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1.
The search for migraine genes: an overview of current knowledge 总被引:3,自引:0,他引:3
Colson NJ Fernandez F Lea RA Griffiths LR 《Cellular and molecular life sciences : CMLS》2007,64(3):331-344
Migraine is a complex familial condition that imparts a significant burden on society. There is evidence for a role of genetic
factors in migraine, and elucidating the genetic basis of this disabling condition remains the focus of much research. In
this review we discuss results of genetic studies to date, from the discovery of the role of neural ion channel gene mutations
in familial hemiplegic migraine (FHM) to linkage analyses and candidate gene studies in the more common forms of migraine.
The success of FHM regarding discovery of genetic defects associated with the disorder remains elusive in common migraine,
and causative genes have not yet been identified. Thus we suggest additional approaches for analysing the genetic basis of
this disorder. The continuing search for migraine genes may aid in a greater understanding of the mechanisms that underlie
the disorder and potentially lead to significant diagnostic and therapeutic applications.
Received 16 December 2005; received after revision 9 October 2006; accepted 13 November 2006 相似文献
2.
3.
Hearing molecules: contributions from genetic deafness 总被引:1,自引:0,他引:1
Considerable progress has been made over the past decade identifying many genes associated with deafness. With the identification
of these hereditary deafness genes and the proteins they encode, molecular elements of basic hearing mechanisms emerge. As
functional studies of these molecular elements become available, we can put together the pieces of the puzzle and begin to
reach an understanding of the molecular mechanisms of hearing. The goal of this review is to discuss studies over the past
decade that address the function of the proteins implicated in genetic deafness and to place them in the context of basic
molecular mechanisms in hearing. The first part of this review highlights structural and functional features of the cochlea
and auditory nerve. This background will provide a context for the second part, which addresses the molecular mechanisms underlying
cochlear function as elucidated by genetic causes of deafness.
Received 20 September 2006; received after revision 24 October 2006; accepted 5 December 2006 相似文献
4.
Garg V 《Cellular and molecular life sciences : CMLS》2006,63(10):1141-1148
Cardiovascular malformations are the most common type of birth defect and result in significant mortality worldwide. The etiology
for the majority of these anomalies remains unknown. Advances in the characterization of the molecular pathways critical for
normal cardiac development have led to the identification of numerous genes necessary for this complex morphogenetic process.
This work has aided the discovery of an increasing number of single genes being implicated as the cause of human cardiovascular
malformations. This review summarizes normal cardiac development and outlines the recent discoveries of the genetic causes
of congenital heart disease.
Received 4 November 2005; received after revision 14 January 2006; accepted 1 February 2006 相似文献
5.
Peter A. Doris 《Cellular and molecular life sciences : CMLS》2012,69(22):3751-3763
Hypertensive renal disease occurs at increased frequency among the relatives of patients with this disease compared to individuals who lack a family history of disease. This suggests a heritable risk in which genetic variation may play a role. These observations have motivated a search for genetic variation contributing to this risk in both experimental animal models and in human populations. Studies of animal models indicate the capacity of natural genetic variants to contribute to disease risk and have produced a few insights into the disease mechanism. In its current phase, human population genetic studies have sought to associate genetic variation with disease in large populations by testing genotypes at a large number of common genetic variations in the genome, expecting that common genetic variants contributing to renal disease risk will be identified. These genome-wide association studies (GWAS) have been productive and are a clear technical success; they have also identified narrowly defined loci and genes containing variation contributing to disease risk. Further extension and refinement of these GWAS are likely to extend this success. However, it is also clear that few additional variants with substantial effects accounting for the greatest part of heritability will be uncovered by GWAS. This raises an interesting biological question regarding where the remaining unaccounted heritable risk may be located. At present, much consideration is being given to this question and to the challenge of testing hypotheses that lead from the various alternative mechanisms under consideration. One result of the progress of GWAS is likely to be a renewed interest in mechanisms by which related individuals can share and transmit traits independently of Mendelian inheritance. This paper reviews the current progress in this area and considers other mechanisms by which familial aggregation of risk for renal disease may arise. 相似文献
6.
