| Human Molecular Genetics | Pages |
©1999 Oxford University Press |
The limb-girdle muscular dystrophies-multiple genes, multiple mechanisms
Introduction
Autosomal Dominant LGMD-Phenotypic Variation And Novel Mechanisms
Caveolin 3 mutations as a cause of muscular dystrophy
Autosomal Recessive LGMD-Pathophysiological Insights And A Novel Protein
The DGC-insights into pathophysiology
Calpainopathy-autosomal recessive muscular dystrophy caused by an enzyme deficiency
Dysferlinopathy-a novel plasma membrane protein involved in a variable phenotype
Conclusions
Acknowledgements
References
The limb-girdle muscular dystrophies-multiple genes, multiple mechanisms
Received May 5, 1999; Revised and Accepted June 17, 1999
In the field of muscular dystrophy, advances in understanding the molecular basis of the various disorders in this group have been rapidly translated into readily applicable diagnostic tests, allowing the provision of more accurate prognostic and genetic counselling. The limb-girdle muscular dystrophies (LGMD) have recently undergone a major reclassification according to their genetic basis. Currently 13 different types can be recognized. Amongst this group, increasing diversity of the mechanisms involved in producing a muscular dystrophy phenotype is emerging. Recent insights into the involvement of the dystrophin glycoprotein complex in muscular dystrophy suggests that its members may play distinct or even multiple roles in the maintenance of muscle fibre integrity. In other forms of LGMD, proteins have been implicated which may be important in intracellular signalling, vesicle trafficking or the control of transcription. As these various mechanisms are more fully elucidated, further insights will be gained into the pathophysiology of muscular dystrophy. At a practical level, despite the marked heterogeneity of this group real progress can at last be made in determining a precise diagnosis.
INTRODUCTION
The limb-girdle muscular dystrophies (LGMD) have been the subject of intense study over the last 10 years, revealing unexpected heterogeneity and intriguing insights into the possible pathogenesis of these types of muscular dystrophy (1-3). The most recent developments have illustrated new mechanisms for the production of muscular dystrophy, as well as providing constantly new interpretations of old ones.
Originally something of a diagnosis of exclusion, used to describe patients with a progressive proximal muscular dystrophy of otherwise undetermined type, LGMD has been completely redefined by the ability to determine the genetic basis of the various disorders within the group (1; Tables 1 and 2). As unlinked dominant and recessive families remain, there is bound to be yet further heterogeneity. Autosomal dominant LGMD is relatively rare, with at present five loci recognized, most defined only in small groups of patients (4-9). Amongst the autosomal recessive forms of LGMD, eight genetically distinct subtypes have been determined, most of which have been recognized world-wide, though with regional variations in their relative frequency (10-18). Progress in defining these different types of LGMD represents a massive increase in our understanding of the molecular basis for these diseases. From a practical point of view, however, achieving a diagnosis in an individual patient may remain complex, requiring the integration of clinical assessment (based on the increasing understanding of detailed phenotypic correlates for the different disorders), protein analysis and genetic studies (19). Few families are large enough for linkage studies to determine which locus might be involved, though even in smaller families haplotyping may help if enough family members are available. Protein-based strategies are probably the most logical way to approach diagnosis, but require not only a muscle biopsy but also the availability of a whole range of diagnostic antibodies and techniques (20,21). Mutations in all of the LGMD genes currently known are very heterogeneous, with very few recurrent mutations (except in [alpha]-sarcoglycan; Table 1) described outside rare founder populations (22-27). Technological advances will in time no doubt remove some of the problems currently experienced in detecting mutations in this group of genes but at present, even directed by protein analysis (28), the mutation detection techniques which are currently widely used may not always reveal the underlying mutations (24,29,30).
