The role of ATP7A in copper homeostasis

Menkes disease is a fatal genetic copper deficiency. The Menkes protein (ATP7A) was found to remove copper from tissues in mice that expressed the human ATP7A. Promising results were obtained with the use of a new copper complex for treatment of Menkes disease using a mouse model.

Ulnar ray a/hypoplasia: evidence for a developmental field defect on the basis of genetic heterogeneity. Report of three Brazilian families.

We report on five Brazilian patients from three unrelated families with congenital anomalies of the upper limbs. Ulnar aplasia/hypoplasia was the main reason for examining these patients. Evidence for existence of an ulnar developmental field is based on genetic heterogeneity. Clinical and genetic aspects of the ulnar ray defects are discussed.

The endangered species Brycon orbignyanus: genetic analysis and definition of priority areas for conservation

Currently, biodiversity is threatened by several factors often associated with human population growth and the extension of areas occupied by human activity. In particular, freshwater fish fauna is affected by overfishing, deforestation, water pollution, introduction of exotic species and habitat fragmentation promoted by hydroelectric dams, among other environmental impact factors. Several action plans to preserve ichthyofauna biodiversity have been adopted; however, these plans frequently cover only a small number of species, and decisions are often made without strong scientific support. This study aimed to evaluate the genetic aspects of wild groups of Brycon orbignyanus, an endangered fish species, using microsatellites and D-loop regions to identify the genetic structure of the samples and to establish priority areas for conservation based on the genetic patterns of this species. The results indicated that the samples showed levels of genetic variability compatible with others studies with Neotropical fishes. However, the results obtained in the analysis of molecular variance (AMOVA) for microsatellites (F (ST) = 0.258) and D-loop (F (ST) = 0.234) and the interpopulation fixation index revealed that B. orbignyanus was structured in different subpopulations in the La Plata River basin; the areas with better environmental conditions also showed subgroups with higher rates of genetic variability. Future conservation actions addressing these sites should consider two different management units: the complex formed by the Ivinhema River, Upper Parana, Camargo Port and Ilha Grande groups; and the complex formed by the Verde River and Sucuriu River groups.

[White sponge naevus. Report of a family with respect to histopathologic, cytopathologic and DNA-cytometric aspects]

The white sponge naevus is a rare benign, hereditary autosomal dominant disorder of the mucosa. The oral mucosa is most often affected, but vaginal and anal mucosal surfaces may also be involved. Clinically, a whitish-grey, ragged, and folded surface that has no clear demarcation and appears sponge-like is characteristic, often creating problems in differential diagnosis. A potential risk for malignant transformation of white sponge naevus lesions has not been reported. The therapy for this benign hereditary disorder is unknown, however does not appear to be necessary. In the present report of a family with known white sponge naevus in three different generations, clinical, histopathologic, cytopathologic, DNA-cytomertric, and genetic aspects are described and discussed.

A new model to analyze metaphyseal bone healing in mice

Background: Despite the increasing clinical problems with metaphyseal fractures, most experimental studies investigate the healing of diaphyseal fractures. Although the mouse would be the preferable species to study the molecular and genetic aspects of metaphyseal fracture healing, a murine model does not exist yet. Using a special locking plate system, we herein introduce a new model, which allows the analysis of metaphyseal bone healing in mice. Methods: In 24 CD-1 mice the distal metaphysis of the femur was osteotomized. After stabilization with the locking plate, bone repair was analyzed radiologically, biomechanically, and histologically after 2 (n = 12) and 5 wk (n = 12). Additionally, the stiffness of the bone-implant construct was tested biomechanically ex vivo. Results: The torsional stiffness of the bone-implant construct was low compared with nonfractured control femora (0.23 ± 0.1 Nmm/°versus 1.78 ± 0.15 Nmm/°, P < 0.05). The cause of failure was a pullout of the distal screw. At 2 wk after stabilization, radiological analysis showed that most bones were partly bridged. At 5 wk, all bones showed radiological union. Accordingly, biomechanical analyses revealed a significantly higher torsional stiffness after 5 wk compared with that after 2 wk. Successful healing was indicated by a torsional stiffness of 90% of the contralateral control femora. Histological analyses showed new woven bone bridging the osteotomy without external callus formation and in absence of any cartilaginous tissue, indicating intramembranous healing. Conclusion: With the model introduced herein we report, for the first time, successful metaphyseal bone repair in mice. The model may be used to obtain deeper insights into the molecular mechanisms of metaphyseal fracture healing. © 2012 Elsevier Inc. All rights reserved.