Focal and segmental glomerulosclerosis 总被引:3,自引:0,他引:3
An increasing cause of end-stage renal disease is the pathological lesion focal and segmental glomerulosclerosis (FSGS). FSGS
is characterized by proteinuria and frequently nephrotic syndrome with ensuing renal failure. The etiology remains unknown
in the majority of individuals. The idiopathic form of FSGS is most common; however, secondary forms of FSGS do exist. There
is a form of FSGS that is fulminant that frequently recurs after renal transplantation with an estimated frequency of approximately
30%, suggesting that the pathogenesis is not solely a result of intrinsic kidney disease. Recently, hereditary forms of the
disease were recognized as well as those associated with other congenital syndromes. Known genetic causes of the hereditary
form of this disease have been suggested to account for upwards of 18% of cases. This review will address recent discoveries
of the genetic mechanisms of hereditary FSGS and the current interpretations of their interactions at the slit diaphragm.
Received 17 April 2006; received after revision 23 May 2006; accepted 6 July 2006 相似文献
7.
Kallmann’s syndrome, a neuronal migration defect 总被引:1,自引:0,他引:1
Infertility and inability to smell are the phenotypical features of Kallmann’s syndrome (KS), a genetic disease which affects
1 in 10,000 males and 1 in 50,000 females, the majority of the cases being sporadic. The molecular pathogenesis of KS is complex
but mainly referable to the impairment of olfactory axon development and of the migration of gonadotropin-releasing hormone
(GnRH) neurons. Only two different genes have been identified so far as responsible for the disease: KAL1 and KAL2, encoding
anosmin-1 and fibroblast growth factor receptor 1 (FGFR1), respectively. In this review we focus our attention on insights
evoked by recent studies, which propose a new direct role for anosmin-1 in the migration GnRH neurons, and a fascinating hypothesis
of interactions between anosmin-1 and FGFR1 systems.
Received 23 December 2005; received after revision 31 May 2006; accepted 6 July 2006 相似文献
8.
Obesity is a multifactorial and heterogeneous condition that results from alterations of various genes, each having a partial
and additive effect. The inheritance pattern of obesity is thus complex, and environmental factors play an important role
in promoting or delaying its development. The identification of susceptibility genes and genetic variants for obesity requires
various methodological approaches. Obesity is classified into three main categories on the basis of genetic etiology: monogenic,
syndromic, and polygenic obesity. Here we review monogenic and syndromic obesity. We also review the linkage analysis studies
followed by the candidate gene approaches and genome-wide association studies. Identification of the underlying genetic causes
of obesity will likely provide a basis both for the development of new therapeutic agents and for the personalized prevention
of this condition.
Received 2 October 2007; received after revision 15 November 2007; accepted 19 November 2007 相似文献
9.
Nutrigenomics has the potential to tailor diets to optimize health, based on knowledge of key genetic polymorphisms. Identification
of candidate genes is often based on a priori knowledge of disease processes. However, genome-wide association methods are not only validating previously identified genes
and polymorphisms, but also revealing new gene-disease associations not anticipated from prior knowledge. In Crohn’s disease
(CD), such studies not only confirm the importance of caspase-activated recruitment domain 15 and major histocompatability
complex II molecules, but also reveal strong associations with the proinflammatory cytokine interleukin-23 receptor and autophagy-related
16-like gene. Genes identified to date in CD can be linked into two interrelated pathways: receptor-mediated cytokine induction
or autophagocytosis. New genomic technologies need to be matched with innovative methodologies to characterize the likely
impact of foods and to take the field to another dimension of value for human diet development and optimized health.
Received 2 July 2007; received after revision 31 July 2007; accepted 29 August 2007 相似文献
10.
Recent advances in the genetics of schizophrenia 总被引:13,自引:0,他引:13
Waterwort DM Bassett AS Brzustowicz LM 《Cellular and molecular life sciences : CMLS》2002,59(2):331-348
The genetic etiology of schizophrenia, a common and debilitating psychiatric disorder, is supported by a wealth of data.
Review of the current findings suggests that considerable progress has been made in recent years, with a number of chromosomal
regions consistently implicated by linkage analysis. Three groups have shown linkage to 1q21-22 using similar models, with
HLOD scores of 6.5, 3.2, and 2.4. Other replicated loci include 13q32 that has been implicated by two independent groups with
significant HLOD scores (4.42) or NPL values (4.18), and 5p14.1-13.1, 5q21-33, 8p21-22, and 10p11-15, each of which have been
reported as suggestive by at least three separate groups. Different studies have also replicated evidence for a modest number
of candidate genes that were not ascertained through linkage. Of these, the greatest support exists for the DRD3 (3q13.3),
HTR2A (13q14.2), and CHRNA7 (15q13-q14) genes. The refinement of phenotypes, the use of endophenotypes, reduction of heterogeneity,
and extensive genetic mapping have all contributed to this progress. The rapid expansion of information from the human genome
project will likely further accelerate this progress and assist in the discovery of susceptibility genes for schizophrenia.
