Hearing molecules: contributions from genetic deafness

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     

The search for migraine genes: an overview of current knowledge

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     

The role of inflammation in sporadic and familial Parkinson’s disease

The etiology of Parkinson’s disease (PD) is complex and most likely involves numerous environmental and heritable risk factors. Interestingly, many genetic variants, which have been linked to familial forms of PD or identified as strong risk factors, also play a critical role in modulating inflammatory responses. There has been considerable debate in the field as to whether inflammation is a driving force in neurodegeneration or simply represents a response to neuronal death. One emerging hypothesis is that inflammation plays a critical role in the early phases of neurodegeneration. In this review, we will discuss emerging aspects of both innate and adaptive immunity in the context of the pathogenesis of PD. We will highlight recent data from genetic and functional studies that strongly support the theory that genetic susceptibility plays an important role in modulating immune pathways and inflammatory reactions, which may precede and initiate neuronal dysfunction and subsequent neurodegeneration. A detailed understanding of such cellular and molecular inflammatory pathways is crucial to uncover pathogenic mechanisms linking sporadic and hereditary PD and devise tailored neuroprotective interventions.     

The human genome and understanding of common disease: present and future technologies

The study of candidate genes over the past three decades has yielded notable successes in common-disease genetics. During this time, however, interpretation of genetic association studies has been hampered by the use of clinical cohorts of inadequate power and insufficient information on genetic variation in candidate genes. The unavailability of highthroughput and low-cost genotyping technologies has also limited the scope of complex-disease genetic studies. More recently, however, the sequencing and characterization of variation within the human genome has revolutionized genetic studies and enabled full genome-wide scans for genes associated with disease. The identification of disease-associated (causative) genes has illuminated disease mechanisms. The translation of this knowledge into direct clinical benefit in diagnosis, prognosis and therapy for an individual’s disease still remains a challenge. Received 11 September 2006; received after revision 17 December 2006; accepted 18 January 2007     

The polycystins: a novel class of membrane-associated proteins involved in renal cystic disease

Polycystin-1, polycystin-2 and polycystin-L are the predicted protein products of the PKD1, PKD2 and PKDL genes, respectively. Mutations in PKD1 and PKD2 are responsible for almost all cases of autosomal dominant polycystic kidney disease (ADPKD). This condition is one of the commonest mendelian disorders of man with a prevalence of 1:800 and is responsible for nearly 10% of cases of end-stage renal failure in adults. The cloning of PKD1 and PKD2 in recent years has provided the initial steps in defining the mechanisms underlying renal cyst formation in this condition, with the aim of defining pharmacological and genetic interventions that may ameliorate the diverse and often serious clinical manifestations of this disease. The PKD genes share regions of sequence similarity, and all predict integral membrane proteins. Whilst the predicted protein domain structure of polycystin-1 suggests it is involved in cell-cell or cell-matrix interactions, the similarity of polycystin-2 and polycystin-L to the pore-forming domains of some cation channels suggests that they all form subunits of a large plasma membrane ion channel. In the few years since the cloning of the PKD genes, a consensus that defines the range of mutations, expression pattern, interactions and functional domains of these genes and their protein products is emerging. This review will therefore attempt to summarise these data and provide an insight in to the key areas in which polycystin research is unravelling the mechanisms involved in renal cyst formation. Received 22 February 1999; received after revision 5 July 1999; accepted 6 July 1999     

Heritable trinucleotide repeats and neurological disorders

In the past 3 years, seven human neurological disorders have been found to be associated with an abnormal number of unstable trinucleotide repeats within exons or non-expressed regions of a gene. These forms of mutations are called dynamic mutations. The expansion in copy number of trinucleotide repeats may represent a large number of hereditary disorders. The correlation between the length of the repeated size and the disease severity and variable onset has provided some genetic explanation for a phenomenon called anticipation. However, there are numerous questions which cannot be explained by anticipation. Many other factors such as genomic imprinting and variable DNA methylation may also contribute to the puzzling features of these phenotypes.     