Table 1. The currently recognized forms of autosomal dominant LGMD
| Locus name (gene symbol) | Distribution | Genetics | Protein | Key clinical features | References |
| LGMD1A | Single large US family | Linkage to chr 5q: candidate gene under investigation | Not yet | Proximal weakness, slow progression, possible anticipation | 8,84,85 |
| VPDMD | Single large US family | Overlapping candidate region to LGMD1A, haplotypes not shared, same gene as LGMD1A | Not yet | Aspiration, nasal voice, distal muscle involvement | 34 |
| LGMD1B | Described in Dutch families | Overlapping candidate region to ADEDMD (lamin A/C) | Not yet | Proximal weakness, cardiac conduction defects | 9,86 |
| ADEDMD(LMNA) | French, British, other families | Mutations identified in lamin A/C gene; may be new dominant mutations | Lamin A/C involved but expression not reduced in patients with mutations | Humeroperoneal weakness, dominant contractures, cardiac conduction defects | 32,33 |
| LGMD1C(CAV3) | Two reports | Mutations reported in caveolin 3 gene on chr 3p25. Mutations predominantly located in scaffolding domain of protein: heterozygous in three families, homozygous in one | Caveolin 3 implicated: expression in affected patients unclear | Proximal muscle weakness, calf hypertrophy | 5,6 |
| LGMD1D (FDC-CDM) | One large family (>25 affected) | 3 cM locus on 6q22, candidate gene; homologue of band 4.1 | Not yet | Cardiac complications important; skeletal and cardiac problems worse in males | 7 |
| LGMD1E | Two families | Linkage to 9 cM region on 7q | Not yet | Presentation as young adults | 4 |
Table 2. Genetically determined types of autosomal recessive LGMD
| Disease, locus name, gene symbol | Distribution | Genetics | Protein | Key clinical features | References |
| Sarcoglycanopathy (LGMD2C-2F) SGCA, SGCG, SGCB, SGCD | World-wide, regional differences in different types | (i) [alpha]-R77C seen in 42% of chr(ii) [gamma]-R77C two predominant muts, N African and gypsy otherwise muts very heterogeneous(iii) Missense mutations in all sarcoglycans mainly in extracellular domain | (i) Dystrophin may be mildly abnormal (most often with [gamma])(ii) [gamma] and [alpha] may see selective reduction of the sarcoglycans(iii) [beta] and [delta] mostly see depletion of all sarcoglycans | Calf (and other muscle) hypertrophy common; scapular winging common at onset; highly variable onset and progression but most childhood; intrafamilial variability marked | 26,27,29, 39-43,47 |
| Calpainopathy (LGMD2A) CAPN3 | World-wide, some isolates (e.g. Reunion, Amish, Basque) | Mutations widely distributed, few recurrent; all types of mutation seen, large deletions rare; changes may be non-pathogenic; except in homozygotes, difficult to correlate mutation type with rate of progression | Calpain 3 detectable by monoclonal antibody on blots: absent or reduced in calpainopathy | Onset typically 8-15, posterior thigh, scapular weakness early; often hip abductor sparing; calf hypertrophy rare | 15,22,23, 25,62,64 |
| Dysferlinopathy (LGMD2B/MM) DYSF | World-wide; founder effect in Libyan Jewish population; ? others | Mutations widely distributed, few so far recurrent; no clear genotype-phenotype correlations so far | Dysferlin detectable on sections and blots: absent or reduced in dysferlinopathy | Onset usually late teens; onset may involve proximal or distal muscle or a mixture of the two; little shoulder girdle involvement, calf hypertrophy rare | 10,11,79, 83 |
| LGMD2G | Brazil | Linkage to chr 17q | Not yet | Distal involvement seen as prominent feature | 18 |
| LGMD2H | Manitoba Hutterites | Linkage to chr 9q31-33 | Not yet | Proximal symptoms often in mid 20s, slow progression | 17 |
As the genes and proteins involved in these different disorders are elucidated, new questions arise. Fundamentally, the mechanism or mechanisms by which `muscular dystrophy' (the necrotic degenerative/regenerative process which can be identified in muscle, resulting in progressive weakness and wasting) actually comes about as a result of these various molecular defects is still not fully clear. Various model systems are being developed to explore these issues. The characteristic clinical hallmark of any muscular dystrophy is the pattern of muscle involvement seen in affected patients, this being the historical benchmark for disease classification. In at least one (dysferlinopathy) (11,31), but maybe also other types of LGMD (8,9,32-34), there is likely to be allelic heterogeneity, with mutations in the same gene involved in producing recognizably different phenotypes. While this is a well-known phenomenon outside muscle disease, within muscular dystrophy it necessitates a fundamental rethink of the classification of these disorders.
