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41.
Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A) 总被引:14,自引:0,他引:14
Allikmets R Raskind WH Hutchinson A Schueck ND Dean M Koeller DM 《Human molecular genetics》1999,8(5):743-749
X-linked sideroblastic anemia and ataxia (XLSA/A) is a recessive disorder characterized by an infantile to early childhood onset of non-progressive cerebellar ataxia and mild anemia with hypochromia and microcytosis. A gene encoding an ATP-binding cassette (ABC) transporter was mapped to Xq13, a region previously shown by linkage analysis to harbor the XLSA/A gene. This gene, ABC7, is an ortholog of the yeast ATM1 gene whose product localizes to the mitochondrial inner membrane and is involved in iron homeostasis. The full-length ABC7 cDNA was cloned and the entire coding region screened for mutations in a kindred in which five male members manifested XLSA/A. An I400M variant was identified in a predicted transmembrane segment of the ABC7 gene in patients with XLSA/A. The mutation was shown to segregate with the disease in the family and was not detected in at least 600 chromosomes of general population controls. Introduction of the corresponding mutation into the Saccharomyces cerevisiae ATM1 gene resulted in a partial loss of function of the yeast Atm1 protein. In addition, the human wild-type ABC7 protein was able to complement ATM1 deletion in yeast. These data indicate that ABC7 is the causal gene of XLSA/A and that XLSA/A is a mitochondrial disease caused by a mutation in the nuclear genome. 相似文献
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The P-selectin gene is highly polymorphic: reduced frequency of the Pro715 allele carriers in patients with myocardial infarction 总被引:10,自引:3,他引:10
Herrmann SM; Ricard S; Nicaud V; Mallet C; Evans A; Ruidavets JB; Arveiler D; Luc G; Cambien F 《Human molecular genetics》1998,7(8):1277-1284
P-selectin is an adhesion molecule, expressed at the surface of activated
cells, that mediates the interaction of activated endothelial cells or
platelets with leukocytes. P-selectin expression is increased in
atherosclerotic plaques, and high plasma levels of this molecule have been
observed in patients with unstable angina. We investigated the P-selectin
gene as a possible candidate for myocardial infarction (MI). The P-selectin
gene is situated on chromosome 1q21-q24, spans >50 kb and contains 17
exons. The sequences of the 5'-flanking region and exons of 40 alleles from
patients with MI were screened for polymorphisms using polymerase chain
reaction/single-strand conformation polymorphism (PCR-SSCP) and sequencing.
Thirteen polymorphisms were identified: five in the 5'-flanking and eight
in the exonic sequences. Four polymorphisms (Ser290Asn, Asn562Asp,
Leu599Val and Thr715Pro) predicted a change in the amino acid sequence of
the P- selectin protein. All P-selectin polymorphisms as well as a common
E- selectin polymorphism, Ser128Arg which has been reported as being
associated with an increased risk of premature coronary heart disease
(CHD), and is in tight linkage disequilibrium with several P-selectin
polymorphisms, were investigated in 647 patients with MI and 758 control
subjects from four regions of France and Northern Ireland (the ECTIM
study). The entire set of P-selectin polymorphisms provided a
heterozygosity of 91%. The polymorphisms were tightly associated with one
another and displayed patterns of linkage disequilibrium suggesting the
existence of highly conserved ancestral haplotypes. The five polymorphisms
in the 5'-flanking region of the gene were unrelated to MI or any relevant
phenotype measured in the ECTIM study. We inferred that the four missense
variants identified in the coding region predicted eight common forms of
the P-selectin protein. The Pro715 allele which characterizes one of these
forms was less frequent in France than in Northern Ireland ( P < 0.002)
and in cases than in controls ( P < 0.002; P < 0.02 after correction
for the number of tests). We conclude that the P-selectin gene is highly
polymorphic and hypothesize that the Pro715 variant may be protective for
MI. Whether this variant affects the properties of the P-selectin protein
in a way which is compatible with this hypothesis needs to be checked
experimentally.
相似文献
45.
