Human Molecular Genetics Research Articles

Speicher, Antonarakis, Motulsky (eds): Vogel and Motulsky’s human genetics, 4th edn

Vogel & Motulsky is an unusual book. The four editions span 40 years, the first in 1970, the second in 1976, the third in 1997 and now in 2010 the fourth. Planning of this latest version stalled with the death of Friedrich Vogel in 2006. Eventually, Stylianos Antonarakis and Michael Speicher joined Arno Motulsky, and this substantial volume is the result, just short of 1,000 pages and weighing in at 2.6 kg. Maybe I should declare an interest, as co-author of the recently published fourth edition of Strachan & Read’s Human Molecular Genetics. But actually, the two books are very different. S&R is a course textbook for advanced undergraduates, and an overview of the principles for people coming into the area from another discipline who want to hit the ground running. V&M is a series of highlevel reviews, produced with the help of 76 co-authors. However, it is not the usual sort of multi-author tome that always gives me a sinking feeling, those dinosaurs of the information era, large, blundering compilations out-performed by their nimbler Internet competitors and surely overdue for extinction. The editors have done a lot more than just assemble a suitable list of authors and sit back waiting for the chapters to come in. Antonarakis and Speicher have both contributed substantial amounts of the content, at least a quarter of the total length of the book is authored or co-authored by one or other of them. It must have been a huge amount of work. From Motulsky, there are chapters on the history of human genetics and on the formal genetics of humans, both revised from the third edition, and a co-authored chapter on linkage. All three have obviously been involved in signing up a very distinguished panel of co-authors, the list is almost a Who’s Who of current human genetics. A downside (from the point of view of booksellers) of having such an A-list set of authors is that many will have written reviews on their subject that those of us with access to an academic library can read free of charge. The content is broad, but generally covers methods and applications rather than specific diseases. There is a welcome emphasis on formal genetics, which sets this book apart from most others. Chapters on monogenic, oligogenic and multifactorial inheritance go into considerable mathematical detail. This is a valuable feature, and one that will not date. It is not easy to find treatments of these topics that go beyond the basics, yet are comprehensible to nonmathematicians. Population genetics, epidemiology and aspects of evolution also get solid chapters. Another strong point of previous editions was the detailed treatment of behavioural genetics, and again this is carried through in seven chapters covering personality, mental retardation, Alzheimer disease, autism, addiction, psychoses and behavioural aspects of chromosomal variants. Inevitably, these will date, but with their extensive reference lists they will provide useful starting points for following the current literature. A new feature is a set of chapters on each of the main model organisms. Processes of mutation, on the other hand, get less attention than in the previous edition. One always wonders whether the shelf life of a book like this would justify its cost. A big book like this is not the place to try to keep up with the furious pace of technical and scientific progress. The combination of in-depth reviews of principles and a notable interest in the history of the various topics should mean it will still be worth reading in five years’ time. Most of the chapters I checked were well A. Read (&) Genetic Medicine, St Mary’s Hospital, Manchester M13 0JH, UK e-mail: Andrew.Read@man.ac.uk

Potential Psychiatric Applications of Metabotropic Glutamate Receptor Agonists and Antagonists

Drugs acting at metabotropic glutamate receptors (mGluRs) are among the most promising agents under development for the treatment of psychiatric disorders. The research in this area is at a relatively early stage, as there are no drugs acting at mGluRs that have been approved for the treatment of any psychiatric disorder. However, in the areas of schizophrenia, anxiety disorders and mood disorders, research conducted in animal models appears to translate well into efficacy in human laboratory-based models of psychopathology and in preliminary clinical trials. Further, the genes coding for mGluRs are implicated in the risk for a growing number of psychiatric disorders. This review highlights the best studied mGluR strategies for psychiatry, based on human molecular genetics, studies in animal models and preliminary clinical trials. It describes the potential value of mGluR2 and mGluR5 agonists and positive allosteric modulators for the treatment of schizophrenia. It also reviews evidence that group II mGluR agonists and positive allosteric modulators as well as group I mGluR antagonists might also treat anxiety disorders and some forms of depression, while mGluR2 and group I mGluR antagonists (particularly mGluR5 antagonists) might have antidepressant properties. This review also links growing insights into the role of glutamate in the pathophysiology of these disorders to hypothesized mGluR-related treatment mechanisms.

