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Fransiska Malfait Ariana Kariminejad Tim Van?Damme Caroline Gauche Delfien Syx Faten Merhi-Soussi Sandrine Gulberti Sofie Symoens Suzanne Vanhauwaert Andy Willaert Bita Bozorgmehr Mohamad?Hasan Kariminejad Nazanin Ebrahimiadib Ingrid Hausser Ann Huysseune Sylvie Fournel-Gigleux Anne De?Paepe 《American journal of human genetics》2013,92(6):935-945
Proteoglycans are important components of cell plasma membranes and extracellular matrices of connective tissues. They consist of glycosaminoglycan chains attached to a core protein via a tetrasaccharide linkage, whereby the addition of the third residue is catalyzed by galactosyltransferase II (β3GalT6), encoded by B3GALT6. Homozygosity mapping and candidate gene sequence analysis in three independent families, presenting a severe autosomal-recessive connective tissue disorder characterized by skin fragility, delayed wound healing, joint hyperlaxity and contractures, muscle hypotonia, intellectual disability, and a spondyloepimetaphyseal dysplasia with bone fragility and severe kyphoscoliosis, identified biallelic B3GALT6 mutations, including homozygous missense mutations in family 1 (c.619G>C [p.Asp207His]) and family 3 (c.649G>A [p.Gly217Ser]) and compound heterozygous mutations in family 2 (c.323_344del [p.Ala108Glyfs∗163], c.619G>C [p.Asp207His]). The phenotype overlaps with several recessive Ehlers-Danlos variants and spondyloepimetaphyseal dysplasia with joint hyperlaxity. Affected individuals’ fibroblasts exhibited a large decrease in ability to prime glycosaminoglycan synthesis together with impaired glycanation of the small chondroitin/dermatan sulfate proteoglycan decorin, confirming β3GalT6 loss of function. Dermal electron microcopy disclosed abnormalities in collagen fibril organization, in line with the important regulatory role of decorin in this process. A strong reduction in heparan sulfate level was also observed, indicating that β3GalT6 deficiency alters synthesis of both main types of glycosaminoglycans. In vitro wound healing assay revealed a significant delay in fibroblasts from two index individuals, pointing to a role for glycosaminoglycan defect in impaired wound repair in vivo. Our study emphasizes a crucial role for β3GalT6 in multiple major developmental and pathophysiological processes. 相似文献
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Masahiro Nakajima Shuji Mizumoto Noriko Miyake Ryo Kogawa Aritoshi Iida Hironori Ito Hiroshi Kitoh Aya Hirayama Hiroshi Mitsubuchi Osamu Miyazaki Rika Kosaki Reiko Horikawa Angeline Lai Roberto Mendoza-Londono Lucie Dupuis David Chitayat Andrew Howard Gabriela F. Leal Denise Cavalcanti Yoshinori Tsurusaki Hirotomo Saitsu Shigehiko Watanabe Ekkehart Lausch Sheila Unger Luisa Bonafé Hirofumi Ohashi Andrea Superti-Furga Naomichi Matsumoto Kazuyuki Sugahara Gen Nishimura Shiro Ikegawa 《American journal of human genetics》2013
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《American journal of human genetics》2013,92(6):927-934
Proteoglycans (PGs) are a major component of the extracellular matrix in many tissues and function as structural and regulatory molecules. PGs are composed of core proteins and glycosaminoglycan (GAG) side chains. The biosynthesis of GAGs starts with the linker region that consists of four sugar residues and is followed by repeating disaccharide units. By exome sequencing, we found that B3GALT6 encoding an enzyme involved in the biosynthesis of the GAG linker region is responsible for a severe skeletal dysplasia, spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMD-JL1). B3GALT6 loss-of-function mutations were found in individuals with SEMD-JL1 from seven families. In a subsequent candidate gene study based on the phenotypic similarity, we found that B3GALT6 is also responsible for a connective tissue disease, Ehlers-Danlos syndrome (progeroid form). Recessive loss-of-function mutations in B3GALT6 result in a spectrum of disorders affecting a broad range of skeletal and connective tissues characterized by lax skin, muscle hypotonia, joint dislocation, and spinal deformity. The pleiotropic phenotypes of the disorders indicate that B3GALT6 plays a critical role in a wide range of biological processes in various tissues, including skin, bone, cartilage, tendon, and ligament. 相似文献
