Mutation of the diamond-blackfan anemia gene Rps7 in mouse results in morphological and neuroanatomical phenotypes.

The ribosome is an evolutionarily conserved organelle essential for cellular function. Ribosome construction requires assembly of approximately 80 different ribosomal proteins (RPs) and four different species of rRNA. As RPs co-assemble into one multi-subunit complex, mutation of the genes that encode RPs might be expected to give rise to phenocopies, in which the same phenotype is associated with loss-of-function of each individual gene. However, a more complex picture is emerging in which, in addition to a group of shared phenotypes, diverse RP gene-specific phenotypes are observed. Here we report the first two mouse mutations (Rps7(Mtu) and Rps7(Zma)) of ribosomal protein S7 (Rps7), a gene that has been implicated in Diamond-Blackfan anemia. Rps7 disruption results in decreased body size, abnormal skeletal morphology, mid-ventral white spotting, and eye malformations. These phenotypes are reported in other murine RP mutants and, as demonstrated for some other RP mutations, are ameliorated by Trp53 deficiency. Interestingly, Rps7 mutants have additional overt malformations of the developing central nervous system and deficits in working memory, phenotypes that are not reported in murine or human RP gene mutants. Conversely, Rps7 mouse mutants show no anemia or hyperpigmentation, phenotypes associated with mutation of human RPS7 and other murine RPs, respectively. We provide two novel RP mouse models and expand the repertoire of potential phenotypes that should be examined in RP mutants to further explore the concept of RP gene-specific phenotypes

Role of cytoskeletal abnormalities in the neuropathology and pathophysiology of type I lissencephaly

Type I lissencephaly or agyria-pachygyria is a rare developmental disorder which results from a defect of neuronal migration. It is characterized by the absence of gyri and a thickening of the cerebral cortex and can be associated with other brain and visceral anomalies. Since the discovery of the first genetic cause (deletion of chromosome 17p13.3), six additional genes have been found to be responsible for agyria–pachygyria. In this review, we summarize the current knowledge concerning these genetic disorders including clinical, neuropathological and molecular results. Genetic alterations of LIS1, DCX, ARX, TUBA1A, VLDLR, RELN and more recently WDR62 genes cause migrational abnormalities along with more complex and subtle anomalies affecting cell proliferation and differentiation, i.e., neurite outgrowth, axonal pathfinding, axonal transport, connectivity and even myelination. The number and heterogeneity of clinical, neuropathological and radiological defects suggest that type I lissencephaly now includes several forms of cerebral malformations. In vitro experiments and mutant animal studies, along with neuropathological abnormalities in humans are of invaluable interest for the understanding of pathophysiological mechanisms, highlighting the central role of cytoskeletal dynamics required for a proper achievement of cell proliferation, neuronal migration and differentiation

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Protocolo de reabilitação acelerada após reconstrução de ligamento cruzado anterior - dados normativos

OBJETIVO: Avaliar os resultados obtidos com o protocolo de reabilitação acelerada, adaptado às condições de clínica, em pacientes submetidos à operação de reconstrução do ligamento cruzado anterior. MÉTODOS: Foram incluídos 30 pacientes, praticantes de atividade esportiva recreacional, submetidos à operação de reconstrução do ligamento cruzado anterior por meio do tendão patelar. Todos fizeram a reabilitação com o mesmo protocolo de tratamento e no mesmo local. A avaliação isocinética em diferentes ângulos foi realizada antes da operação e no 4° mês de pós-operatório utilizando dinamômetro isocinético computadorizado da marca Cybex Norm. RESULTADOS: As avaliações no pré-operatório em média demonstraram: pico de torque flexor 93% a 60°/s e 97,3% a 180°/s; extensor 87,3% a 60°/s e 94,7% a 180°/s; potência nos músculos flexores de 93,3% e nos extensores de 96,7%; trabalho muscular dos flexores de 91,7% e nos extensores de 90,3%; o ângulo do pico de torque flexor de 28,7°, na musculatura extensora o ângulo foi de 62,2°; pico de torque excêntrico nos flexores de 78,3% e nos extensores de 12,8%. Com quatro meses de pós-operatório os resultados obtidos em média foram: pico de torque flexor 95,4% a 60°/s e 97,1% 180°/s; extensor 70% a 60°/s e 75,7% a 180°/s; potência nos músculos flexores de 97,1% e nos extensores de 79,8%; trabalho muscular dos flexores de 94,2% e nos extensores de 94,2%; pico de torque excêntrico dos flexores de 84% e nos extensores de 24,2%; o ângulo do pico de torque flexor foi a 27,3°; na musculatura extensora o ângulo foi de 61,7°. CONCLUSÃO: Os resultados demonstraram que os pacientes tratados com o protocolo adaptado apresentam resultados semelhantes aos obtidos com o protocolo original em relação às condições musculares