Human Molecular Genetics

Hudson, Gavin; Chinnery, Patrick F.

doi: 10.1093/hmg/ddl233pmid: 16987890

The maintenance of mitochondrial DNA (mtDNA) is critically dependent upon polymerase- (pol-), encoded by the nuclear gene POLG. Over the last 5 years, it has become clear that mutations of POLG are a major cause of human disease. Secondary mtDNA defects characterize these disorders, with mtDNA depletion, multiple mtDNA deletions or multiple point mutations of mtDNA in clinically affected tissues. The secondary mtDNA defects cause cell and tissue-specific deficiencies of mitochondrial oxidative phosphorylation, leading to organ dysfunction and human disease. Functional genetic variants of POLG are present in up to 0.5 of the general population, and pathogenic mutations have been described in most exons of the gene. Clinically, POLG mutations can present from early neonatal life to late middle age, with a spectrum of phenotypes that includes common neurological disorders such as migraine, epilepsy and Parkinsonism. Transgenic mice and biochemical studies of recombinant mutated proteins are helping to unravel mechanisms of pathogenesis, and patterns are beginning to emerge relating genotype to phenotype.

Duan, Dongsheng

doi: 10.1093/hmg/ddl180pmid: 16987891

The last decade has evidenced unprecedented progress in gene therapy of Duchenne and Becker muscular dystrophy (DMD and BMD) skeletal muscle disease. Cardiomyopathy is a leading cause of morbidity and mortality in both patients and carriers of DMD, BMD and X-linked dilated cardiomyopathy. However, there is little advance in heart gene therapy. The gene, the vector, vector delivery, the target tissue and animal models are five fundamental components in developing an effective gene therapy. Intensive effort has been made in optimizing gene transfer vectors and methods. Systemic and/or local delivery of recombinant adeno-associated viral vector have resulted in widespread transduction in the rodent heart. The current challenge is to define other parameters that are essential for a successful gene therapy such as the best candidate gene(s), the optimal expression level and the target tissue. This review focuses on these long-ignored aspects and points out future research directions. In particular, we need to address whether all or only some of the recently developed mini- and microgenes are protective in the heart, whether partial correction can lead to whole heart function improvement, whether over-expression is hazardous and whether correcting skeletal muscle disease can slow down or stop the progression of cardiomyopathy. Discussion is also made on whether the current mouse models can meet these research needs.

Raymond, F. Lucy; Tarpey, Patrick

doi: 10.1093/hmg/ddl189pmid: 16987873

Genetic abnormalities frequently give rise to a mental retardation phenotype. Recent advances in resolution of comparative genomic hybridization and genomic sequence annotation has identified new syndromes at chromosome 3q29 and 9q34. The finding of a significant number of copy number polymorphisms in the genome in the normal population, means that assigning pathogenicity to deletions and duplications in patients with mental retardation can be difficult but has been identified for duplications of MECP2 and L1CAM. Novel autosomal genes that cause mental retardation have been identified recently including CC2D1A identified by homozygosity mapping. Several new genes and pathways have been identified in the field of X-linked mental retardation but many more still await identification. Analysis of families where only a single male is affected reveals that the chance of this being due to a single X-linked gene abnormality is significantly less than would be expected if the excess of males in the population is entirely due to X-linked disease. Recent identification of novel X-linked mental retardation genes has identified components of the post-synaptic density and multiple zinc finger transcription factors as disease causing suggesting new mechanisms of disease causation. The first therapeutic treatments of animal models of mental retardation have been reported, a Drosophila model of Fragile X syndrome has been treated with lithium or metabotropic glutamate receptor (mGluR) antagonists and a mouse model of NF1 has been treated with the HMG-CoA reductase inhibitor lavastatin, which improves the learning and memory skills in these models.

Freeman, H.; Cox, R.D.

doi: 10.1093/hmg/ddl191pmid: 16987885

Diabetes is one of the most challenging health problems of the 21st century with an alarming increase in the prevalence of type-2 diabetes mellitus (T2DM) and associated conditions such as hypertension, dyslipidemias and obesity. T2DM is a complex genetic disease comprised of many metabolic disorders with a common phenotype of glucose intolerance. Patients with T2DM would have inherited a variety of different genetic factors that together with environmental factors combine as the primary cause. This complicates the genetic study of the disease and means that different methodological approaches are needed if we hope to identify susceptibility genes and genetic variants. The biochemical and physiological processes that underpin T2DM are still unclear although most certainly involve impairment in insulin secretion and insulin action. In this review, we will discuss the most exciting advances in understanding the genetics of T2DM by looking at recent discoveries employing human association studies and candidate genes arising from animal models.