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Penelope E. Bonnen John W. Yarham Arnaud Besse Ping Wu Eissa A. Faqeih Ali Mohammad Al-Asmari Mohammad A.M. Saleh Wafaa Eyaid Alrukban Hadeel Langping He Frances Smith Shu Yau Eve M. Simcox Satomi Miwa Taraka Donti Khaled K. Abu-Amero Lee-Jun Wong William J. Craigen Brett H. Graham Kenneth L. Scott Robert McFarland Robert W. Taylor 《American journal of human genetics》2013
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Janneke H.M. Schuurs-Hoeijmakers Edwin C. Oh Lisenka E.L.M. Vissers Mariëlle E.M. Swinkels Christian Gilissen Michèl A. Willemsen Maureen Holvoet Marloes Steehouwer Joris A. Veltman Bert B.A. de Vries Hans van Bokhoven Arjan P.M. de Brouwer Nicholas Katsanis Koenraad Devriendt Han G. Brunner 《American journal of human genetics》2012
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Francine P. Favaro Lucas Alvizi Roseli M. Zechi-Ceide Debora Bertola Temis M. Felix Josiane de Souza Salmo Raskin Stephen R.F. Twigg Andrea M.J. Weiner Pablo Armas Ezequiel Margarit Nora B. Calcaterra Gregers R. Andersen Simon J. McGowan Andrew O.M. Wilkie Antonio Richieri-Costa Maria L.G. de Almeida Maria Rita Passos-Bueno 《American journal of human genetics》2014
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Cultivation of fourth stage Brugia pahangi and B. malayi larvae from infective larvae (stage 3) were obtained in culture medium RPMI 1640 supplemented with 10% human AB serum and an LCC-MK2 rhesus monkey kidney continuous cell line feeder layer. This culture system kept larvae alive in excess of 7 weeks, and served as a source for collection of the worms' secretory, excretory, and moulting antigens. 相似文献
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Autosomal dominant polycystic kidney disease is the most common human monogenic disorder and is caused by mutations in the PKD1 or PKD2 genes. Most patients with the disease present mutations in PKD1, and a considerable number of these alterations are single base substitutions within the coding sequence that are usually predicted to lead to missense or synonymous mutations. There is growing evidence that some of these mutations can be detrimental by affecting the pre-mRNA splicing process. The aim of our study was to test PKD1 mutations, described as missense or synonymous in the literature or databases, for their effects on exon inclusion. Bioinformatics tools were used to select mutations with a potential effect on pre-mRNA splicing. Mutations were experimentally tested using minigene assays. Exons and adjacent intronic sequences were PCR-amplified and cloned in the splicing reporter minigene, and selected mutations were introduced by site-directed mutagenesis. Minigenes were transfected into kidney derived cell lines. RNA from cultured cells was analyzed by RT-PCR and DNA sequencing. Analysis of thirty-three PKD1 exonic mutations revealed three mutations that induce splicing defects. The substitution c.11156G > A, previously predicted as missense mutation p.R3719Q, abolished the donor splice site of intron 38 and resulted in the incorporation of exon 38 with 117 bp of intron 38 and skipping of exon 39. Two synonymous variants, c.327A > T (p.G109G) and c.11257C > A (p.R3753R), generated strong donor splice sites within exons 3 and 39 respectively, resulting in incorporation of incomplete exons. These three nucleotide substitutions represent the first PKD1 exonic mutations that induce aberrant mRNAs. Our results strengthen the importance to evaluate the consequences of presumed missense and synonymous mutations at the mRNA level. 相似文献
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Julie Jerber Maha S. Zaki Jumana Y. Al-Aama Rasim Ozgur Rosti Tawfeg Ben-Omran Esra Dikoglu Jennifer L. Silhavy Caner Caglar Damir Musaev Beate Albrecht Kevin P. Campbell Tobias Willer Mariam Almuriekhi Ahmet Okay Çağlayan Jiri Vajsar Kaya Bilgüvar Gonul Ogur Rami Abou Jamra Murat Günel Joseph G. Gleeson 《American journal of human genetics》2016,99(5):1181-1189