AUTOSOMAL DOMINANT LGMD-PHENOTYPIC VARIATION AND NOVEL MECHANISMS
Five different loci have been described as associated with autosomal dominant forms of LGMD and phenotypic variability seems to be emerging as a hallmark of this group. The locus for LGMD1A overlaps with a clinically distinct muscle disorder characterized by velopharyngeal weakness and distal muscle involvement (8,34). The locus for LGMD1B encompasses the lamin A/C gene, a nuclear envelope protein recently implicated in autosomal dominant Emery-Dreifuss muscular dystrophy (ADEDMD) (9,32,33). Though ADEDMD tends to be characterized by the development of contractures not usually seen in LGDM1B, very important cardiac involvement is seen in both these disorders, which tends to deteriorate leading to the requirement for pacemaker therapy in most patients by middle age. Cardiac involvement is also important in another mapped form of dominant LGMD (LGMD1D).
Caveolin 3 mutations as a cause of muscular dystrophy
Caveolin 3 is a muscle-specific caveolin, one of a family of proteins believed to act as part of a selective framework within the plasma membrane for signal transduction events (35). It has been implicated in a form of probably autosomal dominant LGMD, known as LGMD1C (5,6), with two reports recently describing mutations in the caveolin 3 gene on chromosome 3p25. Caveolin 3 is expressed during the differentiation of skeletal myoblasts (36) and binds to the muscle-specific isoform of phosphofructokinase (PFK-M), suggesting that it may play a role in the regulation of glycolysis in muscle. Although caveolin is a plasma membrane protein (36), it does not appear to be an integral part of the dystrophin glycoprotein complex (DGC), as adjudged by failure of caveolin 3 to enrich specifically in purified DGC preparations or to co-migrate with the complex on high speed centrifugation or affinity chromatography. Caveolin 3 is not lost in muscle from patients with dystrophin or sarcoglycan deficiency, thereby distinguishing it also in vivo from the other complex members, which tend to be absent or reduced as a group when one member is lost (37).
The mechanism by which caveolin 3 disruption causes muscular dystrophy remains speculative; however, caveolins have been associated with several other diseases with a strong genetic component, including cancer, diabetes mellitus and Alzheimer's disease. This suggests that there may be a whole novel class of disease-causing mutations acting via the failure of proper interactions of regulatory proteins with the intracellular scaffolding network (36).
AUTOSOMAL RECESSIVE LGMD-PATHOPHYSIOLOGICAL INSIGHTS AND A NOVEL PROTEIN
The autosomal recessive forms of LGMD for which the genetic basis is known can be further subdivided depending on the gene and protein involved (Table 2). The sarcoglycanopathies are defined by the involvement of the dystrophin-glycoprotein complex (DGC) in the muscle fibre membrane (38), while the complex is normal in the other forms of AR (and AD) LGMD. In two forms of ARLGMD (LGMD2G and LGMD2H) the genes are not yet cloned.
The DGC-insights into pathophysiology
The vital importance of the DGC (Fig. 1) in the maintenance of muscle fibre integrity is illustrated by the effect of mutations in dystrophin (causing Duchenne or Becker muscular dystrophy) or the sarcoglycans.
Figure 1. Diagrammatic representation of the DGC in the muscle fibre membrane. The sarcoglycans ([alpha], [beta], [gamma] and [delta]) are associated with the various types of LGMD discussed in the text. The positions of caveolin 3 and dysferlin at the plasma membrane are indicated, though their absolute position is not clear. Calpain 3 is not localized to the plasma membrane.
Mutations in any of the [alpha]- (26,29,39-43), [beta]- (29,44,45), [gamma] - (27,46,47) or [delta]-sarcoglycan genes (24,48) result in forms of LGMD. A primary mutation in any one of these genes may lead to total or partial loss of that sarcoglycan as well as a secondary deficiency of the other sarcoglycans, and sometimes reduction of dystrophin labelling in muscle as well (49-51). With any primary sarcoglycan involvement, however, this pattern of secondary deficiencies can be strikingly variable, though total loss of the complex is most commonly seen with mutations of [beta]- or [delta]-sarcoglycan. Where the mutation is in [alpha]- or [gamma]-sarcoglycan, the pattern of sarcoglycan loss may be much more restricted and in fact some sarcoglycans may appear to be expressed normally (3,44,49-51). The extent of the interrelationships of these complex members means that a precise diagnosis of the type of sarcoglycanopathy cannot be reached without the use of a range of antibodies in muscle, followed by mutation detection in the relevant gene, though even there the detection of all mutations may be problematical (24,29). A fifth sarcoglycan, [epsiv]-sarcoglycan, was recently identified through its homology to [alpha]-sarcoglycan, but is not yet known to be involved in any form of muscular dystrophy (52,53).