Leena Palotie-Peltonen, 1952–2010, visionary and role model

Leena Palotie-Peltonen, 1952–2010, visionary and role model

Overview and historical perspective of four papers presented on research related to the endogenous opioid system

Overview and historical perspective of four papers presented on research related to the endogenous opioid system

Abstract 2847: TagSNPs in the podocalyxin (PODXL) gene are associated with prostate cancer risk

Abstract Previous gene mapping efforts, including a recent admixture mapping study, concluded that there is likely at least one prostate cancer susceptibility locus on 7q32. Podocalyxin (PODXL) is the strongest candidate gene in this region, particularly for risk of aggressive disease (Casey et al. Human Molecular Genetics, 5: 735-741, 2006). Therefore, we examined 34 tagSNPs in the PODXL gene in relation to prostate cancer risk and aggressiveness in a sample of unrelated cases (n=626) and controls (n=239) from metropolitan Detroit, MI. Men were recruited from Henry Ford Health System; cases were diagnosed with prostate cancer between 2001 and 2004, and controls were frequency matched to cases on 5 year age groups and race. Logistic regression models were adjusted for family history of prostate cancer, race, age, and ancestry where appropriate. Carrying at least one copy of the variant A allele in SNP rs3212299 was associated with a decrease in prostate cancer risk (OR=0.60, 95% CI: 0.41, 0.90). Having at least on copy of the C allele in SNP rs11773254 was associated with a 70% increased risk of prostate cancer (OR = 1.70, 95% CI: 1.13, 2.58). The G allele of rs1733874 was marginally protective in the entire sample (OR=0.74, 95% CI: 0.49, 1.02). These risk estimates did not appreciably vary after stratifying by race [African American (AA), European American (EA)], age (< age 62, > age 62), or prostate cancer aggressiveness (Gleason sum 3+4 or lower, Gleason sum 4+3 or higher). In addition, a protective effect of the C allele in SNP rs3800684 was observed in AA men (OR=0.56, 95% CI: 0.35, 0.90) but not in EA men (OR=1.38, 95% CI: 0.92, 2.09), and there was a statistically significant interaction between race and genotype at this marker (p=0.005). After stratifying by median age, the A allele of SNP rs10224884 was marginally associated with increased prostate cancer risk in the older age group (OR=1.44, 95% CI : 0.92, 2.27), but not the younger age group (OR=0.69, 95% CI: 0.42, 1.13), and the interaction between age group and genotype was statistically significant (0.03). Overall, we conclude that SNPs in the PODXL gene are associated with prostate cancer risk, but not prostate cancer aggressiveness, and that some of these variants may have race- and age-specific effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2847.

Pendred syndrome in Tunisia

We report a clinical and genetic study of three consanguineous Tunisian families affected by Pendred syndrome. Three families from the south of Tunisia were identified as affected by Pendred syndrome. The patients and their families underwent ENT and general examination and audiovestibular and radiological tests. Molecular DNA analysis was performed by the Sfax Human Molecular Genetics Department. Forty-three patients (mean age: 21 years [2-60 years]) were affected. Tonal audiometry showed bilateral sensorineural hearing loss in 87.5% of cases, and mixed hearing loss in 12.5% with bilateral high frequency sensorineural hearing loss and conductive hearing loss at lower frequencies. Deafness was severe in 21% and profound in 79% of cases. Thyroid goiter was found in 46.5% of cases. Inner ear CT scan found enlarged bilateral vestibular aqueducts in all cases. Hormone analysis was normal and perchlorate test negative in all cases. A single Pendred syndrome (PDS) gene mutation, L445W, was found. Pendred syndrome is the most frequent congenital deafness syndrome. It is characterized by great intrafamilial phenotype variability.