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Naiara Akizu Vincent Cantagrel Jana Schroth Na Cai Keith Vaux Douglas McCloskey Robert K. Naviaux Jeremy Van Vleet Ali G. Fenstermaker Jennifer L. Silhavy Judith S. Scheliga Keiko Toyama Hiroko Morisaki Fatma M. Sonmez Figen Celep Azza Oraby Maha S. Zaki Raidah Al-Baradie Eissa A. Faqeih Mohammed A.M. Saleh Emily Spencer Rasim Ozgur Rosti Eric Scott Elizabeth Nickerson Stacey Gabriel Takayuki Morisaki Edward W. Holmes Joseph G. Gleeson 《Cell》2013
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Jeong Hoon Cho Hyun-Ok Song Gunasekaran Singaravelu Hyun Sung Soonjae Kwon Joohong Ahnn 《FEBS letters》2009,583(18):3050-3056
Calumenin is a Ca2+ binding protein localizing at the lumen of the endoplasmic reticulum (ER). Although it has been implicated in various diseases, the in vivo functions of calumenin are largely unknown. Here, we report that calumenin has pleiotropic roles in muscle and cuticle function in Caenorhabditis elegans. Mutant analysis revealed that the calu-1 is required for regulating fertility, locomotion and body size. In addition, calu-1 is important for two behaviors, defecation and pharyngeal pumping, consistent with its ability to bind Ca2+. The genetic analysis further suggested the possibility that calu-1 regulates the pharyngeal pumping together with the inositol 1,4,5-triphosphate (IP3) receptor encoded by itr-1. Taken together, our data suggest that calumenin is important for calcium signaling pathways in C. elegans. 相似文献
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Patrick R. Blackburn Zhi Xu Kathleen E. Tumelty Rose W. Zhao William J. Monis Kimberly G. Harris Jennifer M. Gass Margot A. Cousin Nicole J. Boczek Mario V. Mitkov Mark A. Cappel Clair A. Francomano Joseph E. Parisi Eric W. Klee Eissa Faqeih Fowzan S. Alkuraya Matthew D. Layne Nazli B. McDonnell Paldeep S. Atwal 《American journal of human genetics》2018,102(4):696-705
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Sandrine Vuillaumier-Barrot Céline Bouchet-Séraphin Malika Chelbi Louise Devisme Samuel Quentin Steven Gazal Annie Laquerrière Catherine Fallet-Bianco Philippe Loget Sylvie Odent Dominique Carles Anne Bazin Jacqueline Aziza Alix Clemenson Fabien Guimiot Maryse Bonnière Sophie Monnot Christine Bole-Feysot Jean-Pierre Bernard Laurence Loeuillet Marie Gonzales Koryna Socha Bernard Grandchamp Tania Attié-Bitach Férechté Encha-Razavi Nathalie Seta 《American journal of human genetics》2012
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Arabidopsis thaliana APETALA3 (AP3) and Antirrhinum majus DEFICIENS (DEF) MADS box genes are required to specify petal and stamen identity. AP3 and DEF are members of the euAP3 lineage, which arose by gene duplication coincident with radiation of the core eudicots. In order to investigate the molecular mechanisms underlying organ development in early diverging clades of core eudicots, we isolated and identified an AP3 homolog, FaesAP3, from Fagopyrum esculentum (buckwheat, Polygonaceae), a multi-food-use pseudocereal with healing benefits. Protein sequence alignment and phylogenetic analyses revealed that FaesAP3 grouped into the euAP3 lineage. Expression analysis showed that FaesAP3 was transcribed only in developing stamens, and differed from AP3 and DEF, which expressed in developing petals and stamens. Moreover, ectopic expression of FaesAP3 rescued stamen development without complementation of petal development in an Arabidopsis ap3 mutant. Our results suggest that FaesAP3 is involved in the development of stamens in buckwheat. These results also suggest that FaesAP3 holds some potential for biotechnical engineering to create a male sterile line of F. esculentum. 相似文献
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Jeanne Hansen Chelsi SnowEmily Tuttle Dalia H. GhoneimChun-Song Yang Adam SpencerSonya A. Gunter Christopher D. SmyserChristina A. Gurnett Marwan ShinawiWilliam B. Dobyns James WhelessMarc W. Halterman Laura A. JansenBryce M. Paschal Alex R. Paciorkowski 《American journal of human genetics》2015,96(6):1009