No human diseases have so far been identified associated with the syntrophins or dystroglycans, and mice homozygous for null dystroglycan alleles are lethal in the embryonic period (54). Distinct subcomplexes (dystrophin, the dystroglycans, the syntrophins, the dystrobrevins and the sarcoglycans) can be recognized within the DGC (55; Fig. 1), raising the possibility that different parts of the complex may have different roles. The absolute function of dystrophin and the dystroglycan complex is still not fully understood, but it is believed to act as a link between the actin cytoskeleton (via dystrophin) and the extracellular matrix laminin proteins (via [alpha]-dystroglycan), protecting the sarcolemma from mechanical stress during contraction. An additional role for [alpha]-dystroglycan in particular may be in the signal transduction framework in the muscle membrane (37). The syntrophins and the sarcoglycans are integral components of the DGC and may play a role in stabilizing the complex. Animal models of sarcoglycan deficiency support this hypothesis, with [alpha]-sarcoglycan-deficient mice (56) developing a progressive muscular dystrophy with complete loss of the sarcoglycan complex and disruption of the membrane association of [alpha]-dystroglycan. A similar abnormality of [alpha]-dystroglycan anchorage in the membrane is seen in the cardiomyopathic hamster (an animal model of [delta]-sarcoglycan deficiency), though here the predominant phenotype is of cardiomyopathy not muscular dystrophy (57). Animal studies also indicate that a common pathogenic mechanism may underlie the muscular dystrophies resulting from dystrophin or sarcoglycan deficiency. Mutants lacking dystrophin or [delta]-sarcoglycan (though not laminin A2) have substantial disruption of the plasma membrane (58). Accumulation of serum proteins in these disrupted fibres may indicate that they play a role in the pathogenic mechanisms leading to cell death, though the full effects of sarcolemmal permeability are not understood (58). Interestingly for the patterning of muscle involvement which is so much a feature of the muscular dystrophies, sarcolemmal permeability varies from muscle to muscle and also within the same muscle. This would seem to indicate that the degree of damage in any particular muscle may not relate completely to the primary gene defect, but that other contributory factors, either environmental or genetic, may be operating and determining the effect of the underlying mutation in any particular area.
The mechanism of the destabilization of the sarcoglycan complex in sarcoglycan deficiency has also been studied in Chinese hamster ovary cells (59). Where the sarcoglycans were expressed together in this cell system they were glycosylated and assembled into a tight complex at the plasma membrane. Individually expressed sarcoglycans were glycosylated but located in internal membrane pools. Where a mutant sarcoglycan was present, however, the complex failed to assemble or locate to the plasma membrane, despite the other sarcoglycans being present and glycosylated as normal. These results suggest that the presence of a mutant sarcoglycan can block assembly of the sarcoglycan complex and trafficking to the plasma membrane. Results from patients with sarcoglycan mutations, however, suggest that this need not be an `all or nothing' situation, because of the extreme variability of the secondary deficiencies observed in the presence of a known primary sarcoglycan defect (3,44,49-51).
The concept that different sarcoglycans may play subtly different roles is yet to be fully explored. [alpha]-Sarcoglycan may have an ecto-ATPase activity, leading to the hypothesis that a contributory factor in Ca2+ overload and muscle fibre death may be an elevated extracellular ATP (60). Studies of human embryonic development (61) indicate that the transcription of the [alpha]- and [beta]-sarcoglycan genes is independent and precedes translation of the proteins by several weeks. So [alpha]-sarcoglycan RNA can be detected from week 4 of development, with muscle-specific expression of the protein detected only at week 11. [beta]-Sarcoglycan RNA is seen ubiquitously from week 4, becoming restricted to skeletal muscle, smooth muscle and the nervous system by week 7. At the same stage, the protein could also be detected, but only in skeletal muscle. The differences in expression of these components of the sarcoglycan complex at such an early stage in development suggests that there might be as yet unknown additional interactions potentially specific to particular complex members (61).
