Current Genomics - Volume 12, Issue 7, 2011

Lynch syndrome (LS) is the most common form of inherited predisposition to develop cancer mainly in the colon and endometrium but also in other organ sites. Germline mutations in DNA mismatch repair (MMR) gene cause the transmission of the syndrome in an autosomal dominant manner. The management of LS patients is complicated by the large variation in age at cancer diagnosis which requires these patients to be enrolled in surveillance protocol starting as early as in their second decade of life. Several environmental and genetic factors have been proposed to explain this phenotypic heterogeneity, but the molecular mechanisms remain unknown. Although the presence of genetic anticipation in Lynch syndrome has been suspected since 15 years, only recently the phenomenon has been increasingly reported to be present in different cancer genetic syndromes including LS. While the biological basis of earlier cancer onset in successive generations remains poorly known, recent findings point to telomere dynamics as a mechanism significantly contributing to genetic anticipation in Lynch syndrome and in other familial cancers. In this review, we summarize the clinical and molecular features of Lynch syndrome, with a particular focus on the latest studies that have investigated the molecular mechanisms of genetic anticipation.

The outbreak of highly pathogenic avian influenza (HPAI) H5N1 disease has led to significant loss of poultry and wild life and case fatality rates in humans of 60%. Wild birds are natural hosts for all avian influenza virus subtypes and over120 bird species have been reported with evidence of H5N1 infection. Influenza A viruses possess a segmented RNA genome and are characterized by frequently occurring genetic reassortment events, which play a very important role in virus evolution and the spread of novel gene constellations in immunologically naïve human and animal populations. Phylogenetic analysis of whole genome or sub-genomic sequences is a standard means for delineating genetic variation, novel reassortment events, and surveillance to trace the global transmission pathways. In this paper, special emphasis is given to the transmission and circulation of H5N1 among wild life populations, and to the reassortment events that are associated with inter-host transmission of the H5N1 viruses when they infect different hosts, such as birds, pigs and humans. In addition, we review the inter-subtype reassortment of the viral segments encoding inner proteins between the H5N1 viruses and viruses of other subtypes, such as H9N2 and H6N1. Finally, we highlight the usefulness of genomic sequences in molecular epidemiological analysis of HPAI H5N1 and the technical limitations in existing analytical methods that hinder them from playing a greater role in virological research.

The GJB2 gene is located on chromosome 13q12 and it encodes the connexin 26, a transmembrane protein involved in cell-cell attachment of almost all tissues. GJB2 mutations cause autosomal recessive (DFNB1) and sometimes dominant (DFNA3) non-syndromic sensorineural hearing loss. Moreover, it has been demonstrated that connexins are involved in regulation of growth and differentiation of epidermis and, in fact, GJB2 mutations have also been identified in syndromic disorders with hearing loss associated with various skin disease phenotypes. GJB2 mutations associated with skin disease are, in general, transmitted with a dominant inheritance pattern. Nonsyndromic deafness is caused prevalently by a loss-of-function, while literature evidences suggest for syndromic deafness a mechanism based on gain-of-function. The spectrum of skin manifestations associated with some mutations seems to have a very high phenotypic variability. Why some mutations can lead to widely varying cutaneous manifestations is poorly understood and in particular, the reason why the skin disease-deafness phenotypes differ from each other thus remains unclear. This review provides an overview of recent findings concerning pathogenesis of syndromic deafness imputable to GJB2 mutations with an emphasis on relevant clinical genotype-phenotype correlations. After describing connexin 26 fundamental characteristics, the most relevant and recent information about its known mutations involved in the syndromic forms causing hearing loss and skin problems are summarized. The possible effects of the mutations on channel expression and function are discussed.

Prostate cancer (PCa) is the most prevalent cancer, a significant contributor to morbidity and a leading cause of cancer-related death in men in Western industrialized countries. In contrast to genetic changes that vary among individual cases, somatic epigenetic alterations are early and highly consistent events. Epigenetics encompasses several different phenomena, such as DNA methylation, histone modifications, RNA interference, and genomic imprinting. Epigenetic processes regulate gene expression and can change malignancy-associated phenotypes such as growth, migration, invasion, or angiogenesis. Methylations of certain genes are associated with PCa progression. Compared to normal prostate tissues, several hypermethylated genes have also been identified in benign prostate hyperplasia, which suggests a role for aberrant methylation in this growth dysfunction. Global and gene-specific DNA methylation could be affected by environmental and dietary factors. Among other epigenetic changes, aberrant DNA methylation might have a great potential as diagnostic or prognostic marker for PCa and could be tested in tumor tissues and various body fluids (e.g., serum, urine). The DNA methylation markers are simple in nature, have high sensitivity, and could be detected either quantitatively or qualitatively. Availability of genome-wide screening methodologies also allows the identification of epigenetic signatures in high throughput population studies. Unlike irreversible genetic changes, epigenetic alterations are reversible and could be used for PCa targeted therapies.

Amyotrophic lateral sclerosis (ALS) is an adult-onset degenerative disease characterized by the loss of upper and lower motor neurons, progressive muscle atrophy, paralysis and death, which occurs within 2-5 years of diagnosis. Most cases appear sporadically but some are familial, usually inherited in an autosomal dominant pattern. It is postulated that the disease results from the combination of multiple pathogenic mechanisms, which affect not only motor neurons but also non-neuronal neighboring cells. Together with the understanding of this intriguing cell biology, important challenges in the field concern the design of effective curative treatments and the discovery of molecular biomarkers for early diagnosis and accurate monitoring of disease progression. During the last decade, transcriptomics has represented a promising approach to address these questions. In this review, we revisit the major findings of the numerous studies that analyzed global gene expression in tissues and cells from biopsy or post-mortem specimens of ALS patients and related animal models. These studies corroborated the implication of previously described disease pathways, and investigated the role of new genes in the pathological process. In addition, they also identified gene expression changes that could be used as candidate biomarkers for the diagnosis and follow-up of ALS. The limitations of these transcriptomics approaches will be also discussed.

A growing list of common and rare genetic risk variants are being implicated in schizophrenia susceptibility. As with other complex genetic disorders most of the variance in genetic risk is still to be attributed. What can be learned from progress to date? The available data challenges how we conceptualize schizophrenia and suggests strong aetiological links with other psychiatric and developmental disorders. With the identification of rare copy number risk variants implicating specific genes (e.g. VIPR2 and NRXN1) it is increasingly possible to investigate molecular aetiology in patient subgroups to establish whether schizophrenia represents one or many different disease processes. This review summarizes recent research progress and suggests how the tools of modern genomics and neuroscience can be applied to best understand this devastating disorder.