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991.
992.
B. Persson J. Hedlund H. Jörnvall 《Cellular and molecular life sciences : CMLS》2008,65(24):3879-3894
The MDR superfamily with ~350-residue subunits contains the classical liver alcohol dehydrogenase (ADH), quinone reductase,
leukotriene B4 dehydrogenase and many more forms. ADH is a dimeric zinc metalloprotein and occurs as five different classes
in humans, resulting from gene duplications during vertebrate evolution, the first one traced to ~500 MYA (million years ago)
from an ancestral formaldehyde dehydrogenase line. Like many duplications at that time, it correlates with enzymogenesis of
new activities, contributing to conditions for emergence of vertebrate land life from osseous fish. The speed of changes correlates
with function, as do differential evolutionary patterns in separate segments. Subsequent recognitions now define at least
40 human MDR members in the Uniprot database (corresponding to 25 genes when excluding close homologues), and in all species
at least 10888 entries. Overall, variability is large, but like for many dehydrogenases, subdivided into constant and variable
forms, corresponding to household and emerging enzyme activities, respectively. This review covers basic facts and describes
eight large MDR families and nine smaller families. Combined, they have specific substrates in metabolic pathways, some with
wide substrate specificity, and several with little known functions. 相似文献
993.
Pasternack SM von Kügelgen I Al Aboud K Lee YA Rüschendorf F Voss K Hillmer AM Molderings GJ Franz T Ramirez A Nürnberg P Nöthen MM Betz RC 《Nature genetics》2008,40(3):329-334
Hypotrichosis simplex is a group of nonsyndromic human alopecias. We mapped an autosomal recessive form of this disorder to chromosome 13q14.11-13q21.33, and identified homozygous truncating mutations in P2RY5, which encodes an orphan G protein-coupled receptor. Furthermore, we identified oleoyl-L-alpha-lysophosphatidic acid (LPA), a bioactive lipid, as a ligand for P2Y5 in reporter gene and radioligand binding experiments. Homology and studies of signaling transduction pathways suggest that P2Y5 is a member of a subgroup of LPA receptors, which also includes LPA4 and LPA5. Our study is the first to implicate a G protein-coupled receptor as essential for and specific to the maintenance of human hair growth. This finding may provide opportunities for new therapeutic approaches to the treatment of hair loss in humans. 相似文献
994.
Aragonés J Schneider M Van Geyte K Fraisl P Dresselaers T Mazzone M Dirkx R Zacchigna S Lemieux H Jeoung NH Lambrechts D Bishop T Lafuste P Diez-Juan A Harten SK Van Noten P De Bock K Willam C Tjwa M Grosfeld A Navet R Moons L Vandendriessche T Deroose C Wijeyekoon B Nuyts J Jordan B Silasi-Mansat R Lupu F Dewerchin M Pugh C Salmon P Mortelmans L Gallez B Gorus F Buyse J Sluse F Harris RA Gnaiger E Hespel P Van Hecke P Schuit F Van Veldhoven P Ratcliffe P Baes M Maxwell P Carmeliet P 《Nature genetics》2008,40(2):170-180
HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparalpha pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress. 相似文献
995.
Benzinou M Creemers JW Choquet H Lobbens S Dina C Durand E Guerardel A Boutin P Jouret B Heude B Balkau B Tichet J Marre M Potoczna N Horber F Le Stunff C Czernichow S Sandbaek A Lauritzen T Borch-Johnsen K Andersen G Kiess W Körner A Kovacs P Jacobson P Carlsson LM Walley AJ Jørgensen T Hansen T Pedersen O Meyre D Froguel P 《Nature genetics》2008,40(8):943-945
Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity. 相似文献
996.
Sulem P Gudbjartsson DF Stacey SN Helgason A Rafnar T Jakobsdottir M Steinberg S Gudjonsson SA Palsson A Thorleifsson G Pálsson S Sigurgeirsson B Thorisdottir K Ragnarsson R Benediktsdottir KR Aben KK Vermeulen SH Goldstein AM Tucker MA Kiemeney LA Olafsson JH Gulcher J Kong A Thorsteinsdottir U Stefansson K 《Nature genetics》2008,40(7):835-837
We present results from a genome-wide association study for variants associated with human pigmentation characteristics among 5,130 Icelanders, with follow-up analyses in 2,116 Icelanders and 1,214 Dutch individuals. Two coding variants in TPCN2 are associated with hair color, and a variant at the ASIP locus shows strong association with skin sensitivity to sun, freckling and red hair, phenotypic characteristics similar to those affected by well-known mutations in MC1R. 相似文献
997.
998.
Müller T Hess MW Schiefermeier N Pfaller K Ebner HL Heinz-Erian P Ponstingl H Partsch J Röllinghoff B Köhler H Berger T Lenhartz H Schlenck B Houwen RJ Taylor CJ Zoller H Lechner S Goulet O Utermann G Ruemmele FM Huber LA Janecke AR 《Nature genetics》2008,40(10):1163-1165
Following homozygosity mapping in a single kindred, we identified nonsense and missense mutations in MYO5B, encoding type Vb myosin motor protein, in individuals with microvillus inclusion disease (MVID). MVID is characterized by lack of microvilli on the surface of enterocytes and occurrence of intracellular vacuolar structures containing microvilli. In addition, mislocalization of transferrin receptor in MVID enterocytes suggests that MYO5B deficiency causes defective trafficking of apical and basolateral proteins in MVID. 相似文献
999.
Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia 总被引:1,自引:0,他引:1
Grzeschik KH Bornholdt D Oeffner F König A del Carmen Boente M Enders H Fritz B Hertl M Grasshoff U Höfling K Oji V Paradisi M Schuchardt C Szalai Z Tadini G Traupe H Happle R 《Nature genetics》2007,39(7):833-835
Focal dermal hypoplasia (FDH) is an X-linked dominant multisystem birth defect affecting tissues of ectodermal and mesodermal origin. Using a stepwise approach of (i) genetic mapping of FDH, (ii) high-resolution comparative genome hybridization to seek deletions in candidate chromosome areas and (iii) point mutation analysis in candidate genes, we identified PORCN, encoding a putative O-acyltransferase and potentially crucial for cellular export of Wnt signaling proteins, as the gene mutated in FDH. The findings implicate FDH as a developmental disorder caused by a deficiency in PORCN. 相似文献