Sperm quality in Hodgkin's disease versus non-Hodgkin's lymphoma 总被引:3,自引:4,他引:3
Botchan A; Hauser R; Gamzu R; Yogev L; Lessing JB; Paz G; Yavetz H 《Human reproduction (Oxford, England)》1997,12(1):73-76
The study was conducted to determine the deleterious effect of lymphoma
disease on spermatogenesis and to evaluate the possibility that the disease
is mediated primarily by inherent mechanisms in Hodgkin's disease and
non-Hodgkin's lymphoma patients. A total of 89 patients with lymphoma
disease (Hodgkin's and non-Hodgkin's) were referred for sperm preservation
prior to adjuvant treatments. A comparison was made of pre- and post-thaw
sperm quality between lymphoma patients and healthy volunteers who applied
for sperm donation. This was followed by further assessment of the
differences between patients with Hodgkin's disease and non-Hodgkin's
lymphoma in terms of sperm variables, clinical parameters and blood hormone
concentrations. It was found that patients with lymphoma disease had
significantly impaired pre-freeze and post-thaw sperm quality compared with
that of healthy volunteers. Patients with non-Hodgkin's lymphoma had
spermatozoa of higher quality than patients with Hodgkin's disease. No
differences were found in the clinical or hormonal parameters between these
two groups. As expected, reduced testicular size and abnormal testicular
consistency were correlated with decreased sperm quality. The mere presence
of cancer disease has a direct negative effect on spermatogenesis, which is
probably not related to incidental side-effects. A variable degree of
impairment should be expected with different categories of cancer.
相似文献
46.
Computerized family practitioner committee records — a data base for general practitioners
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Linda Hargrave Allen Hutchinson Alan Cavill Leonard A. Goldstone Helen Watson 《The British journal of general practice》1988,38(306):22-23
In the primary care environment the role of preventive medicine is assuming increasing importance and general practitioners need accurate and up-to-date information about their practice population. Computerization of family practitioner committee registers should provide a readily accessible data base from which data about groups of patients within the practice area can easily be extracted. This paper describes a study carried out in Northumberland, which set out to establish the type of information which would be of interest to general practitioners and how it could be produced.
It was found that a data base holding only registration data was of limited value to general practitioners, although useful for identifying target groups for screening programmes and showing demographic trends within the practice. The doctors felt that the inclusion of medical data would make the register a far more effective resource.
相似文献47.
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Patrick Haggard Karen Hutchinson John Stein 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》1995,107(2):254-266
In multi-joint reaching movements, the motor system may choose any one of an infinite set of possible joint rotations to move the hand between given start and target positions. In order to find out whether reaching movements are represented in Cartesian hand coordinates or in joint coordinates, it is necessary to measure whether hand paths or joint paths have lower variability. We have measured hand paths and rotations of shoulder, elbow and wrist joints simultaneously in five subjects reaching in four orientations in the horizontal plane. As in earlier studies, we found a preference for nearly straight hand paths, despite different patterns of joint rotation for different orientations of movement. However, movements in three of four orientations showed a single principal joint, which rotated essentially without reversals. This may reflect optimisation in the motor system, preferring the simplest pattern of joint control for a desired hand path. We used generalised Procrustes analysis to quantify the variability in shape of repeated paths in hand space and joint space. Results showed that hand paths were less variable than the joint angles used to realise them, due to the kinematic redundancy of the limb, suggesting that hand paths, rather than joint angles, are directly represented by the motor system. Nevertheless, movements with straighter hand paths, on average, and those requiring coordinated activity at both shoulder and elbow joints also showed more variability in the shape of the hand path. Other orientations such as movement across the body use primarily a single joint and are less variable at the cost of a slightly curved path. These results suggest that coordinating multiple joints to produce a straight hand path has a definite computational cost. The motor system may perform a trade-off between the benefits of planning reaching movements as straight hand paths and the computational simplicity of executing them using patterns of joint rotation which simplify multi-joint coordination. 相似文献
50.
M. J. Hutchinson Patrick T. Harrison R. Andres Floto Janet M. Allen 《European journal of immunology》1995,25(2):481-487
Receptors for the invariant chain of immunoglobulins (FcR) define the cellular response to specific antigens. FcγR recognize IgG and so elicit a variety of effector functions including phagocytosis. We are interested in the structural determinants for FcγR-mediated phagocytosis, specifically FcγRI(p135) and FcγRIIa isoforms. The low-affinity receptor, FcγRIIa, is found on macrophages and its cytoplasmic domain contains a tyrosine activation motif which has previously been shown to regulate endocytosis. In contrast, FcγRI has no known signaling motifs, though a functional interaction has recently been demonstrated with the γ chain of the high-affinity receptor for IgE, FcεRI. This accessory molecule has a cytoplasmic tyrosine activation motif implicated in signal transduction. Here we demonstrate that although FcγRI transiently expressed on COS-7 cells is able to rosette opsonized SRBC, it cannot phagocytose them. If the cytoplasmic domain of either γ chain or FcγRIIa replaces that of FcγRI in a chimeric receptor, efficient phagocytosis occurs. This particle ingestion is sensitive to the tyrosine kinase inhibitor genistein. Chimeric receptors where the extracellular domain of either FcγRI or FcγRIIa is replaced with that of CD2, a T cell antigen, indicate that FcγR-mediated phagocytosis is ligand independent. We conclude that phagocytosis is dependent upon close particle apposition, tyrosine kinase activity, and that the process is ligand independent. 相似文献