PubMed Central (PMC3 - NLM DTD)
(2,081,148 recursos)
Archive of life sciences journal literature at the U.S. National Institutes of Health (NIH), developed and managed by NIH's National Center for Biotechnology Information (NCBI) in the National Library of Medicine (NLM).
63.
Contribution of a Common Single-Nucleotide Polymorphism to the Genetic Predisposition for Erythropoietic Protoporphyria - Gouya, Laurent; Martin-Schmitt, Caroline; Robreau, Anne-Marie; Austerlitz, Frédéric; Silva, Vasco Da; Brun, Patrick; Simonin, Sylvie; Lyoumi, Saïd; Grandchamp, Bernard; Beaumont, Carole; Puy, Hervé; Deybach, Jean-Charles
Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis that results from a partial deficiency of ferrochelatase (FECH). Recently, we have shown that the inheritance of the common hypomorphic IVS3-48C allele trans to a deleterious mutation reduces FECH activity to below a critical threshold and accounts for the photosensitivity seen in patients. Rare cases of autosomal recessive inheritance have been reported. We studied a cohort of 173 white French EPP families and a group of 360 unrelated healthy subjects from four ethnic groups. The prevalences of the recessive and dominant autosomal forms of EPP are 4% (95% confidence interval...
64.
Mutation of the LUNATIC FRINGE Gene in Humans Causes Spondylocostal Dysostosis with a Severe Vertebral Phenotype - Sparrow, D. B.; Chapman, G.; Wouters, M. A.; Whittock, N. V.; Ellard, S.; Fatkin, D.; Turnpenny, P. D.; Kusumi, K.; Sillence, D.; Dunwoodie, S. L.
The spondylocostal dysostoses (SCDs) are a heterogeneous group of vertebral malsegmentation disorders that arise during embryonic development by a disruption of somitogenesis. Previously, we had identified two genes that cause a subset of autosomal recessive forms of this disease: DLL3 (SCD1) and MESP2 (SCD2). These genes are important components of the Notch signaling pathway, which has multiple roles in development and disease. Here, we have used a candidate-gene approach to identify a mutation in a third Notch pathway gene, LUNATIC FRINGE (LFNG), in a family with autosomal recessive SCD. LFNG encodes a glycosyltransferase that modifies the Notch family of cell-surface...
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Deletion of PREPL, a Gene Encoding a Putative Serine Oligopeptidase, in Patients with Hypotonia-Cystinuria Syndrome - Jaeken, Jaak; Martens, Kevin; François, Inge; Eyskens, François; Lecointre, Claudine; Derua, Rita; Meulemans, Sandra; Slootstra, Jerry W.; Waelkens, Etienne; Zegher, Francis de; Creemers, John W. M.; Matthijs, Gert
In 11 patients with a recessive congenital disorder, which we refer to as the hypotonia-cystinuria syndrome, microdeletion of part of the SLC3A1 and PREPL genes on chromosome 2p21 was found. Patients present with generalized hypotonia at birth, nephrolithiasis, growth hormone deficiency, minor facial dysmorphism, and failure to thrive, followed by hyperphagia and rapid weight gain in late childhood. Since loss-of-function mutations in SLC3A1 are known to cause isolated cystinuria type I, and since the expression of the flanking genes, C2orf34 and PPM1B, was normal, the extended phenotype can be attributed to the deletion of PREPL. PREPL is localized in the...
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Strong Genetic Evidence of DCDC2 as a Susceptibility Gene for Dyslexia - Schumacher, Johannes; Anthoni, Heidi; Dahdouh, Faten; König, Inke R.; Hillmer, Axel M.; Kluck, Nadine; Manthey, Malou; Plume, Ellen; Warnke, Andreas; Remschmidt, Helmut; Hülsmann, Jutta; Cichon, Sven; Lindgren, Cecilia M.; Propping, Peter; Zucchelli, Marco; Ziegler, Andreas; Peyrard-Janvid, Myriam; Schulte-Körne, Gerd; Nöthen, Markus M.; Kere, Juha
We searched for linkage disequilibrium (LD) in 137 triads with dyslexia, using markers that span the most-replicated dyslexia susceptibility region on 6p21-p22, and found association between the disease and markers within the VMP/DCDC2/KAAG1 locus. Detailed refinement of the LD region, involving sequencing and genotyping of additional markers, showed significant association within DCDC2 in single-marker and haplotype analyses. The association appeared to be strongest in severely affected patients. In a second step, the study was extended to include an independent sample of 239 triads with dyslexia, in which the associationin particular, with the severe phenotype of dyslexiawas confirmed. Our expression data...