Cell culture models and animal models for studying the patho-physiological role of renal aquaporins

Aquaporins (AQPs) are key players regulating urinary-concentrating ability. To date, eight aquaporins have been characterized and localized along the nephron, namely, AQP1 located in the proximal tubule, thin descending limb of Henle, and vasa recta; AQP2, AQP3 and AQP4 in collecting duct principal cells; AQP5 in intercalated cell type B; AQP6 in intercalated cells type A in the papilla; AQP7, AQP8 and AQP11 in the proximal tubule. AQP2, whose expression and cellular distribution is dependent on vasopressin stimulation, is involved in hereditary and acquired diseases affecting urine-concentrating mechanisms. Due to the lack of selective aquaporin inhibitors, the patho-physiological role of renal aquaporins has not yet been completely clarified, and despite extensive studies, several questions remain unanswered. Until the recent and large-scale development of genetic manipulation technology, which has led to the generation of transgenic mice models, our knowledge on renal aquaporin regulation was mainly based on in vitro studies with suitable renal cell models. Transgenic and knockout technology approaches are providing pivotal information on the role of aquaporins in health and disease. The main goal of this review is to update and summarize what we can learn from cell and animal models that will shed more light on our understanding of aquaporin-dependent renal water regulation.     

Vasopressin antagonists

Effects of vasopressin via V1a- and V2-receptors are closely implicated in a variety of water-retaining diseases and cardiovascular diseases, including heart failure, hyponatraemia, hypertension, renal diseases, syndrome of inappropriate antidiuretic hormone secretion, cirrhosis and ocular hypertension. As vasopressin receptors are found in many different tissues, vasopressin antagonists may benefit the treatment of disorders such as cerebral ischaemia and stroke, Raynaud’s disease, dysmenorrhoea and tocolytic treatment. V1b selective vasopressin antagonists are discussed in terms of their usefulness in the treatment of emotional and psychiatric disorders. The vaptans are vasopressin receptor antagonists with V1a (relcovaptan) or V2 (tolvaptan, lixivaptan) selectivity or non-selective activity (conivaptan) which may be advantageous in some disorders. The V1a/V2 non-selective vasopressin antagonist conivaptan is the first vaptan which is approved by the FDA for the treatment of euvolaemic hyponatraemia. Received 3 February 2006; received after revision 16 March 2006; accepted 26 April 2006     

Pelizaeus-Merzbacher disease: Genetic and cellular pathogenesis

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     

Kallmann’s syndrome, a neuronal migration defect

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     

Potassium-related inherited tubulopathies

Hyper- and hypokalemia may carry severe clinical consequences. Different regulatory mechanisms, including the kidney, exert a tight regulation of plasma potassium levels. The renal pathway of potassium handling begins in the proximal tubule followed by the fine-tuning of its secretion or absorption at the distal tubule, including the thick ascending limb of Henle’s loop, the distal convoluted tubule and the cortical collecting duct. Genetic studies in recent years have clarified the role of specific tubular channels and transporters in the pathogenesis of unique hyper- and hypokalemic tubulopathies, some of them non-hypertensive (pseudohypoaldosteronism, Bartter and Gitelman syndromes) and others hypertensive by definition (including Liddle and Gordon syndromes). This article reviews the genetic and clinical spectrum of hypokalemic and hyperkalemic tubulopathies. Received 13 January 2006; received after revision 19 March 2006; accepted 18 May 2006     

Genetic susceptibility to hypertensive renal disease

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.     

Genetic variability in 3 co-occurring forms of the starfish genusOthilia (=Echinaster)

Summary High levels of genetic variability have been found in 3 (grey, brown, orange) co-occurring forms of the starfishOthilia. These high levels appear to correspond to the generalistic habit of this starfish. The biochemical data, coupled with morphological observations, indicate that the grey and orange forms are morphs of the same species and that the brown form is a species separate from the grey and orange forms.     

Structural characterization of two papaya chitinases, a family GH19 of glycosyl hydrolases

Two chitinases, able to use tetra-N-acetylglucosamine, chitin and chitosan as substrates, were characterized after purification from Carica papaya latex. The complete amino acid sequence of the major form and about 40% of the minor one were determined through proteolytic digestions and mass spectroscopy analysis. Sequencing demonstrated that both papaya chitinases are members of the family 19 of glycosyl hydrolases (GH19). Based on the known 3-D structures of other members of family GH19, it was expected that papaya chitinases would adopt all-alpha structures. However, circular dichroism and infrared spectroscopy indicated, for the papaya chitinases, a content of 15–20% of extended structures besides the expected 40% of alpha helices. Since the fully sequenced papaya chitinase contains a large number of proline residues the possibility that papaya chitinase contains polyproline II stretches was examined in the context of their resistance against proteolytic degradation. Received 11 July 2006; received after revision 13 October 2006; accepted 25 October 2006     

