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41.
Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy 总被引:14,自引:0,他引:14
Pandit B Sarkozy A Pennacchio LA Carta C Oishi K Martinelli S Pogna EA Schackwitz W Ustaszewska A Landstrom A Bos JM Ommen SR Esposito G Lepri F Faul C Mundel P López Siguero JP Tenconi R Selicorni A Rossi C Mazzanti L Torrente I Marino B Digilio MC Zampino G Ackerman MJ Dallapiccola B Tartaglia M Gelb BD 《Nature genetics》2007,39(8):1007-1012
Noonan and LEOPARD syndromes are developmental disorders with overlapping features, including cardiac abnormalities, short stature and facial dysmorphia. Increased RAS signaling owing to PTPN11, SOS1 and KRAS mutations causes approximately 60% of Noonan syndrome cases, and PTPN11 mutations cause 90% of LEOPARD syndrome cases. Here, we report that 18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals) and two of six individuals with LEOPARD syndrome without PTPN11 mutations have missense mutations in RAF1, which encodes a serine-threonine kinase that activates MEK1 and MEK2. Most mutations altered a motif flanking Ser259, a residue critical for autoinhibition of RAF1 through 14-3-3 binding. Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%) showed hypertrophic cardiomyopathy (HCM), compared with the 18% prevalence of HCM among individuals with Noonan syndrome in general. Ectopically expressed RAF1 mutants from the two HCM hotspots had increased kinase activity and enhanced ERK activation, whereas non-HCM-associated mutants were kinase impaired. Our findings further implicate increased RAS signaling in pathological cardiomyocyte hypertrophy. 相似文献
42.
O'Roak BJ Deriziotis P Lee C Vives L Schwartz JJ Girirajan S Karakoc E Mackenzie AP Ng SB Baker C Rieder MJ Nickerson DA Bernier R Fisher SE Shendure J Eichler EE 《Nature genetics》2011,43(6):585-589
Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk. Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs. 相似文献
43.
Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease 总被引:1,自引:0,他引:1
Fisher SA Tremelling M Anderson CA Gwilliam R Bumpstead S Prescott NJ Nimmo ER Massey D Berzuini C Johnson C Barrett JC Cummings FR Drummond H Lees CW Onnie CM Hanson CE Blaszczyk K Inouye M Ewels P Ravindrarajah R Keniry A Hunt S Carter M Watkins N Ouwehand W Lewis CM Cardon L;Wellcome Trust Case Control Consortium Lobo A Forbes A Sanderson J Jewell DP Mansfield JC Deloukas P Mathew CG Parkes M Satsangi J 《Nature genetics》2008,40(6):710-712
We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohn's disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn's disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases. 相似文献
44.
Telesco CM Fisher RS Wyatt MC Dermott SF Kehoe TJ Novotny S Mariñas N Radomski JT Packham C De Buizer J Hayward TL 《Nature》2005,433(7022):133-136
When viewed in optical starlight scattered by dust, the nearly edge-on debris disk surrounding the A5V star beta Pictoris (distance 19.3 pc; ref. 1) extends farther than 1,450 au from the star. Its large-scale complexity has been well characterized, but the detailed structure of the disk's central approximately 200-au region has remained elusive. This region is of special interest, because planets may have formed there during the star's 10-20-million-year lifetime, perhaps resulting in both the observed tilt of 4.6 degrees relative to the large-scale main disk and the partial clearing of the innermost dust. A peculiarity of the central disk (also possibly related to the presence of planets) is the asymmetry in the brightness of the 'wings', in which the southwestern wing is brighter and more extended at 12 microm than the northeastern wing. Here we present thermal infrared images of the central disk that imply that the brightness asymmetry results from the presence of a bright clump composed of particles that may differ in size from dust elsewhere in the disk. We suggest that this clump results from the collisional grinding of resonantly trapped planetesimals or the cataclysmic break-up of a planetesimal. 相似文献
45.
首次引入非超系统的概念,给出了判定一个系统是非超系统的充分必要条件,证明了任何一个非超系统具有超级扩展的存在性定理,并且构造 出了全部超级扩展系统。 相似文献
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49.
In autumn 1998 stream metabolism was measured in the Hassayampa River, Arizona, a Sonoran Desert stream, using single-station diel oxygen curves and an oxygen mass balance model. Oxygen consumption rates of parafluvial and channel sediments were determined with respiration chambers. Bedload of channel sediments (sand) prevented significant primary production by benthic autotrophs, despite favorable nutrient, light, and temperature conditions. Ecosystem respiration was relatively low (1.50 g O 2 m -2 d -1 ) and presumably fueled by production in the riparian zone and riverine marshes. Respiration rates in the parafluvial zone and in channel sediments ranged from 0.6 to 1.4 g O 2 m -3 sediment h -1 . Sediment organic matter (ash-free dry mass) was 4.0 ± 1.8 kg m -3 sediment and did not significantly differ between the channel and the parafluvial zone. Results indicate that heterotrophic processes may dominate the metabolism of desert stream segments over extended periods of time if unstable sandy bed sediments prevail. 相似文献
50.
Berger MF Lawrence MS Demichelis F Drier Y Cibulskis K Sivachenko AY Sboner A Esgueva R Pflueger D Sougnez C Onofrio R Carter SL Park K Habegger L Ambrogio L Fennell T Parkin M Saksena G Voet D Ramos AH Pugh TJ Wilkinson J Fisher S Winckler W Mahan S Ardlie K Baldwin J Simons JW Kitabayashi N MacDonald TY Kantoff PW Chin L Gabriel SB Gerstein MB Golub TR Meyerson M Tewari A Lander ES Getz G Rubin MA Garraway LA 《Nature》2011,470(7333):214-220