Mycoplasma hyorhinisupregulates calpastatin and inhibits calpain-dependent proteolysis in SH-SY5Y neuroblastoma cells

Mycoplasmas often contaminate cultured cells, leading to alterations in cellular gene expression, protein synthesis, signal transduction and metabolic pathways. Mycoplasmal contamination is often unnoticed, so that mycoplasma-induced alterations in cell functions may not be appreciated, unless specifically studied. Here, we show for the first time that contamination of SH-SY5Y cells by Mycoplasma hyorhinis leads to increased levels of calpastatin (the endogenous inhibitor of the Ca(2+)-dependent protease calpain), resulting in inhibition of Ca(2+)-induced calpain activation and inhibition of calpain-promoted proteolysis in the mycoplasmal-infected cells. Calpain activity is recovered upon calpastatin removal from extracts of contaminated cells. The calpain-calpastatin system has been implicated in a variety of physiological and pathological processes (signal transduction, motility, cell cycle, cell differentiation, membrane damage and apoptosis). Because the ratio of calpastatin to calpain is an important factor in the control of calpain activity within the cell, the elevated calpastatin may protect the mycoplasma-infected cells against certain types of damage (e.g. caused by high Ca(2+)). Thus, our results are important for studies on the modulation of host cells by mycoplasmas, and relevant to the pathobiology of processes involving mycoplasmal infections. The mycoplasma-infected cells provide a system for identifying factors that participate in the regulation of cellular calpastatin.

The ghost and the machine.

In Monty Python’s ‘Four Yorkshiremen’ sketch [1], the tuxedo-clad, cigar-puffing gents sit quaffing wine, and get to reminiscing. The conversation moves round the group: “Who’d have thought thirty year ago we’d all be sitting here drinking Château de Chasselas, eh?” “In them days we was glad to have the price of a cup o’ tea.” “A cup o’ cold tea.” “Without milk or sugar.” “Or tea.” “In a cracked cup, an’ all.” “Oh, we never had a cup. We used to have to drink out of a rolled up newspaper.” And so it goes on, the competitive reminiscences becoming more and more absurd in their invocation of hardship. Listening to geneticists of a certain age is sometimes a bit like this. Some event or remark sets off the litany: complaints from the lab about the slowness of the central sequencing service are met with harrumphing, and a tale about polyacrylamide gels and S labelling; this leads to a diatribe about the intricacies of cDNA library construction; at some point the ‘three waterbaths’ story of the early days of PCR is wheeled out; an esteemed colleague might raise the stakes by recounting the tribulations of making his own restriction enzymes. Is this just the universal nostalgia for a past era that is one of the hallmarks of ageing? To an extent, yes, but there’s more to it than that. Certainly in the area of scientific endeavour within which many readers of this journal work, the average project has become experimentally far less interesting and challenging that it used to be. During my own PhD I grew cell-lines, made YAC, cosmid and phage libraries, did pulsed-field gel mapping, southern blotted, subcloned, and enjoyed plentiful exposure to phenol and radioisotopes, as did my labmates; nowadays my students spend their time putting Taq polymerase through its paces, waiting for the garish purple DNA extraction robot to beep, ordering kits, and outsourcing the really tricky stuff to the cheapest supplier. The benches can sometimes become repositories of paper dusty adjuncts to the desk and computer but at least the occasional pipette is in operation. My genome centre colleagues have been presented with spacious and gleaming labs, but every time I visit they lie empty, the workers packed instead into a rather-toosnug office. Part of the unease about this change is to do with the gradual abandonment of manual tasks that are difficult and varied and satisfying. In Matthew Crawford’s book The Case for Working with Your Hands, or Why Office Work is bad for us [2], he extols the virtues of manual and mechanical competence, personifying his argument by having moved from a PhD in political philosophy from Chicago to run his own independent motorcycle repair shop. OK his kind of manual work, fixing broken motorbikes, is not exactly molecular genetics, but there are nonetheless interesting parallels. Crawford bemoans the move by manufacturers towards more complex products that are more difficult to tinker with, making users ‘more passive and more dependent’, and the declining opportunity for ‘the kind of spiritedness that is called forth when we take things in hand for ourselves’. Any ageing geneticist who signs an order for some new and expensive kit knows exactly what he means. The thing that today’s PhD students are doing that their supervisors didn’t do much of is computing, and, for some of the time at least, bioinformatics what the wrench-wielding Crawford would class as ‘the most ghostly kind of work’. Here, the thinking part is just as interesting and challenging as ever it was, and maybe even more so. But the manual, mechanical stuff has been done somewhere else, by someone else. The power of whole genome and exome sequences, high-throughput genotyping data, population genomics and the like is (to use an oft-abused word) truly awesome, as is nicely illustrated by a recent review issue of Human Molecular Genetics [3]. And yet, an appreciation of how data are generated, and some degree of intimacy with Correspondence: maj4@leicester.ac.uk Department of Genetics, University of Leicester, Leicester, UK Jobling Investigative Genetics 2010, 1:11 http://www.investigativegenetics.com/content/1/1/11