The dystrophin-associated complex is clearly of primary importance in muscular dystrophy. With the improving models available for the study of this system, the many questions remaining about the underlying mechanisms involved in producing a dystrophic phenotype will finally be able to be addressed.
Calpainopathy-autosomal recessive muscular dystrophy caused by an enzyme deficiency
The identification of the muscle-specific calcium dependent protease calpain 3 as the gene involved in the autosomal recessive LGMD linked to chromosome 15 (LGMD2A) was the first demonstration of the involvement of an enzyme in the causation of muscular dystrophy (15,25,62). Since the first report of calpain 3 involvement in LGMD2A, many different mutations have been described in this large gene which may account for the largest proportion of `LGMD' patients overall, with no particular hotspots for mutations reported (25,63). Various populations have a particularly high frequency of calpainopathy (notably the Reunion Island population, the Basque population, Turkey and the Amish; 22,23,64). Several detailed reports of the phenotype of this disorder have confirmed its relatively uniform clinical presentation as a predominantly atrophic muscular dystrophy, with relatively rare muscle hypertrophy (22,23,64). While the clinical spectrum of calpainopathy may be becoming clearer, moving towards an understanding of how it causes muscular dystrophy is more problematical. Calpain 3 has, in addition to four protein domains similar to those found in the ubiquitous calpains, three unique regions (NS, IS1 and IS2) which may confer its muscle specificity (65,66). While calpain 3 is skeletal muscle specific in adult tissue, its RNA is detected very early (week 4) in human heart, well before transcription was detected in skeletal muscle at week 8 of development (61).
Despite initial reports that calpain 3 protein might be very rapidly degraded in muscle (67), calpain 3 in fact can behave in a very stable way in fresh human muscle (68,69). An interaction with titin (connectin) has been suggested via the muscle-specific IS2 region of calpain, which also contains a nucleus translocation signal-like sequence (70,71). Calpain 3 appears to localize both to the myofibrils and muscle cell nuclei (72). This dual localization has led to the suggestion that calpain 3 may play a role in the control of expression of muscle-specific transcription factors and thereby play a part in the regulation of muscle differentiation (70). The ubiquitous calpains have also been suggested to play a role in transcription, for example by cleavage of transcription factors or their inhibitors. Expanding on this hypothesis, a recent study shows that muscle biopsies from calpainopathy patients show more apoptotic nuclei (though still a very small proportion) compared with biopsies from patients with a range of other muscular dystrophies (72). These patients also show failure of nuclear localization of NF-[kappa]B (a transcription factor normally present in the nucleus after activation inducing the expression of genes involved in the inflammatory response and cell survival) and nuclear accumulation of I[kappa]B[alpha] (normally inhibitory to the NF-[kappa]B family and degraded after activation). This study therefore suggests that a result of calpain deficiency may be to prevent expression of cell survival genes. The full relevance of these findings in the multinucleate environment of muscle is yet to be established. In another study, calpain 3 mutant constructs consistently lost proteolytic activity, while some retained autolytic properties or connectin-binding activity (73). The loss of proteolysis may therefore be an important part of the picture in patients lacking calpain 3 activity. A combination of these factors may yet prove to be necessary to produce muscular dystrophy.
Dysferlinopathy-a novel plasma membrane protein involved in a variable phenotype
In 1998, our group and the group of Dr R.H. Brown in Boston simultaneously identified a novel mammalian gene as involved in two apparently distinct forms of muscular dystrophy, a form of LGMD linked to chromosome 2p13 designated LGMD2B and a form of distal muscular dystrophy known as Miyoshi myopathy (10,11). The predicted protein product of this gene, dysferlin, which was identified by both groups by a positional cloning strategy, shows significant homology to a protein in Caenorhabditis elegans, FER-1 (74). Very recently, a second human gene (otoferlin) with high homology to both dysferlin and FER-1 has been identified and implicated in an autosomal recessive form of non-syndromic deafness (75). All three proteins are predicted to share a number of common characteristics: a C-terminal transmembrane domain and at least three C2 domains. C2 domain proteins typically play a role in phospholipid or protein interactions, contributing either to transduction pathways or membrane trafficking (76-78). FER-1 is exclusively expressed in primary spermatocytes and homozygous mutants are infertile due to the failure of the fusion of vesicles known as membranous organelles with the plasma membrane in spermatids (74). Dysferlin in much more widely expressed, though with predominant expression in skeletal muscle (10,11). Monoclonal antibodies to dysferlin have confirmed a plasma membrane localization, in a strikingly similar distribution to dystrophin, though dystrophin and the proteins of the DGC are normal in patients with dysferlinopathy (79). Electron microscopic studies indicate localization internal to the plasma membrane, with no localization to any other membrane-bound organelles. Detection of dysferlin early in human development indicates that it is present at the stage when the limbs begin to show regional differentiation, leading to the intriguing possibility that the patterning of muscle involvement in the disorder may be established even at this early stage (79). Expression of otoferlin was detected in a wide range of tissues by RT-PCR, but strong expression was detected only in the ear (cochlea and vestibule) and the brain. In situ hybridization showed localization to the inner hair cells of the cochlea in embryonic and post-natal mice (75). The existence in the EST databases of further ESTs showing homology to FER-1 indicates that additional members of this novel gene family may remain to be identified. It will be of interest to determine whether the diverse, but in each case highly tissue-specific, phenotypes seen in association with mutations in the three members identified so far share a common underlying pathological mechanism, such as for example through the well-documented interactions of C2 domains with phospholipids and Ca2+-triggered vesicle membrane fusions (78).