67.
Determinants of Exon 7 Splicing in the Spinal Muscular Atrophy Genes, SMN1 and SMN2 - Cartegni, Luca; Hastings, Michelle L.; Calarco, John A.; Stanchina, Elisa de; Krainer, Adrian R.
Spinal muscular atrophy is a neurodegenerative disorder caused by the deletion or mutation of the survival-of-motor-neuron gene, SMN1. An SMN1 paralog, SMN2, differs by a C?T transition in exon 7 that causes substantial skipping of this exon, such that SMN2 expresses only low levels of functional protein. A better understanding of SMN splicing mechanisms should facilitate the development of drugs that increase survival motor neuron (SMN) protein levels by improving SMN2 exon 7 inclusion. In addition, exonic mutations that cause defective splicing give rise to many genetic diseases, and the SMN1/2 system is a useful paradigm for understanding exon-identity determinants...
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A Scan of Chromosome 10 Identifies a Novel Locus Showing Strong Association with Late-Onset Alzheimer Disease - Grupe, Andrew; Li, Yonghong; Rowland, Charles; Nowotny, Petra; Hinrichs, Anthony L.; Smemo, Scott; Kauwe, John S. K.; Maxwell, Taylor J.; Cherny, Sara; Doil, Lisa; Tacey, Kristina; van Luchene, Ryan; Myers, Amanda; Wavrant-De Vrièze, Fabienne; Kaleem, Mona; Hollingworth, Paul; Jehu, Luke; Foy, Catherine; Archer, Nicola; Hamilton, Gillian; Holmans, Peter; Morris, Chris M.; Catanese, Joseph; Sninsky, John; White, Thomas J.; Powell, John; Hardy, John; ODonovan, Michael; Lovestone, Simon; Jones, Lesley; Morris, John C.; Thal, Leon; Owen, Michael; Williams, Julie; Goate, Alison
Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In...
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Epimerase-Deficiency Galactosemia Is Not a Binary Condition - Openo, Kimberly K.; Schulz, Jenny M.; Vargas, Claudia A.; Orton, Corey S.; Epstein, Michael P.; Schnur, Rhonda E.; Scaglia, Fernando; Berry, Gerard T.; Gottesman, Gary S.; Ficicioglu, Can; Slonim, Alfred E.; Schroer, Richard J.; Yu, Chunli; Rangel, Vanessa E.; Keenan, Jennifer; Lamance, Kerri; Fridovich-Keil, Judith L.
Epimerase-deficiency galactosemia results from the impairment of UDP-galactose 4?-epimerase (GALE), the third enzyme in the Leloir pathway of galactose metabolism. Originally identified as a clinically benign peripheral condition with enzyme impairment restricted to circulating blood cells, GALE deficiency was later demonstrated also to exist in a rare but clinically severe generalized form, with enzyme impairment affecting a range of tissues. Isolated cases of clinically and/or biochemically intermediate cases of epimerase deficiency have also been reported. We report here studies of 10 patients who, in the neonatal period, received the diagnosis of hemolysate epimerase deficiency. We have characterized these patients with...
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SLC34A3 Mutations in Patients with Hereditary Hypophosphatemic Rickets with Hypercalciuria Predict a Key Role for the Sodium-Phosphate Cotransporter NaPi-IIc in Maintaining Phosphate Homeostasis - Bergwitz, Clemens; Roslin, Nicole M.; Tieder, Martin; Loredo-Osti, J C.; Bastepe, Murat; Abu-Zahra, Hilal; Frappier, Danielle; Burkett, Kelly; Carpenter, Thomas O.; Anderson, Donald; Garabédian, Michèle; Sermet, Isabelle; Fujiwara, T. Mary; Morgan, Kenneth; Tenenhouse, Harriet S.; Jüppner, Harald
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of autosomal recessive inheritance that was first described in a large consanguineous Bedouin kindred. HHRH is characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histological evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption. We performed a genomewide linkage scan combined with homozygosity mapping, using genomic DNA from a large consanguineous Bedouin kindred that included 10...
72.
Hereditary Hypophosphatemic Rickets with Hypercalciuria Is Caused by Mutations in the Sodium-Phosphate Cotransporter Gene SLC34A3 - Lorenz-Depiereux, Bettina; Benet-Pages, Anna; Eckstein, Gertrud; Tenenbaum-Rakover, Yardena; Wagenstaller, Janine; Tiosano, Dov; Gershoni-Baruch, Ruth; Albers, Norbert; Lichtner, Peter; Schnabel, Dirk; Hochberg, Zeev; Strom, Tim M.