2009 in Review

2009 in Review

Drug-induced and genetic alterations in stress-responsive systems: Implications for specific addictive diseases

From the earliest work in our laboratory, we hypothesized, and with studies conducted in both clinical research and animal models, we have shown that drugs of abuse, administered or self-administered, on a chronic basis, profoundly alter stress-responsive systems. Alterations of expression of specific genes involved in stress responsivity, with increases or decreases in mRNA levels, receptor, and neuropeptide levels, and resultant changes in hormone levels, have been documented to occur after chronic intermittent exposure to heroin, morphine, other opiates, cocaine, other stimulants, and alcohol in animal models and in human molecular genetics. The best studied of the stress-responsive systems in humans and mammalian species in general is undoubtedly the HPA axis. In addition, there are stress-responsive systems in other parts in the brain itself, and some of these include components of the HPA axis, such as CRF and CRF receptors, along with POMC gene and gene products. Several other stress-responsive systems are known to influence the HPA axis, such as the vasopressin–vasopressin receptor system. Orexin–hypocretin, acting at its receptors, may effect changes which suggest that it should be properly categorized as a stress-responsive system. However, less is known about the interactions and connectivity of some of these different neuropeptide and receptor systems, and in particular, about the possible connectivity of fast-acting (e.g., glutamate and GABA) and slow-acting (including dopamine, serotonin, and norepinephrine) neurotransmitters with each of these stress-responsive components and the resultant impact, especially in the setting of chronic exposure to drugs of abuse. Several of these stress-responsive systems and components, primarily based on our laboratory-based and human molecular genetics research of addictive diseases, will be briefly discussed in this review.

MCAD mutations identified in newborn screening cause different levels of enzymatic dysfunction

Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screeningMaier et al. (2009)Human Molecular Genetics 18: 1612–1623

‘ERAD'icating Mislocalized Proteins in an Acromesomelic Dwarfism Disorder

Defective cellular trafficking of missense NPR‐B mutants is the major mechanism underlying acromesomelic dysplasia‐type MaroteauxHume et al. (2009)Human Molecular Genetics 18: 267–277

LRRK2 G2385R modulates age at onset in Parkinson's disease: A multi‐center pooled analysis

