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991.
Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer 总被引:26,自引:0,他引:26
Tomlinson IP Alam NA Rowan AJ Barclay E Jaeger EE Kelsell D Leigh I Gorman P Lamlum H Rahman S Roylance RR Olpin S Bevan S Barker K Hearle N Houlston RS Kiuru M Lehtonen R Karhu A Vilkki S Laiho P Eklund C Vierimaa O Aittomäki K Hietala M Sistonen P Paetau A Salovaara R Herva R Launonen V Aaltonen LA;Multiple Leiomyoma Consortium 《Nature genetics》2002,30(4):406-410
992.
Thyroid hormone controls carnitine status through modifications of γ-butyrobetaine hydroxylase activity and gene expression 总被引:1,自引:0,他引:1
Galland S Georges B Le Borgne F Conductier G Dias JV Demarquoy J 《Cellular and molecular life sciences : CMLS》2002,59(3):540-545
The carnitine system plays a key role in β-oxidation of long-chain fatty acids by permitting their transport into the mitochondrial
matrix. The effects of hypothyroidism and hyperthyroidism were studied on γ-butyrobetaine hydroxylase (BBH), the enzyme responsible
for carnitine biosynthesis in the rat. In rat liver, BBH activity was decreased in the hypothyroid state and increased in
hyperthyroid animals. The modifications in BBH activity correlated with changes in the enzyme Vmax values. These changes were
shown to be related to hepatic BBH mRNA abundance. Thyroid hormones are known to interact with lipid metabolism, in particular
by increasing long-chain fatty acid oxidation through activation of carnitine-dependent fatty acid import into mitochondria.
Our study showed that thyroid hormones also increased carnitine bioavailability.
Received 23 October 2001; received after revision 11 January 2002; accepted 15 January 2002 相似文献
993.
Immunomodulatory properties of cystatins 总被引:8,自引:0,他引:8
Cystatins are natural tight-binding reversible inhibitors of cysteine proteases. Because these cysteine proteases exist in
all living organisms and because they are involved in various biological and pathological processes, the control of these
protease functions by cystatins is of cardinal importance. Cystatins are found in mammals but cystatin-like molecules are
also present in mammals and parasites. In the immune system, cystatins modulate cathepsin activities and antigen presentation.
They also induce tumor necrosis factor α and interleukin 10 synthesis, and they stimulate nitric oxide production by interferon
γ-activated murine macrophages. In turn, nitric oxide has inhibitory activity on cysteine proteases, especially those from
parasitic protozoa. Cystatins isolated from parasitic nematodes also have immunomodulatory activities that are distinguishable
from those induced by lipopolysacharide-like molecules from endosymbiotic bacteria. On the whole, cystatins and cystatin-like
molecules belong to a new category of immunomodulatory molecules. Doubtless increasing data will improve our knowledge of
this property, leading to practical applications in immunotherapy.
Received 11 April 2002; accepted 18 April 2002
RID="*"
ID="*"Corresponding author. 相似文献
994.
995.
996.
Rosenberg MJ Agarwala R Bouffard G Davis J Fiermonte G Hilliard MS Koch T Kalikin LM Makalowska I Morton DH Petty EM Weber JL Palmieri F Kelley RI Schäffer AA Biesecker LG 《Nature genetics》2002,32(1):175-179
The disorder Amish microcephaly (MCPHA) is characterized by severe congenital microcephaly, elevated levels of alpha-ketoglutarate in the urine and premature death. The disorder is inherited in an autosomal recessive pattern and has been observed only in Old Order Amish families whose ancestors lived in Lancaster County, Pennsylvania. Here we show, by using a genealogy database and automated pedigree software, that 23 nuclear families affected with MCPHA are connected to a single ancestral couple. Through a whole-genome scan, fine mapping and haplotype analysis, we localized the gene affected in MCPHA to a region of 3 cM, or 2 Mb, on chromosome 17q25. We constructed a map of contiguous genomic clones spanning this region. One of the genes in this region, SLC25A19, which encodes a nuclear mitochondrial deoxynucleotide carrier (DNC), contains a substitution that segregates with the disease in affected individuals and alters an amino acid that is highly conserved in similar proteins. Functional analysis shows that the mutant DNC protein lacks the normal transport activity, implying that failed deoxynucleotide transport across the inner mitochondrial membrane causes MCPHA. Our data indicate that mitochondrial deoxynucleotide transport may be essential for prenatal brain growth. 相似文献
997.
998.
Systematic screen for human disease genes in yeast 总被引:19,自引:0,他引:19
Steinmetz LM Scharfe C Deutschbauer AM Mokranjac D Herman ZS Jones T Chu AM Giaever G Prokisch H Oefner PJ Davis RW 《Nature genetics》2002,31(4):400-404
High similarity between yeast and human mitochondria allows functional genomic study of Saccharomyces cerevisiae to be used to identify human genes involved in disease. So far, 102 heritable disorders have been attributed to defects in a quarter of the known nuclear-encoded mitochondrial proteins in humans. Many mitochondrial diseases remain unexplained, however, in part because only 40-60% of the presumed 700-1,000 proteins involved in mitochondrial function and biogenesis have been identified. Here we apply a systematic functional screen using the pre-existing whole-genome pool of yeast deletion mutants to identify mitochondrial proteins. Three million measurements of strain fitness identified 466 genes whose deletions impaired mitochondrial respiration, of which 265 were new. Our approach gave higher selection than other systematic approaches, including fivefold greater selection than gene expression analysis. To apply these advantages to human disorders involving mitochondria, human orthologs were identified and linked to heritable diseases using genomic map positions. 相似文献
999.
We have characterized the human gene SLC39A4, which encodes a protein with features characteristic of a ZIP zinc transporter. The chromosomal location and expression of SLC39A4, together with mutational analysis of eight families affected with acrodermatitis enteropathica, suggest that SLC39A4 is centrally involved in the pathogenesis of this condition. 相似文献
1000.
Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors 总被引:5,自引:0,他引:5
Al-Tassan N Chmiel NH Maynard J Fleming N Livingston AL Williams GT Hodges AK Davies DR David SS Sampson JR Cheadle JP 《Nature genetics》2002,30(2):227-232
Inherited defects of base excision repair have not been associated with any human genetic disorder, although mutations of the genes mutM and mutY, which function in Escherichia coli base excision repair, lead to increased transversions of G:C to T:A. We have studied family N, which is affected with multiple colorectal adenomas and carcinoma but lacks an inherited mutation of the adenomatous polyposis coli gene (APC) that is associated with familial adenomatous polyposis. Here we show that 11 tumors from 3 affected siblings contain 18 somatic inactivating mutations of APC and that 15 of these mutations are G:C-->A transversions--a significantly greater proportion than is found in sporadic tumors or in tumors associated with familial adenomatous polyposis. Analysis of the human homolog of mutY, MYH, showed that the siblings were compound heterozygotes for the nonconservative missense variants Tyr165Cys and Gly382Asp. These mutations affect residues that are conserved in mutY of E. coli (Tyr82 and Gly253). Tyrosine 82 is located in the pseudo-helix-hairpin-helix (HhH) motif and is predicted to function in mismatch specificity. Assays of adenine glycosylase activity of the Tyr82Cys and Gly253Asp mutant proteins with 8-oxoG:A and G:A substrates show that their activity is reduced significantly. Our findings link the inherited variants in MYH to the pattern of somatic APC mutation in family N and implicate defective base excision repair in predisposition to tumors in humans. 相似文献