A greater understanding of disease mechanisms and the application of pharmacogenetics should also lead to improvements in
therapeutic interventions.
Received 11 May 2001; received after revision: 20 July 2001; accepted 18 September 2001 相似文献
11.
Genetic factors affect sleep. Studies in twin pairs demonstrate that the strong hereditary influences on sleep architecture
and some sleep disorders are transmitted through families. Evidence like this strongly suggests that sleep regulation receives
significant influence from genetic factors. Although recent molecular technologies have revealed evidence that genetic traits
or gene products trigger particular changes in sleep electroencephalogram activity, we are still far from finding candidate
genes or multiple mutations responsible for individual sleep disorders. Sleep is a very complex phenotype. Genetic susceptibility
and environmental factors should be also considered as contributors to sleep phenotype. The aim of this review is to present
a current summary and future prospects for genetic studies on sleep and selected sleep-associated disorders.
An erratum to this article is available at . 相似文献
12.
From a handful of uncloned genetic loci 6 years ago, great strides have been made in understanding the genetic and molecular
aetiology of Bardet-Biedl syndrome (BBS), a rare pleiotropic disorder characterised by a multitude of symptoms, including
obesity, retinal degeneration and cystic kidneys. Presently, 11 BBS genes have been cloned, with the likelihood that yet more BBS genes remain undiscovered. In 2003, a major breakthrough was made when it was shown that BBS is likely caused by defects
in basal bodies and/or primary cilia. Since then, studies in numerous animal models of BBS have corroborated the initial findings
and, in addition, have further refined the specific functions of BBS proteins. These include roles in establishing planar
cell polarity (noncanonical Wnt signaling) in mice and zebrafish, modulating intraflagellar transport and lipid homeostasis
in worms, and regulating intracellular trafficking and centrosomal functions in zebrafish and human tissue culture cells.
From these discoveries, a common theme has emerged, namely that the primary function of BBS proteins may be to mediate and
regulate microtubule-based intracellular transport processes.
Received 20 April 2006; received after revision 30 May 2006; accepted 15 June 2006 相似文献
13.
Peutz-Jeghers syndrome (PJS, OMIM 175200) is an unusual inherited intestinal polyposis syndrome associated with distinct peri-oral
blue/black freckling [1–9]. Variable penetrance and clinical heterogeneity make it difficult to determine the exact frequency
of PJS [4]. PJS is a cancer predisposition syndrome. Affected individuals are at high risk for intestinal and extra-intestinal
cancers. In 1997, linkage studies mapped PJS to chromosome 19p [10, 11], and subsequently a serine/threonine kinase gene defect
(LKB1) was noted in a majority of PJS cases [12, 13]. A phenotypically similar syndrome has been produced in an LKB1 mouse
knockout model [14–18]. Several PJS kindred without LKB1 mutations have been described, suggesting other PJS loci [19–22].
The management of PJS is complex and evolving. New endoscopic technologies may improve management of intestinal polyposis.
Identification of specific genetic mutations and their targets will more accurately assess the clinical course, and help gage
the magnitude of cancer risk for affected individuals.
Received 20 February 2006; received after revision 5 May 2006; accepted 15 June 2006 相似文献
14.
Garbern JY 《Cellular and molecular life sciences : CMLS》2007,64(1):50-65
Pelizaeus-Merzbacher disease (PMD) and the allelic spastic paraplegia type 2 (SPG2) arise from mutations in the X-linked gene
encoding myelin proteolipid protein (PLP). Analysis of mutations affecting PLP, the major protein in central nervous system
myelin, has revealed previously unsuspected roles for myelinating glia in maintaining the integrity of the nervous system.
The disease spectrum for PMD and SPG2 is extraordinarily broad and can be best understood by accounting not only for the wide
range of mutations that can occur but also for the effects of PLP1 mutations on both cell autonomous and non-cell autonomous processes in myelinating cells. Appreciating the wide range of
genetic and cellular effects of PLP1 mutations is important for patient and family counseling, understanding disease pathogenesis, and, ultimately, for developing
future disease-specific therapies.
Received 24 April 2006; received after revision 3 July 2006; accepted 9 October 2006 相似文献
15.
Talos IF Mian AZ Zou KH Hsu L Goldberg-Zimring D Haker S Bhagwat JG Mulkern RV 《Cellular and molecular life sciences : CMLS》2006,63(10):1106-1124
The introduction and development, over the last three decades, of magnetic resonance (MR) imaging and MR spectroscopy technology
for in vivo studies of the human brain represents a truly remarkable achievement, with enormous scientific and clinical ramifications.