American Journal of Medical Genetics Part B: Neuropsychiatric GeneticsVolume 150B, Issue 7 p. 1022-1023 Letter to the Editor LRRK2 G2385R modulates age at onset in Parkinson's disease: A multi-center pooled analysis† E.K. Tan, E.K. Tan Departments of Neurology and Clinical Research, Singapore General Hospital, National Neuroscience Institute, Singapore, Singapore Duke-NUS Graduate Medical School, Singapore, SingaporeSearch for more papers by this authorR. Peng, R. Peng Department of Neurology, West China Hospital, Sichuan University, Chengdu, ChinaSearch for more papers by this authorY.R. Wu, Y.R. Wu Department of Neurology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei, TaiwanSearch for more papers by this authorR.M. Wu, R.M. Wu Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, TaiwanSearch for more papers by this authorY.H. Wu-Chou, Y.H. Wu-Chou Human Molecular Genetics Laboratory, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei, TaiwanSearch for more papers by this authorL.C. Tan, L.C. Tan Departments of Neurology and Clinical Research, Singapore General Hospital, National Neuroscience Institute, Singapore, SingaporeSearch for more papers by this authorX.K. An, X.K. An Department of Neurology, West China Hospital, Sichuan University, Chengdu, ChinaSearch for more papers by this authorC.M. Chen, C.M. Chen Department of Neurology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei, TaiwanSearch for more papers by this authorS. Fook-Chong, S. Fook-Chong Departments of Neurology and Clinical Research, Singapore General Hospital, National Neuroscience Institute, Singapore, SingaporeSearch for more papers by this authorC.S. Lu, Corresponding Author C.S. Lu c81214@adm.cgmh.org.tw Department of Neurology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei, TaiwanDepartment of Neurology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei, Taiwan, No. 5, Fu-Shin Street, Kweishan, Taoyuan 33305, Taiwan.Search for more papers by this author E.K. Tan, E.K. Tan Departments of Neurology and Clinical Research, Singapore General Hospital, National Neuroscience Institute, Singapore, Singapore Duke-NUS Graduate Medical School, Singapore, SingaporeSearch for more papers by this authorR. Peng, R. Peng Department of Neurology, West China Hospital, Sichuan University, Chengdu, ChinaSearch for more papers by this authorY.R. Wu, Y.R. Wu Department of Neurology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei, TaiwanSearch for more papers by this authorR.M. Wu, R.M. Wu Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, TaiwanSearch for more papers by this authorY.H. Wu-Chou, Y.H. Wu-Chou Human Molecular Genetics Laboratory, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei, TaiwanSearch for more papers by this authorL.C. Tan, L.C. Tan Departments of Neurology and Clinical Research, Singapore General Hospital, National Neuroscience Institute, Singapore, SingaporeSearch for more papers by this authorX.K. An, X.K. An Department of Neurology, West China Hospital, Sichuan University, Chengdu, ChinaSearch for more papers by this authorC.M. Chen, C.M. Chen Department of Neurology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei, TaiwanSearch for more papers by this authorS. Fook-Chong, S. Fook-Chong Departments of Neurology and Clinical Research, Singapore General Hospital, National Neuroscience Institute, Singapore, SingaporeSearch for more papers by this authorC.S. Lu, Corresponding Author C.S. Lu c81214@adm.cgmh.org.tw Department of Neurology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei, TaiwanDepartment of Neurology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei, Taiwan, No. 5, Fu-Shin Street, Kweishan, Taoyuan 33305, Taiwan.Search for more papers by this author First published: 16 January 2009 https://doi.org/10.1002/ajmg.b.30923Citations: 24 † How to Cite this Article: Tan EK, Peng R, Wu YR, Wu RM, Wu-Chou YH, Tan LC, An XK, Chen CM, Fook-Chong S Lu CS. 2009. LRRK2 G2385R Modulates Age at Onset in Parkinson's Disease: A Multi-Center Pooled Analysis. Am J Med Genet Part B 150B:1022–1023. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume150B, Issue75 October 2009Pages 1022-1023 RelatedInformation