Hypophosphatemia due to isolated renal phosphate wasting results from a heterogeneous group of disorders. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive form that is characterized by reduced renal phosphate reabsorption, hypophosphatemia, and rickets. It can be distinguished from other forms of hypophosphatemia by increased serum levels of 1,25-dihydroxyvitamin D resulting in hypercalciuria. Using SNP array genotyping, we mapped the disease locus in two consanguineous families to the end of the long arm of chromosome 9. The candidate region contained a sodium-phosphate cotransporter gene, SLC34A3, which has been shown to be expressed in proximal tubulus cells. Sequencing of...
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Polarity and Temporality of High-Resolution Y-Chromosome Distributions in India Identify Both Indigenous and Exogenous Expansions and Reveal Minor Genetic Influence of Central Asian Pastoralists - Sengupta, Sanghamitra; Zhivotovsky, Lev A.; King, Roy; Mehdi, S. Q.; Edmonds, Christopher A.; Chow, Cheryl-Emiliane T.; Lin, Alice A.; Mitra, Mitashree; Sil, Samir K.; Ramesh, A.; Usha Rani, M. V.; Thakur, Chitra M.; Cavalli-Sforza, L. Luca; Majumder, Partha P.; Underhill, Peter A.
Although considerable cultural impact on social hierarchy and language in South Asia is attributable to the arrival of nomadic Central Asian pastoralists, genetic data (mitochondrial and Y chromosomal) have yielded dramatically conflicting inferences on the genetic origins of tribes and castes of South Asia. We sought to resolve this conflict, using high-resolution data on 69 informative Y-chromosome binary markers and 10 microsatellite markers from a large set of geographically, socially, and linguistically representative ethnic groups of South Asia. We found that the influence of Central Asia on the pre-existing gene pool was minor. The ages of accumulated microsatellite variation in...
74.
A Novel Framework for Sib Pair Linkage Analysis - Poznik, G. David; Adamska, Katarzyna; Xu, Xin; Krolewski, Andrzej S.; Rogus, John J.
Sib pair linkage analysis of a dichotomous trait is a popular method for narrowing the search for genes that influence complex diseases. Although the pedigree structures are uncomplicated and the underlying genetic principles straightforward, a surprising degree of complexity is involved in implementing a sib pair study and interpreting the results. Ascertainment may be based on affected, discordant, or unaffected sib pairs, as well as on pairs defined by threshold values for quantitative traits, such as extreme discordant sib pairs. To optimize power, various domain restrictions and null hypotheses have been proposed for each of these designs, yielding a wide...
75.
Regression-Based Association Analysis with Clustered Haplotypes through Use of Genotypes - Tzeng, Jung-Ying; Wang, Chih-Hao; Kao, Jau-Tsuen; Hsiao, Chuhsing Kate
Haplotype-based association analysis has been recognized as a tool with high resolution and potentially great power for identifying modest etiological effects of genes. However, in practice, its efficacy has not been as successfully reproduced as expected in theory. One primary cause is that such analysis tends to require a large number of parameters to capture the abundant haplotype varieties, and many of those are expended on rare haplotypes for which studies would have insufficient power to detect association even if it existed. To concentrate statistical power on more-relevant inferences, in this study, we developed a regression-based approach using clustered haplotypes...
76.
Using Linkage Genome Scans to Improve Power of Association in Genome Scans - Roeder, Kathryn; Bacanu, Silvi-Alin; Wasserman, Larry; Devlin, B.
Scanning the genome for association between markers and complex diseases typically requires testing hundreds of thousands of genetic polymorphisms. Testing such a large number of hypotheses exacerbates the trade-off between power to detect meaningful associations and the chance of making false discoveries. Even before the full genome is scanned, investigators often favor certain regions on the basis of the results of prior investigations, such as previous linkage scans. The remaining regions of the genome are investigated simultaneously because genotyping is relatively inexpensive compared with the cost of recruiting participants for a genetic study and because prior evidence is rarely sufficient...
77.