These effectively non-invasive techniques allow for studies of the anatomy, the function and the metabolism of the living
human brain. They have allowed for new understandings of how the healthy brain works and have provided insights into the mechanisms
underlying multiple disease processes which affect the brain. Different MR techniques have been developed for studying anatomy,
function and metabolism. The primary focus of this review is to describe these different methodologies and to briefly review
how they are being employed to more fully appreciate the intricacies associated with the organ, which most distinctly differentiates
the human species from the other animal forms on earth.
Received 1 November 2005; received after revision 11 January 2006; accepted 25 January 2006 相似文献
16.
The recent identification of candidate receptor genes for sweet, umami and bitter taste in mammals has opened a door to elucidate the molecular and neuronal mechanisms of taste. Drosophila provides a suitable system to study the molecular, physiological and behavioral aspects of taste, as sophisticated molecular genetic techniques can be applied. A gene family for putative gustatory receptors has been found in the Drosophila genome. We discuss here current knowledge of the gustatory physiology of Drosophila. Taste cells in insects are primary sensory neurons whereupon each receptor neuron responds to either sugar, salt or water. We found that particular tarsal gustatory sensilla respond to bitter compounds. Electrophysiological studies indicate that gustatory sensilla on the labellum and tarsi are heterogeneous in terms of their taste sensitivity. Determination of the molecular bases for this heterogeneity could lead to an understanding of how the sensory information is processed in the brain and how this in turn is linked to behavior.Received 12 May 2003; received after revision 9 June 2003; accepted 13 June 2003 相似文献
17.
18.
Comparative genome analyses reveal that most functional domains of human genes have homologs in widely divergent species.
These shared functional domains, however, are differentially shuffled among evolutionary lineages to produce an increasing
number of domain architectures. Combined with duplication and adaptive evolution, domain shuffling is responsible for the
great phenotypic complexity of higher eukaryotes. Although the domain-shuffling hypothesis is generally accepted, determining
the molecular mechanisms that lead to domain shuffling and novel gene creation has been challenging, as sequence features
accompanying the formation of known genes have been obscured by accumulated mutations. The growing availability of genome
sequences and EST databases allows us to study the characteristics of newly emerged genes. Here we review recent genome-wide
DNA and EST analyses, and discuss the three major molecular mechanisms of gene formation: (1) atypical spicing, both within
and between genes, followed by adaptation, (2) tandem and interspersed segmental duplications, and (3) retrotransposition
events.
Received 18 October 2006; received after revision 18 November 2006; accepted 28 November 2006 相似文献
19.
The molecular architecture of tight junctions has been a subject of extensive studies that have shown tight junctions to be
composed of many peripheral and integral membrane proteins. Claudins have been considered the main tight junction-forming
proteins; however, the role they play in a series of pathophysiological events, including human carcinoma development, is
only now beginning to be understood. Increasing evidence from in vitro and in vivo studies have identified the influence of claudins on tight junction structure and function, although claudins also participate
in cellular contexts other than tight junctions. The aim of this review is to summarize and discuss the conceptual framework
concerning claudins, focusing on the involvement of these proteins in epithelial cell polarity establishment, paracellular
transport control, signal transduction and tumorigenesis.
Received 5 July 2006; received after revision 29 August 2006; accepted 29 September 2006 相似文献
20.
Cristina Lanni Marco Racchi Stefano Govoni 《Cellular and molecular life sciences : CMLS》2013,70(18):3327-3340
This review examines the role of drug metabolism and drug target polymorphism in determining the clinical response to antidepressants. Even though antidepressants are the most effective available treatment for depressive disorders, there is still substantial need for improvement due to the slow onset of appreciable clinical improvement and the association with side effects. Moreover, a substantial group of patients receiving antidepressant therapy does not achieve remission or fails to respond entirely. Even if the large variation in antidepressant treatment outcome across individuals remains poorly understood, one possible source of this variation in treatment outcome are genetic differences. The review focuses on a few polymorphisms which have been extensively studied, while reporting a more comprehensive reference to the existing literature in table format. It is relatively easy to predict the effect of polymorphisms in drug metabolizing enzymes, such as cytochromes P450 2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19), which may be determined in the clinical context in order to explain or prevent serious adverse effects. The role of target polymorphism, however, is much more difficult to establish and may be more relevant for disease susceptibility and presentation rather than for response to therapy. 相似文献