Identification of genes associated with tumorigenesis of meibomian cell carcinoma by microarray analysis

Meibomian cell carcinoma (MCC) is a malignant tumor of the meibomian glands located in the eyelids. No information exists on the cytogenctic and genetic aspects of MCC. There is no report on the gene expression profile of MCC. Thus there is a need, for both scientific and clinical reasons, to identify genes and pathways that are involved in the development and progression of MCC. We analyzed the gene expression profile of MCC by the microarray technique. Forty-four genes were upregulated and 149 genes were downregulated in MCC. Differential expression data were confirmed for 5 genes by semiquantitative RT-PCR in MCC tumors: GTF2H4, RBM12, UBE2D3, DDX17, and LZTS1. We found dysregulation of two major pathways in MCC: MAPK and JAK/STAT. Clusters of genes on chromosomes 1, 12, and 19 were dysregUlated in MCC. The data presented here will facilitate the identification of specific markers and therapeutic targets for the treatment of MCC patients. (c) 2007 Elsevier Inc. All rights reserved.

Caracterização de alterações epigenéticas no gene JARID1C e desequilíbrios genéticos como causas do retardo mental ligado ao x de etiologia idiopática

O retardo mental (RM) é caracterizado por um funcionamento intelectual significantemente abaixo da média (QI<70). A prevalência de RM varia entre estudos epidemiológicos, sendo estimada em 2-3% da população mundial, constituindo assim, um dos mais importantes problemas de saúde pública. Há um consenso geral de que o RM é mais comum no sexo masculino, um achado atribuído às numerosas mutações nos genes encontrados no cromossomo X, levando ao retardo mental ligado ao X (RMLX). Dentre os genes presentes no cromossomo X, o Jumonji AT-rich interactive domain IC (JARID1C) foi recentemente identificado como um potencial candidato etiológico do RM, quando mutado. O JARID1C codifica uma proteína que atua como uma desmetilase da lisina 4 da histona H3 (H3K4), imprescindível para a regulação epigenética. Tão recente como a identificação do gene JARID1C, é a descoberta de que mudanças no número de cópias de sequências de DNA, caracterizadas por microdeleções e microduplicações, poderiam ser consideradas como razões funcionalmente importantes de RMLX. Atualmente, cerca de 5-10% dos casos de RM em homens são reconhecidos por ocorrerem devido a estas variações do número de cópias no cromossomo X. Neste estudo, investigamos mutações no gene JARID1C, através do rastreamento dos éxons 9, 11, 12, 13, 15 e 16, em 121 homens de famílias com RM provavelmente ligado ao X. Paralelamente, realizamos a análise da variação do número de cópias em 16 genes localizados no cromossomo X através da técnica de MLPA no mesmo grupo de pacientes. Esta metodologia consiste em uma amplificação múltipla que detecta variações no número de cópias de até 50 sequências diferentes de DNA genômico, sendo capaz de distinguir sequências que diferem em apenas um nucleotídeo. O DNA genômico foi extraído a partir de sangue periférico e as amostras foram amplificadas pela técnica de PCR, seguida da análise por sequenciamento direto. Foram identificadas três variantes na sequência do gene JARID1C entre os pacientes analisados: a variante intrônica 2243+11 G>T, que esteve presente em 67% dos pacientes, a variante silenciosa c.1794C>G e a mutação inédita nonsense c.2172C>A, ambas presentes em 0,82% dos indivíduos investigados. A análise através do MLPA revelou uma duplicação em um dos pacientes envolvendo as sondas referentes ao gene GDI1 e ao gene HUWE1. Este trabalho expande o estudo de mutações no gene JARID1C para a população brasileira ereforça a importância da triagem de mutações neste gene em homens portadores de RM familiar de origem idiopática, assim como, é primeiro relato científico relativo à investigação de variações no número de cópias de genes localizados no cromossomo X em homens brasileiros com RM, através da técnica de MLPA.