ZNF674: A New Krüppel-Associated BoxContaining Zinc-Finger Gene Involved in Nonsyndromic X-Linked Mental Retardation - Lugtenberg, Dorien; Yntema, Helger G.; Banning, Martijn J. G.; Oudakker, Astrid R.; Firth, Helen V.; Willatt, Lionel; Raynaud, Martine; Kleefstra, Tjitske; Fryns, Jean-Pierre; Ropers, Hans-Hilger; Chelly, Jamel; Moraine, Claude; Gécz, Jozef; Reeuwijk, Jeroen van; Nabuurs, Sander B.; de Vries, Bert B. A.; Hamel, Ben C. J.; de Brouwer, Arjan P. M.; Bokhoven, Hans van
Array-based comparative genomic hybridization has proven to be successful in the identification of genetic defects in disorders involving mental retardation. Here, we studied a patient with learning disabilities, retinal dystrophy, and short stature. The family history was suggestive of an X-linked contiguous gene syndrome. Hybridization of full-coverage X-chromosomal bacterial artificial chromosome arrays revealed a deletion of ?1 Mb in Xp11.3, which harbors RP2, SLC9A7, CHST7, and two hypothetical zinc-finger genes, ZNF673 and ZNF674. These genes were analyzed in 28 families with nonsyndromic X-linked mental retardation (XLMR) that show linkage to Xp11.3; the analysis revealed a nonsense mutation, p.E118X, in the...
78.
Diversity and Functional Consequences of Germline and Somatic PTPN11 Mutations in Human Disease - Tartaglia, Marco; Martinelli, Simone; Stella, Lorenzo; Bocchinfuso, Gianfranco; Flex, Elisabetta; Cordeddu, Viviana; Zampino, Giuseppe; Burgt, Ineke van der; Palleschi, Antonio; Petrucci, Tamara C.; Sorcini, Mariella; Schoch, Claudia; Foà, Robin; Emanuel, Peter D.; Gelb, Bruce D.
Germline mutations in PTPN11, the gene encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome (NS) and the clinically related LEOPARD syndrome (LS), whereas somatic mutations in the same gene contribute to leukemogenesis. On the basis of our previously gathered genetic and biochemical data, we proposed a model that splits NS- and leukemia-associated PTPN11 mutations into two major classes of activating lesions with differential perturbing effects on development and hematopoiesis. To test this model, we investigated further the diversity of germline and somatic PTPN11 mutations, delineated the association of those mutations with disease, characterized biochemically a panel of mutant SHP-2...
79.
Single-Nucleotide Polymorphisms in NAGNAG Acceptors Are Highly Predictive for Variations of Alternative Splicing - Hiller, Michael; Huse, Klaus; Szafranski, Karol; Jahn, Niels; Hampe, Jochen; Schreiber, Stefan; Backofen, Rolf; Platzer, Matthias
Aberrant or modified splicing patterns of genes are causative for many human diseases. Therefore, the identification of genetic variations that cause changes in the splicing pattern of a gene is important. Elsewhere, we described the widespread occurrence of alternative splicing at NAGNAG acceptors. Here, we report a genomewide screen for single-nucleotide polymorphisms (SNPs) that affect such tandem acceptors. From 121 SNPs identified, we extracted 64 SNPs that most likely affect alternative NAGNAG splicing. We demonstrate that the NAGNAG motif is necessary and sufficient for this type of alternative splicing. The evolutionarily young NAGNAG alleles, as determined by the comparison with...
80.
Spectrum of CHD7 Mutations in 110 Individuals with CHARGE Syndrome and Genotype-Phenotype Correlation - Lalani, Seema R.; Safiullah, Arsalan M.; Fernbach, Susan D.; Harutyunyan, Karine G.; Thaller, Christina; Peterson, Leif E.; McPherson, John D.; Gibbs, Richard A.; White, Lisa D.; Hefner, Margaret; Davenport, Sandra L. H.; Graham, John M.; Bacino, Carlos A.; Glass, Nancy L.; Towbin, Jeffrey A.; Craigen, William J.; Neish, Steven R.; Lin, Angela E.; Belmont, John W.
CHARGE syndrome is a well-established multiple-malformation syndrome with distinctive consensus diagnostic criteria. Characteristic associated anomalies include ocular coloboma, choanal atresia, cranial nerve defects, distinctive external and inner ear abnormalities, hearing loss, cardiovascular malformations, urogenital anomalies, and growth retardation. Recently, mutations of the chromodomain helicase DNA-binding protein gene CHD7 were reported to be a major cause of CHARGE syndrome. We sequenced the CHD7 gene in 110 individuals who had received the clinical diagnosis of CHARGE syndrome, and we detected mutations in 64 (58%). Mutations were distributed throughout the coding exons and conserved splice sites of CHD7. Of the 64 mutations, 47...
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