Apolipoprotein CIII and Atherosclerosis

The prevailing concept of mechanisms responsible for the development of atherosclerotic lesions largely focuses on the accumulation and retention of low-density lipoproteins in the arterial intima and their subsequent oxidative modification. This oxidation leads to activation of the endothelium, and particularly, expression of adhesion molecules that mediate leukocyte adherence and chemokines which initiate the inflammation reaction that is widely accepted as being responsible for the development and progression of atherosclerotic lesions.1,2 There is also a strong body of evidence to indicate that elevated triacylglycerides (triglycerides) are an independent risk factor for atherosclerosis.3–5 Article p 731 One mechanism that can contribute to elevated triglycerides involves apolipoprotein CIII (apoCIII). apoCIII is a small protein that resides on the surface of very-low-density lipoproteins (VLDLs), low-density lipoproteins, chylomicrons, and high-density lipoproteins (Figure). It exists as multiple species, as either a nonglycosylated isoform (apoCIIIo) or a glycosylated isoform (apoCIII1 or apoCIII2); all three isoforms have similar plasma half-lives and probably have very similar physiological functions. Increased apoCIII production is a characteristic feature of patients with hypertriglyceridemia,6 and plasma apoCIII levels have been positively correlated with plasma triacylglycerol concentrations and also have been associated with severity of hypertriglyceridemia.7 Elevated plasma apoCIII concentration and, specifically, accumulation of apoCIII in triacylglycerol-rich lipoproteins is casually related to hypertriglyceridemia in patients with metabolic syndrome and has also been associated with insulin resistance.8 apoCIII is a major regulator of lipolysis, as it noncompetitively inhibits endothelial-bound lipoprotein lipase, the enzyme that hydrolyzes triacylglycerols in …

FACIAL EMOTION IDENTIFICATION AND EXPRESSION IN SCHIZOPHRENIA: LESSONS FROM IMAGE ANALYSIS OF BRAINS AND FACES

s / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279 3 compared to the castrated monkeys (p=0.019). On the other hand, the intact monkey showed no difference in latency to retrieve a treat when it was placed in front of the fear-invoking plastic snake (p=0.18). Conclusions: The castrated monkeys showed longer latency in response to the threatening face of another monkey, but no difference in latency in response to an innately fear-provoking object. This suggests that specific behavioral responses particularly those involving responses to emotional faces may be more sensitive to late maturational changes in sex steroids.

Sarcomere Mutations in Cardiomyopathy, Noncompaction, and the Developing Heart

In this issue of Circulation , Klaassen and colleagues1 describe mutations in the genes encoding myosin heavy chain (MHC), cardiac actin, and troponin T in patients with left ventricular noncompaction (LVNC). LVNC, defined as excessive and unusual trabeculation of the mature left ventricle, is thought to reflect a developmental failure of the heart to form fully the compact myocardium during the later stages of cardiac development. Previously, mutations in sarcomeric genes have been linked extensively to the development of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). The finding of similar, but not identical, mutations in patients with LVNC suggests a continuum of cardiomyopathy that includes LVNC and further supports the essential role for normal sarcomere function during cardiac development. Article p 2893 Noncompaction of the ventricular myocardium is characterized by a spongy morphological appearance of the myocardium occurring primarily in the left ventricle and most evident in the apical portion.2 Noncompaction often is visualized as deep recesses within the thickened apex, and these sinusoids communicate with the ventricular cavity. During heart development, the myocardium is initially trabeculated during a period before coronary artery development and is thought to be an adaptation to provide blood flow to the developing myocardium. The development of the coronary vasculature is associated temporally with the loss of trabeculae and the full maturation of the compact myocardium. Between embryonic weeks 5 and 8, the trabeculae regress as the compact myocardium develops from base to apex. Isolated LVNC is defined as occurring in the absence of other cardiac structural malformation. Nonsyndromic LVNC refers to the absence of other extracardiac developmental disorders. In 2006, the American Heart Association scientific statement on classification of cardiomyopathies reclassified LVNC as its own disease entity.3 Klaassen et al now link genetic sarcomere defects to both familial and sporadic isolated, …

