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51.
The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum 总被引:4,自引:0,他引:4
Howard HC Mount DB Rochefort D Byun N Dupré N Lu J Fan X Song L Rivière JB Prévost C Horst J Simonati A Lemcke B Welch R England R Zhan FQ Mercado A Siesser WB George AL McDonald MP Bouchard JP Mathieu J Delpire E Rouleau GA 《Nature genetics》2002,32(3):384-392
Peripheral neuropathy associated with agenesis of the corpus callosum (ACCPN) is a severe sensorimotor neuropathy associated with mental retardation, dysmorphic features and complete or partial agenesis of the corpus callosum. ACCPN is transmitted in an autosomal recessive fashion and is found at a high frequency in the province of Quebec, Canada. ACCPN has been previously mapped to chromosome 15q. The gene SLC12A6 (solute carrier family 12, member 6), which encodes the K+-Cl- transporter KCC3 and maps within the ACCPN candidate region, was screened for mutations in individuals with ACCPN. Four distinct protein-truncating mutations were found: two in the French Canadian population and two in non-French Canadian families. The functional consequence of the predominant French Canadian mutation (2436delG, Thr813fsX813) was examined by heterologous expression of wildtype and mutant KCC3 in Xenopus laevis oocytes; the truncated mutant is appropriately glycosylated and expressed at the cellular membrane, where it is non-functional. Mice generated with a targeted deletion of Slc12a6 have a locomotor deficit, peripheral neuropathy and a sensorimotor gating deficit, similar to the human disease. Our findings identify mutations in SLC12A6 as the genetic lesion underlying ACCPN and suggest a critical role for SLC12A6 in the development and maintenance of the nervous system. 相似文献
52.
Molecular basis of xeroderma pigmentosum group C DNA recognition by engineered meganucleases 总被引:1,自引:0,他引:1
Redondo P Prieto J Muñoz IG Alibés A Stricher F Serrano L Cabaniols JP Daboussi F Arnould S Perez C Duchateau P Pâques F Blanco FJ Montoya G 《Nature》2008,456(7218):107-111
Xeroderma pigmentosum is a monogenic disease characterized by hypersensitivity to ultraviolet light. The cells of xeroderma pigmentosum patients are defective in nucleotide excision repair, limiting their capacity to eliminate ultraviolet-induced DNA damage, and resulting in a strong predisposition to develop skin cancers. The use of rare cutting DNA endonucleases-such as homing endonucleases, also known as meganucleases-constitutes one possible strategy for repairing DNA lesions. Homing endonucleases have emerged as highly specific molecular scalpels that recognize and cleave DNA sites, promoting efficient homologous gene targeting through double-strand-break-induced homologous recombination. Here we describe two engineered heterodimeric derivatives of the homing endonuclease I-CreI, produced by a semi-rational approach. These two molecules-Amel3-Amel4 and Ini3-Ini4-cleave DNA from the human XPC gene (xeroderma pigmentosum group C), in vitro and in vivo. Crystal structures of the I-CreI variants complexed with intact and cleaved XPC target DNA suggest that the mechanism of DNA recognition and cleavage by the engineered homing endonucleases is similar to that of the wild-type I-CreI. Furthermore, these derivatives induced high levels of specific gene targeting in mammalian cells while displaying no obvious genotoxicity. Thus, homing endonucleases can be designed to recognize and cleave the DNA sequences of specific genes, opening up new possibilities for genome engineering and gene therapy in xeroderma pigmentosum patients whose illness can be treated ex vivo. 相似文献
53.
Verpy E Weil D Leibovici M Goodyear RJ Hamard G Houdon C Lefèvre GM Hardelin JP Richardson GP Avan P Petit C 《Nature》2008,456(7219):255-258
Although the cochlea is an amplifier and a remarkably sensitive and finely tuned detector of sounds, it also produces conspicuous mechanical and electrical waveform distortions. These distortions reflect nonlinear mechanical interactions within the cochlea. By allowing one tone to suppress another (masking effect), they contribute to speech intelligibility. Tones can also combine to produce sounds with frequencies not present in the acoustic stimulus. These sounds compose the otoacoustic emissions that are extensively used to screen hearing in newborns. Because both cochlear amplification and distortion originate from the outer hair cells-one of the two types of sensory receptor cells-it has been speculated that they stem from a common mechanism. Here we show that the nonlinearity underlying cochlear waveform distortions relies on the presence of stereocilin, a protein defective in a recessive form of human deafness. Stereocilin was detected in association with horizontal top connectors, lateral links that join adjacent stereocilia within the outer hair cell's hair bundle. These links were absent in stereocilin-null mutant mice, which became progressively deaf. At the onset of hearing, however, their cochlear sensitivity and frequency tuning were almost normal, although masking was much reduced and both acoustic and electrical waveform distortions were completely lacking. From this unique functional situation, we conclude that the main source of cochlear waveform distortions is a deflection-dependent hair bundle stiffness resulting from constraints imposed by the horizontal top connectors, and not from the intrinsic nonlinear behaviour of the mechanoelectrical transducer channel. 相似文献
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55.
