RESUMO
"Simple" 1-way interchromosomal insertions involving an interstitial 1q segment are rare, and therefore, their characterization at the base pair level remains understudied. Here, we describe the genomic characterization of a previously unreported de novo interchromosomal insertion (3;1) entailing an about 12-Mb pure gain of 1q21.3q23.3 that causes typical (microcephaly, developmental delay, and facial dysmorphism) and atypical (interauricular communication, small feet with bilateral deep plantar creases, syndactyly of II-IV toes, and mild pachyonychia of all toes) clinical manifestations associated with this region. Based on our analyses, we hypothesize that the duplication of a subset of morbid genes (including LMNA, USF1, VANGL2, LOR, and POGZ) could account for most clinical findings in our patient. Furthermore, the apparent disruption of a promoter region (between CPNE9 and BRPF1) and a topologically associated domain also suggests likely pathogenic reconfiguration/position effects to contribute to the patient's phenotype. In addition to further expanding the clinical spectrum of proximal 1q duplications and evidencing the phenotypical heterogeneity among similar carriers, our genomic findings and observations suggest that randomness - rather than lethality issues - may account for the paucity of "simple" interchromosomal insertions involving the 1q21.3q23.3 region as genomic donor and distal 3p25.3 as receptor. Moreover, the microhomology sequence found at the insertion breakpoint is consistent with a simple nonhomologous end-joining mechanism, in contrast to a chromothripsis-like event, which has previously been seen in other nonrecurrent insertions. Taken together, the data gathered in this study allowed us to inform this family about the low recurrence risk but not to predict the reproductive prognosis for hypothetical carriers. We highlight that genomic-level assessment is a powerful tool that allows the visualization of the full landscape of sporadic chromosomal injuries and can be used to improve genetic counseling.
Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 3/genética , Anormalidades Congênitas/genética , Genoma Humano , Adulto , Pré-Escolar , Duplicação Cromossômica/genética , Hibridização Genômica Comparativa , Humanos , Lactente , Recém-Nascido , Mapas de Interação de Proteínas , Sequenciamento Completo do GenomaRESUMO
Nigella sativa (N. sativa) is a medicinal plant used for its therapeutic pharmacological effects such as anti-inflammatory, antioxidant, anticancer, antidiabetic, and immunomodulation. This study explored the anti-cytotoxic and anti-genotoxic effect of N. sativa through a micronucleus test (MNT) of BALB/c mice peripheral blood. Using 6-to-8-week-old healthy male BALB/c mice, four groups were formed: (1) Control (sterile water), single-dose 2 mg/kg/intraperitoneal (i.p); (2) N. sativa oil, 500 mg/kg/24 h/7 days/i.p; (3) Cisplatin (CP), single-dose 2 mg/kg/subcutaneous (s.c); (4) N. sativa + CP with their respective dosage. When evaluating polychromatic erythrocytes (PCE), a biomarker of cytotoxicity, the group treated with N. sativa + CP experienced an increase in the frequency of PCE, which demonstrated the recovery of bone marrow and modulation of cell proliferation. The analysis of micronucleated polychromatic erythrocytes (MNPCE), an acute genotoxicity biomarker, showed similar frequency of MNPCE within the groups except in CP, but, in the N. sativa + CP group, the frequency of MNPCE decreased and then regulated. Finally, the frequency of micronucleated erythrocytes (MNE), a biomarker of genotoxicity, the supplementation of N. sativa oil did not induce genotoxic damage in this model. Thus, we conclude that N. sativa has both cytoprotective, genoprotective effects and modulates cell proliferation in BALB/c mice.
Assuntos
Cisplatino/toxicidade , Citoproteção/efeitos dos fármacos , Eritroblastos/efeitos dos fármacos , Testes para Micronúcleos/métodos , Nigella sativa/química , Óleos de Plantas/farmacologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/administração & dosagem , Masculino , Camundongos Endogâmicos BALB C , Óleos de Plantas/administração & dosagem , Óleos de Plantas/isolamento & purificaçãoRESUMO
We describe a patient severely affected with multiple congenital anomalies, including brain malformations and skeletal dysplasia suggestive of cranioectodermal dysplasia (CED) ciliopathy, who unusually carries several homozygosity tracts involving homozygous missense mutations in SPAG17 (exon 8; c.1069G > C; p.Asp357His) and WDR35 (exon 13; c.1415G > A; p.Arg472Gln) as revealed by homozygosity mapping and next generation sequencing. SPAG17 is essential for the function and structure of motile cilia, while WDR35 belongs to the same intraflagellar transport (IFT) gene family whose protein products are part of functional IFT A and B complexes. Formerly, SPAG17 was related - through polymorphic variants - to an influence on individuals' height; more recently, Spag17-/- mice models were reported to present skeletal and bone defects, reduced mucociliary clearance, respiratory distress, and cerebral ventricular enlargement. Homozygous or compound heterozygous mutations in WDR35 have mainly been related to CED2 or short-rib thoracic dysplasia 7, with only three cases showing some brain anomalies. Given that our patient presents these clinical features and the close functional relationship between SPAG17 and WDR35, it is feasible that the combined effects from both mutations contribute to his phenotype. To our knowledge, this patient is the first to harbor a likely pathogenic homozygous mutation in both genes at the same time. Thus, the resulting complex phenotype of this patient illustrates the heterogeneity associated with ciliopathies and further expands the clinical and mutational spectrum of these diseases. Finally, we highlight the combined use of high-throughput tools to diagnose and support the proper handling of this and other patients.