Increasing data on the range of mutations in the dysferlin gene can begin to be accumulated following clarification of the genomic structure of the gene. The gene encompasses 55 exons, as well as some very large introns (M. Aoki et al., submitted for publication). So far, the mutations described have shown no hotspots, though an apparently founder mutation is present at high frequency in the Libyan Jewish population (Z. Argov et al., submitted for publication). As expected from the finding of large chromosome 2-linked families in which different family members presented with either a proximal (LGMD2B-like) or distal (Miyoshi myopathy-like) phenotype in the presence of a shared haplotype (80-82), the same homozygous mutation has been described in association with a variable presentation, leading to the suggestion that another factor, genetic or environmental, may act to modify the phenotype (11,79; Z. Argov et al., submitted for publication).
Although some variability may exist in the pattern of muscle involvement at presentation, in many other ways the `dysferlinopathies' have a number of shared clinical characteristics, including age at onset (typically in the late teens with normal athletic prowess up to then) with massive elevation of creatine kinase. Typically, progression is relatively slow, with most patients maintaining ambulation well into adult life (10,11,83).
CONCLUSIONS
Combined positional cloning and candidate gene approaches have shown that at least 13 different genetically defined conditions can be identified within the broad `umbrella' designation of LGMD. This gene- and protein-led classification has allowed clinical distinctions between the different groups to be clarified and means that, provided clinical assessment and protein and genetic analyses are used together, there is a realistic possibility that a precise diagnosis may be achieved in a patient presenting with an LGMD phenotype. As the multiplicity of the genes and proteins involved increases, so do the proposed (but still poorly understood) pathogenic mechanisms underlying this heterogeneity.
ACKNOWLEDGEMENTS
Thanks are due to Louise Anderson for comments on the manuscript. The LGMD group in Newcastle upon Tyne is supported by the Medical Research Council, the Muscular Dystrophy Campaign, Action Research and Italian Telethon.
REFERENCES
+Tel: +44 191 222 7461; Fax: +44 191 222 7143; Email: kate.bushby{at}ncl.ac.uk
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 C. S. Lebakken, D. P. Venzke, R. F. Hrstka, C. M. Consolino, J. A. Faulkner, R. A. Williamson, and K. P. Campbell Sarcospan-Deficient Mice Maintain Normal Muscle Function Mol. Cell. Biol., March 1, 2000; 20(5): 1669 - 1677. [Abstract] [Full Text]
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 J Hadchouel, S Tajbakhsh, M Primig, T. Chang, P Daubas, D Rocancourt, and M Buckingham Modular long-range regulation of Myf5 reveals unexpected heterogeneity between skeletal muscles in the mouse embryo Development, January 10, 2000; 127(20): 4455 - 4467. [Abstract] [PDF]
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A. Hack, M. Lam, L Cordier, D. Shoturma, C. Ly, M. Hadhazy, M. Hadhazy, H. Sweeney, and E. McNally Differential requirement for individual sarcoglycans and dystrophin in the assembly and function of the dystrophin-glycoprotein complex J. Cell Sci., January 7, 2000; 113(14): 2535 - 2544. [Abstract] [PDF]
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