Nury H Van Renterghem C Weng Y Tran A Baaden M Dufresne V Changeux JP Sonner JM Delarue M Corringer PJ 《Nature》2011,469(7330):428-431
General anaesthetics have enjoyed long and widespread use but their molecular mechanism of action remains poorly understood. There is good evidence that their principal targets are pentameric ligand-gated ion channels (pLGICs) such as inhibitory GABA(A) (γ-aminobutyric acid) receptors and excitatory nicotinic acetylcholine receptors, which are respectively potentiated and inhibited by general anaesthetics. The bacterial homologue from Gloeobacter violaceus (GLIC), whose X-ray structure was recently solved, is also sensitive to clinical concentrations of general anaesthetics. Here we describe the crystal structures of the complexes propofol/GLIC and desflurane/GLIC. These reveal a common general-anaesthetic binding site, which pre-exists in the apo-structure in the upper part of the transmembrane domain of each protomer. Both molecules establish van der Waals interactions with the protein; propofol binds at the entrance of the cavity whereas the smaller, more flexible, desflurane binds deeper inside. Mutations of some amino acids lining the binding site profoundly alter the ionic response of GLIC to protons, and affect its general-anaesthetic pharmacology. Molecular dynamics simulations, performed on the wild type (WT) and two GLIC mutants, highlight differences in mobility of propofol in its binding site and help to explain these effects. These data provide a novel structural framework for the design of general anaesthetics and of allosteric modulators of brain pLGICs. 相似文献
56.
Ehlmann BL Mustard JF Murchie SL Bibring JP Meunier A Fraeman AA Langevin Y 《Nature》2011,479(7371):53-60
Clay minerals, recently discovered to be widespread in Mars's Noachian terrains, indicate long-duration interaction between water and rock over 3.7 billion years ago. Analysis of how they formed should indicate what environmental conditions prevailed on early Mars. If clays formed near the surface by weathering, as is common on Earth, their presence would indicate past surface conditions warmer and wetter than at present. However, available data instead indicate substantial Martian clay formation by hydrothermal groundwater circulation and a Noachian rock record dominated by evidence of subsurface waters. Cold, arid conditions with only transient surface water may have characterized Mars's surface for over 4 billion years, since the early-Noachian period, and the longest-duration aqueous, potentially habitable environments may have been in the subsurface. 相似文献
57.
Putoux A Thomas S Coene KL Davis EE Alanay Y Ogur G Uz E Buzas D Gomes C Patrier S Bennett CL Elkhartoufi N Frison MH Rigonnot L Joyé N Pruvost S Utine GE Boduroglu K Nitschke P Fertitta L Thauvin-Robinet C Munnich A Cormier-Daire V Hennekam R Colin E Akarsu NA Bole-Feysot C Cagnard N Schmitt A Goudin N Lyonnet S Encha-Razavi F Siffroi JP Winey M Katsanis N Gonzales M Vekemans M Beales PL Attié-Bitach T 《Nature genetics》2011,43(6):601-606
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Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype 总被引:4,自引:0,他引:4
Brems H Chmara M Sahbatou M Denayer E Taniguchi K Kato R Somers R Messiaen L De Schepper S Fryns JP Cools J Marynen P Thomas G Yoshimura A Legius E 《Nature genetics》2007,39(9):1120-1126
We report germline loss-of-function mutations in SPRED1 in a newly identified autosomal dominant human disorder. SPRED1 is a member of the SPROUTY/SPRED family of proteins that act as negative regulators of RAS->RAF interaction and mitogen-activated protein kinase (MAPK) signaling. The clinical features of the reported disorder resemble those of neurofibromatosis type 1 and consist of multiple café-au-lait spots, axillary freckling and macrocephaly. Melanocytes from a café-au-lait spot showed, in addition to the germline SPRED1 mutation, an acquired somatic mutation in the wild-type SPRED1 allele, indicating that complete SPRED1 inactivation is needed to generate a café-au-lait spot in this syndrome. This disorder is yet another member of the recently characterized group of phenotypically overlapping syndromes caused by mutations in the genes encoding key components of the RAS-MAPK pathway. To our knowledge, this is the first report of mutations in the SPRY (SPROUTY)/SPRED family of genes in human disease. 相似文献
60.
Rivière JB van Bon BW Hoischen A Kholmanskikh SS O'Roak BJ Gilissen C Gijsen S Sullivan CT Christian SL Abdul-Rahman OA Atkin JF Chassaing N Drouin-Garraud V Fry AE Fryns JP Gripp KW Kempers M Kleefstra T Mancini GM Nowaczyk MJ van Ravenswaaij-Arts CM Roscioli T Marble M Rosenfeld JA Siu VM de Vries BB Shendure J Verloes A Veltman JA Brunner HG Ross ME Pilz DT Dobyns WB 《Nature genetics》2012,44(4):440-4, S1-2
Brain malformations are individually rare but collectively common causes of developmental disabilities. Many forms of malformation occur sporadically and are associated with reduced reproductive fitness, pointing to a causative role for de novo mutations. Here, we report a study of Baraitser-Winter syndrome, a well-defined disorder characterized by distinct craniofacial features, ocular colobomata and neuronal migration defect. Using whole-exome sequencing of three proband-parent trios, we identified de novo missense changes in the cytoplasmic actin-encoding genes ACTB and ACTG1 in one and two probands, respectively. Sequencing of both genes in 15 additional affected individuals identified disease-causing mutations in all probands, including two recurrent de novo alterations (ACTB, encoding p.Arg196His, and ACTG1, encoding p.Ser155Phe). Our results confirm that trio-based exome sequencing is a powerful approach to discover genes causing sporadic developmental disorders, emphasize the overlapping roles of cytoplasmic actin proteins in development and suggest that Baraitser-Winter syndrome is the predominant phenotype associated with mutation of these two genes. 相似文献