Showing papers by "Martin Bobrow published in 1998"

Dystrophins in Vertebrates and Invertebrates

Abstract: Members of the dystrophin family of proteins perform a critical but incompletely characterized role in themaintenance of membrane-associated complexes at points of intercellular contact in many vertebrate cell types.They interact with, amongst others, the transmembrane laminin receptor dystroglycan, cytoskeletal actin and,indirectly, the intracellular membrane-associated signalling enzyme neuronal nitric oxide synthase (nNOS). Herewe describe sequences of a range of dystrophin-related proteins from vertebrate and invertebrate animals(including the important model organism Drosophila melanogaster) and infer an evolutionary history of thisfamily and its relationship to the distantly related dystrobrevins. It appears that most metazoa possess sequencesencoding a single highly conserved dystrophin-like protein in addition to a presumed distinct dystrobrevin,derived from an early duplication of an ancestral gene. In the vertebrates (but not the protochordate Amphioxus),the single invertebrate dystrophin-like gene has undergone serial duplication to generate at least three distinctgenes encoding proteins which have adopted specialized roles. It is hoped that this broadening of the biologyof the dystrophins will afford further opportunities for the advancement of our understanding of the fundamentaldefect underlying the variety of human genetic disorders which result from aberrant or absent dystrophin-asso-ciated complexes.INTRODUCTIONDystrophin (1) is a large (427 kDa) protein which is highlyconserved in vertebrates. Its largest isoform comprises anN-terminal domain which binds to F-actin, 24 spectrin-likerepeats and a characteristic C-terminal set of domains. Althoughmultiple isoforms are expressed widely in a complex tissue-specific manner (reviewed in ref. 2), null mutations in its genewhich are expected to disrupt all protein isoforms tend to give acharacteristic syndrome (Duchenne muscular dystrophy, DMD)of progressive skeletal and cardiac myopathy, electroretinopathyand a relatively specific form of mental retardation. Despite thiswell-known phenotype, the actual function of dystrophin remainsunclear.A number of related vertebrate proteins, whose function is evenless clear, have been described. Utrophin (3) is very similar inoverall structure to dystrophin itself, and its disruption in mice hasbeen found to cause subtle abnormalities of the neuromuscularjunction (4,5). Dystrophin-related protein 2 (DRP2; ref. 6)resembles certain small (∼110 kDa) isoforms of dystrophin andutrophin in that it comprises the last two spectrin-like repeats andthe C-terminal region. Dystrophin, utrophin and DRP2 areexpressed in distinct but partially overlapping regions of thevertebrate body. The rather distantly related protein dystrobrevin(7), also known as 87K tyrosine kinase substrate ( 8) and A0 ( 10),retains sequences corresponding to the C-terminal 70 kDa ofdystrophin. Dystrobrevin is widely expressed and binds todystrophin, utrophin and, presumably, DRP2.A number of motifs are recognizable in the C-terminal regionof this family of proteins. The WW domain, which is missingfrom dystrobrevin, has been implicated in mediating the inter-action between dystrophin and the transmembrane proteinβ-dystroglycan (10). Motifs in the remaining C-terminalsequences comprise two EF hands, a ZZ domain with the abilityto bind Zn

The new genetics. Implications for clinical services in Britain and the United States.

Abstract: This is the third of four articles discussing the broader implications of advances in genetics Meeting the rising demand for genetic information and advice will require a major reorganisation of genetic services. In the United States, demand has led to the growth of private genetics services that are marketed directly to the public. In the United Kingdom, specialist genetic services are struggling to cope with increased workloads and it is acknowledged that some genetics services will have to be incorporated into mainstream clinical medicine, particularly at primary care level. A range of pilot schemes has been set up to establish how to do this, but few schemes have been fully evaluated. A broad educational effort is needed to increase awareness of the scope and potential of genetic information among health professionals and the public. This article reviews current developments and argues that contrasting approaches in Britain and the United States each offer special opportunities in innovation and evaluation. #### Summary points Advances in genetics underpin the need to equip primary care teams with skills to assess genetic risk of disease, discuss the implications of gene testing, and control access to specialist services Involvement of primary care teams will vary with public awareness and uptake of tests, type and prevalence of disorder, precision of genetic tests, and therapeutic choices available Despite increasing availability of genetic tests, it is premature to offer population screening for genetic predisposition (such as to breast cancer), and even the case for screening carriers for cystic fibrosis through primary care is uncertain Different cultures of American and British health care may lead to faster innovation in United States but greater opportunity for development within a research framework in Britain The organisation of genetic services in the United Kingdom is currently based on regional centres. These mainly deal with relatively uncommon …

Objectives of genetic counselling: differing views of purchasers, providers and users.

Abstract: Background This study aimed to compare the views of purchasers, providers and users about the objectives of genetic counselling. Methods A modified Delphi technique was used, incorporating two postal questionnaires that were sent to six study groups with a three-month interval: purchasers (public health doctors (n = 37) and regional advisers in general practice (n = 35)); providers (clinical geneticists [n = 33) and genetic counsellors (n = 25)); and users (out-patients (n = 36) and members of genetic support groups (n = 32)). The response rate for the first questionnaire was 115/198 (58 per cent) and for the second, 102/198 (52 per cent). The first questionnaire asked an open-ended question about what the objectives of genetic counselling should be and asked respondents to rank order them. The second questionnaire summarized the views expressed in the first questionnaire and asked respondents to rank order the most frequently cited and most highly ranked five objectives. Results The five most frequently cited and highly ranked objectives from Questionnaire One were, in descending order: provide information, give support, facilitate decisionmaking, assess risk and achieve understanding. In response to Questionnaire Two, purchasers differed from providers and users in rating 'facilitate decision-making' more highly than did providers and users. By contrast, providers and users rated 'give information' more highly than did purchasers. Conclusions Purchasers hold different views from providers and users about what the objectives of genetic counselling should be. This raises two questions: (1) Which views are or should be most influential in the future development of genetic counselling? (2) By what processes can more than one view on genetic counselling be integrated?