Pittman, Alan M.; Fung, Hon-Chung; de Silva, Rohan

doi: 10.1093/hmg/ddl190pmid: 16987883

Pathological tau protein inclusions have long been recognized to define the diverse range of neurodegenerative disorders called the tauopathies, which include Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration. Mutations in the tau gene, MAPT, cause familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and common variation in MAPT is strongly associated with the risk of PSP, corticobasal degeneration and, to a lesser extent, AD and Parkinson's disease (PD), implicating the involvement of tau in common neurodegenerative pathway(s). This review will discuss recent work towards the unravelling of the functional basis of this MAPT gene association. The region of chromosome 17q21 containing MAPT locus is characterized by the complex genomic architecture, including a large inversion that leads to a bipartite haplotype architecture, an inversion-mediated deletion and multiplications resulting from non-allelic homologous recombination between the MAPT family of low-copy repeats.

Hohenstein, Peter; Hastie, Nicholas D.

doi: 10.1093/hmg/ddl196pmid: 16987884

Over the years, many apparently contradictory findings and functions have been ascribed to the protein product of the WT1 tumour suppressor gene. These include being a transcriptional activator or repressor, a function in transcription versus RNA metabolism, and these days even a function as oncogene or tumour suppressor gene. To fully understand the role of WT1 in different diseases and normal development, we will need to understand these contradictions. In this review, we will discuss the present state of knowledge and suggest that a role for WT1 in influencing the mesenchymalepithelial state of cells might be a common function that could explain many of the previously described findings.

Wallingford, John B.

doi: 10.1093/hmg/ddl216pmid: 16987888

Cilia are microtubule-based protrusions that are found on the surface of most vertebrate cells. Long studied by cell biologists, these organelles have recently caught the attention of developmental biologists and human geneticists. In this review, I will discuss recent findings suggesting a link between cilia and the planar cell polarity signaling cascade. In particular, I will focus on how this interaction may influence the process of neural tube closure and how these results may be relevant to our understanding of common human birth defects in which neural tube closure is compromised.

Whitelaw, Nadia C.; Whitelaw, Emma

doi: 10.1093/hmg/ddl200pmid: 16987876

Despite our detailed characterization of the human genome at the level of the primary DNA sequence, we are still far from understanding the molecular events underlying phenotypic variation. Epigenetic modifications to the DNA sequence and associated chromatin are known to regulate gene expression and, as such, are a significant contributor to phenotype. Studies of inbred mice and monozygotic twins show that variation in the epigenotype can be seen even between genetically identical individuals and that this, in some cases at least, is associated with phenotypic differences. Moreover, recent evidence suggests that the epigenome can be influenced by the environment and these changes can last a lifetime. However, we also know that epigenetic states in real-time are in continual flux and, as a result, the epigenome exhibits instability both within and across generations. We still do not understand the rules governing the establishment and maintenance of the epigenotype at any particular locus. The underlying DNA sequence itself and the sequence at unlinked loci (modifier loci) are certainly involved. Recent support for the existence of transgenerational epigenetic inheritance in mammals suggests that the epigenetic state of the locus in the previous generation may also play a role. Over the next decade, many of these processes will be better understood, heralding a greater capacity for us to correlate measurable molecular marks with phenotype and providing the opportunity for improved diagnosis and presymptomatic healthcare.

Schanen, N. Carolyn

doi: 10.1093/hmg/ddl213pmid: 16987877

The autism spectrum disorders (ASD) comprise a complex group of behaviorally related disorders that are primarily genetic in origin. Involvement of epigenetic regulatory mechanisms in the pathogenesis of ASD has been suggested by the occurrence of ASD in patients with disorders arising from epigenetic mutations (fragile X syndrome) or that involve key epigenetic regulatory factors (Rett syndrome). Moreover, the most common recurrent cytogenetic abnormalities in ASD involve maternally derived duplications of the imprinted domain on chromosome 15q1113. Thus, parent of origin effects on sharing and linkage to imprinted regions on chromosomes 15q and 7q suggest that these regions warrant specific examination from an epigenetic perspective, particularly because epigenetic modifications do not change the primary genomic sequence, allowing risk epialleles to evade detection using standard screening strategies. This review examines the potential role of epigenetic factors in the etiology of ASD.

Walley, Andrew J.; Blakemore, Alexandra I.F.; Froguel, Philippe

doi: 10.1093/hmg/ddl215pmid: 16987875

Obesity has always existed in human populations, but until very recently was comparatively rare. The availability of abundant, energy-rich processed foods in the last few decades has, however, resulted in a sharp rise in the prevalence of obesity in westernized countries. Although it is the obesogenic environment that has resulted in this major healthcare problem, it is acting by revealing a sub-population with a pre-existing genetic predisposition to excess adiposity. There is substantial evidence for the heritability of obesity, and research in both rare and common forms of obesity has identified genes with significant roles in its aetiology. Application of this understanding to patient care has been slower. Until very recently, the health risks of obesity were thought to be well understood, with a straightforward correlation between increasing obesity and increasing risk of health problems such as type 2 diabetes, coronary heart disease, hypertension, arthritis and cancer. It is becoming clear, however, that the location of fat deposition, variation in the secretion of adipokines and other factors govern whether a particular obese person develops such complications. Prediction of the health risks of obesity for individual patients is not straightforward, but continuing advances in understanding of genetic factors influencing obesity risk and improved diagnostic technologies mean that the future for such prediction is looking increasingly bright.