Stems cells and regeneration: Special Review Issue

Stems cells and regeneration: Special Review Issue

Clinical and molecular genetics of acromegaly: MEN1, Carney complex, McCune–Albright syndrome, familial acromegaly and genetic defects in sporadic tumors

Pituitary tumors are among the most common neoplasms in man; they account for approximately 15% of all primary intracranial lesions (Jagannathan et al., Neurosurg Focus, 19:E4, 2005). Although almost never malignant and rarely clinically expressed, pituitary tumors may cause significant morbidity in affected patients. First, given the critical location of the gland, large tumors may lead to mass effects, and, second, proliferation of hormone-secreting pituitary cells leads to endocrine syndromes. Acromegaly results from oversecretion of growth hormone (GH) by the proliferating somatotrophs. Despite the significant efforts made over the last decade, still little is known about the genetic causes of common pituitary tumors and even less is applied from this knowledge therapeutically. In this review, we present an update on the genetic syndromes associated with pituitary adenomas and discuss the related genetic defects. We next review findings on sporadic, non-genetic, pituitary tumors with an emphasis on pathways and animal models of pituitary disease. In conclusion, we attempt to present an overall, integrative approach to the human molecular genetics of both familiar and sporadic pituitary tumors.

On the necessity of different statistical treatment for Illumina BeadChip and Affymetrix GeneChip data and its significance for biological interpretation

BackgroundThe original spotted array technology with competitive hybridization of two experimental samples and measuring relative expression levels is increasingly displaced by more accurate platforms that allow determining absolute expression values for a single sample (for example, Affymetrix GeneChip and Illumina BeadChip). Unfortunately, cross-platform comparisons show a disappointingly low concordance between lists of regulated genes between the latter two platforms.ResultsWhereas expression values determined with a single Affymetrix GeneChip represent single measurements, the expression results obtained with Illumina BeadChip are essentially statistical means from several dozens of identical probes. In the case of multiple technical replicates, the data require, therefore, different stistical treatment depending on the platform. The key is the computation of the squared standard deviation within replicates in the case of the Illumina data as weighted mean of the square of the standard deviations of the individual experiments. With an Illumina spike experiment, we demonstrate dramatically improved significance of spiked genes over all relevant concentration ranges. The re-evaluation of two published Illumina datasets (membrane type-1 matrix metalloproteinase expression in mammary epithelial cells by Golubkov et al. Cancer Research (2006) 66, 10460; spermatogenesis in normal and teratozoospermic men, Platts et al. Human Molecular Genetics (2007) 16, 763) significantly identified more biologically relevant genes as transcriptionally regulated targets and, thus, additional biological pathways involved.ConclusionThe results in this work show that it is important to process Illumina BeadChip data in a modified statistical procedure and to compute the standard deviation in experiments with technical replicates from the standard errors of individual BeadChips. This change leads also to an improved concordance with Affymetrix GeneChip results as the spermatogenesis dataset re-evaluation demonstrates.ReviewersThis article was reviewed by I. King Jordan, Mark J. Dunning and Shamil Sunyaev.

'Private fears in public places?' Ethical and regulatory concerns regarding human genomic databases.

Barbara Prainsack1† & David Gurwitz2 †Author for correspondence 1King’s College London, Centre for Biomedicine & Society (CBAS), Strand, London, WC2R 2LS, UK Tel.: +44 (0)20 7848 1585; E-mail: barbara.prainsack@ kcl.ac.uk 2National Laboratory for the Genetics of Israeli Populations, Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel Tel.: +972 3640 7611; Fax: +972 3640 7611; E-mail: gurwitz@post.tau.ac.il ‘...the increasing prevalence of large public databases and the uncertainty surrounding their potential future uses drives public fears and raises questions regarding their legitimacy in the era of the internet.’