Giant axonal neuropathy

Giant axonal neuropathy (GAN) is a rare autosomal recessive disorder affecting both the central and peripheral nervous systems. Cytopathologically, the disorder is characterized by giant axons with derangements of cytoskeletal components. Geneticists refined the chromosomal interval containing the locus, culminating in the cloning of the defective gene, GAN. To date, many distinct mutations scattered throughout the coding region of the locus have been reported by researchers from different groups around the world. GAN encodes the protein, gigaxonin. Recently, a genetic mouse model of the disease was generated by targeted disruption of the locus. Over the years, the molecular mechanisms underlying GAN have attracted much interest. Studies have revealed that gigaxonin appears to play an important role in cytoskeletal functions and dynamics by directing ubiquitin-mediated degradations of cytoskeletal proteins. Aberrant accumulations of cytoskeletal-associated proteins caused by a defect in the ubiquitinproteasome system (UPS) have been shown to be responsible for neurodegeneration occurring in GAN-null neurons, providing strong support for the notion that UPS plays crucial roles in cytoskeletal functions and dynamics. However, many key questions about the disease remain unanswered. Received 6 September 2006; received after revision 11 October 2006; accepted 5 December 2006 Y. Yang, E. Allen The authors contributed equally to this work.     

Insights into the genetic basis of congenital heart disease

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     

Aneuploidy in the normal and diseased brain

The brain is remarkable for its complex organization and functions, which have been historically assumed to arise from cells with identical genomes. However, recent studies have shown that the brain is in fact a complex genetic mosaic of aneuploid and euploid cells. The precise function of neural aneuploidy and mosaicism are currently being examined on multiple fronts that include contributions to cellular diversity, cellular signaling and diseases of the central nervous system (CNS). Constitutive aneuploidy in genetic diseases has proven roles in brain dysfunction, as observed in Down syndrome (trisomy 21) and mosaic variegated aneuploidy. The existence of aneuploid cells within normal individuals raises the possibility that these cells might have distinct functions in the normal and diseased brain, the latter contributing to sporadic CNS disorders including cancer. Here we review what is known about neural aneuploidy, and offer speculations on its role in diseases of the brain. Received 13 April 2006; received after revision 2 June 2006; accepted 13 July 2006     

Oncogenic mechanisms in myeloproliferative disorders

Myeloproliferative disorders (MPDs) are clonal haematopoietic malignancies involving the abnormal proliferation of myeloid lineages. The World Health Organisation (WHO) classification of haematopoietic malignancies distinguishes MPDs from myelodysplastic/ myeloproliferative disorders and systemic mastocytosis. These malignancies frequently involve constitutive tyrosine kinase activity, resulting from either oncogenic fusion protein production or from point mutations. Chronic myelogenous leukaemia is the model used for studies of the consequences of such molecular defects. However, the heterogeneity of the clinical course of MPDs should be seen in a more rationale conceptual framework, including the many molecular events associated with these diseases. This review focuses on the various tyrosine kinase-related molecular mechanisms underlying both MPDs and rare diseases with myeloproliferative features. We pay particular attention to the newly identified JAK2 V617F mutation in polycythaemia vera, essential thrombocythaemia and idiopathic myelofibrosis and deal with disease heterogeneity and putative additional molecular mechanisms. Received 9 June 2006; received after revision 28 July 2006; accepted 11 September 2006     

Regulation of SNARE fusion machinery by fatty acids

Vesicle fusion is a ubiquitous biological process involved in membrane trafficking and a variety of specialised events such as exocytosis and neurite outgrowth. The energy to drive biological membrane fusion is provided by fusion proteins called SNAREs. Indeed, SNARE proteins play critical roles in neuronal development as well as neurotransmitter and hormone release. SNARE proteins form a very tight alpha-helical bundle that can pull two membranes together, thereby initiating fusion. Whereas a great deal of attention has been paid to partner proteins that can affect SNARE function, recent genetic and biochemical evidence suggests that local lipid environment may be as important in SNARE regulation. Direct lipid modification of SNARE fusion proteins and their regulation by fatty acids following phospholipase action will be discussed here in detail. Our analysis highlights the fact that lipids are not a passive platform in vesicle fusion but intimately regulate SNARE function. Received 20 December 2006; received after revision 6 February 2007; accepted 15 March 2007