptoms, hypotension, myopia, retinal dystrophy, neutropenia, and obesity. VPS13B regulates intracellular membrane transport and supports the Golgi apparatus structure, which is critical for neuron formation. We generated induced pluripotent stem cells from two patients with pronounced manifestations of Cohen syndrome and differentiated them into neural stem cells and neurons. Using transmission electron microscopy, we documented multiple new ultrastructural changes associated with Cohen syndrome in the neuronal cells. We discovered considerable disturbances in the structure of some organelles: Golgi apparatus fragmentation and swelling, endoplasmic reticulum structural reorganization, mitochondrial defects, and the accumulation of large autophagosomes with undigested contents. These abnormalities underline the ultrastructural similarity of Cohen syndrome to many neurodegenerative diseases. The cell models that we developed based on patient-specific induced pluripotent stem cells can serve to uncover not only neurodegenerative processes, but the causes of intellectual disability in general.
Assuntos
Células-Tronco Pluripotentes Induzidas , Deficiência Intelectual , Microcefalia , Miopia , Células-Tronco Neurais , Humanos , Deficiência Intelectual/genética , Microcefalia/genética , Proteínas de Transporte Vesicular/genética , Obesidade/genética , NeurôniosRESUMO
This study provides new data on the whole-exome sequencing of a cohort of children with autistic spectrum disorders (ASD) from an underexplored Russian population. Using both a cross-sectional approach involving a control cohort of the same ancestry and an annotation-based approach involving relevant public databases, we explored exonic single nucleotide variants and copy-number variation potentially involved in the manifestation of ASD. The study results reveal new potential ASD candidate-variants found in the studied Russian cohort and show a high prevalence of common ASD-associated genomic variants, especially those in the genes known to be associated with the manifestation of intellectual disabilities. Our screening of an ASD cohort from a previously understudied population allowed us to flag at least a few novel genes (IGLJ2, FAM21A, OR11H12, HIP1, PRAMEF10, and ZNF717) regarding their potential involvement in ASD.
Assuntos
Transtorno do Espectro Autista , Transtorno do Espectro Autista/genética , Criança , Estudos de Coortes , Variações do Número de Cópias de DNA , Genômica , Humanos , Sequenciamento do ExomaRESUMO
We have identified RAP80/UIMC1, the protein highly expressed in testis, as a new cancer-associated antigen. Sera from 5% to 10% of patients with different types of cancer contain specific antibodies to RAP80/UIMC1. In order to investigate the possible reasons for RAP80/UIMC1 immunogenicity, we characterized its numerous splice isoforms and mapped immunogenic regions of the protein. The majority of RAP80/UIMC1 transcripts was detected both in normal tissues and in colon tumors. There are several RAP80/UIMC1 isoforms that are predominantly expressed in testis, however we did not observe elevated expression of these transcripts in tumors from seropositive patients. We mapped the major immunogenic region of RAP80/UIMC1 to the central part of the protein encoded by exon 9 which is present in a number of ubiquitous splice forms. Thus, based on our data, autoreactivity to RAP80/UIMC1 is related to reasons other than overexpression or tumor-specific splicing.
