Página 26 dos resultados de 4394 itens digitais encontrados em 0.007 segundos

‣ CNGA3 Mutations in Hereditary Cone Photoreceptor Disorders

Wissinger, Bernd; Gamer, Daphne; Jägle, Herbert; Giorda, Roberto; Marx, Tim; Mayer, Simone; Tippmann, Sabine; Broghammer, Martina; Jurklies, Bernhard; Rosenberg, Thomas; Jacobson, Samuel G.; Sener, E. Cumhur; Tatlipinar, Sinan; Hoyng, Carel B.; Castellan
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
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We recently showed that mutations in the CNGA3 gene encoding the α-subunit of the cone photoreceptor cGMP-gated channel cause autosomal recessive complete achromatopsia linked to chromosome 2q11. We now report the results of a first comprehensive screening for CNGA3 mutations in a cohort of 258 additional independent families with hereditary cone photoreceptor disorders. CNGA3 mutations were detected not only in patients with the complete form of achromatopsia but also in incomplete achromats with residual cone photoreceptor function and (rarely) in patients with evidence for severe progressive cone dystrophy. In total, mutations were identified in 53 independent families comprising 38 new CNGA3 mutations, in addition to the 8 mutations reported elsewhere. Apparently, both mutant alleles were identified in 47 families, including 16 families with presumed homozygous mutations and 31 families with two heterozygous mutations. Single heterozygous mutations were identified in six additional families. The majority of all known CNGA3 mutations (39/46) are amino acid substitutions compared with only four stop-codon mutations, two 1-bp insertions and one 3-bp in-frame deletion. The missense mutations mostly affect amino acids conserved among the members of the cyclic nucleotide gated (CNG) channel family and cluster at the cytoplasmic face of transmembrane domains (TM) S1 and S2...

‣ The ATM missense mutation Ser49Cys and risk of breast cancer

Stredrick, Denise L.; Garcia-Closas, Montserrat; Pineda, Marbin A.; Bhatti, Parveen; Alexander, Bruce H.; Doody, Michele M.; Lissowska, Jolanta; Peplonska, Beata; Brinton, Louise A.; Chanock, Stephen J.; Struewing, Jeffery P.; Sigurdson, Alice J.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/2006 Português
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Homozygous mutation in the ATM gene causes ataxia telangiectasia and heterozygous mutation carriers may be at increased risk of breast cancer. We studied a total of 22 ATM variants in two large population-based studies of 2856 breast cancer cases and 3344 controls from the U.S. and Poland. The missense mutation Ser49Cys (S49C), carried by approximately 2% of subjects, was more common in cases than controls in both study populations, combined odds ratio (OR) 1.69, 95% CI 1.19 – 2.40, P = 0.004. Another missense mutation at approximately 2% frequency, F858L, was associated with a significant increased risk in the U.S. study but not in Poland, combined OR of 1.44, 95% CI 0.98 – 2.11, P = 0.06. These analyses provide the most convincing evidence thus far that some missense mutations in ATM, particularly S49C, may be breast cancer susceptibility alleles. Because of their low frequency, even larger sample sizes are required to more firmly establish these associations.

‣ Genetics of P450 oxidoreductase: Sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations

Huang, Ningwu; Agrawal, Vishal; Giacomini, Kathleen M.; Miller, Walter L.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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P450 oxidoreductase (POR) is an electron-donating flavoprotein required for the activity of all microsomal cytochrome P450 enzymes. We sequenced 5,655 bp of the POR gene in a representative population of 842 healthy unrelated individuals in four ethnic groups: 218 African Americans, 260 Caucasian Americans, 179 Chinese Americans, and 185 Mexican Americans. One hundred forty SNPs were detected, of which 43 were found in ≥1% of alleles. Twelve SNPs were in the POR promoter region. Fifteen of 32 exonic variations altered the POR amino acid sequence; 13 of these 15 are previously undescribed missense variations. We found eight indels, only one of which was in the coding region. A previously described variant, A503V, was found on 27.9% of all alleles with some ethnic predilection (19.1% in African Americans, 26.4% in Caucasian Americans, 36.7% Chinese Americans, and 31.0% in Mexican Americans). We built cDNA expression vectors for the 13 previously undescribed missense variants, expressed each protein lacking 27 N-terminal residues in Escherichia coli, and assayed the apparent Km and Vmax of each in four assays: reduction of cytochrome c, oxidation of NADPH, 17α-hydroxylase activity of P450c17, and 17,20 lyase activity of P450c17. The catalytic activities of several missense mutants differed substantially in these assays...

‣ The first missense mutation of NHS gene in a Tunisian family with clinical features of NHS syndrome including cardiac anomaly

Chograni, Manèl; Rejeb, Imen; Jemaa, Lamia Ben; Châabouni, Myriam; Bouhamed, Habiba Chaabouni
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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Nance-Horan Syndrome (NHS) or X-linked cataract-dental syndrome is a disease of unknown gene action mechanism, characterized by congenital cataract, dental anomalies, dysmorphic features and, in some cases, mental retardation. We performed linkage analysis in a Tunisian family with NHS in which affected males and obligate carrier female share a common haplotype in the Xp22.32-p11.21 region that contains the NHS gene. Direct sequencing of NHS coding exons and flanking intronic sequences allowed us to identify the first missense mutation (P551S) and a reported SNP-polymorphism (L1319F) in exon 6, a reported UTR–SNP (c.7422 C>T) and a novel one (c.8239 T>A) in exon 8. Both variations P551S and c.8239 T>A segregate with NHS phenotype in this family. Although truncations, frame-shift and copy number variants have been reported in this gene, no missense mutations have been found to segregate previously. This is the first report of a missense NHS mutation causing NHS phenotype (including cardiac defects). We hypothesize also that the non-reported UTR–SNP of the exon 8 (3′-UTR) is specific to the Tunisian population.

‣ Response to DNA damage of CHEK2 missense mutations in familial breast cancer

Roeb, Wendy; Higgins, Jake; King, Mary-Claire
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Comprehensive sequencing of tumor suppressor genes to evaluate inherited predisposition to cancer yields many individually rare missense alleles of unknown functional and clinical consequence. To address this problem for CHEK2 missense alleles, we developed a yeast-based assay to assess in vivo CHEK2-mediated response to DNA damage. Of 25 germline CHEK2 missense alleles detected in familial breast cancer patients, 12 alleles had complete loss of DNA damage response, 8 had partial loss and 5 exhibited a DNA damage response equivalent to that mediated by wild-type CHEK2. Variants exhibiting reduced response to DNA damage were found in all domains of the CHEK2 protein. Assay results were in agreement with epidemiologic assessments of breast cancer risk for those variants sufficiently common for case–control studies to have been undertaken. Assay results were largely concordant with consensus predictions of in silico tools, particularly for damaging alleles in the kinase domain. However, of the 25 variants, 6 were not consistently classifiable by in silico tools. An in vivo assay of cellular response to DNA damage by mutant CHEK2 alleles may complement and extend epidemiologic and genetic assessment of their clinical consequences.

‣ Proteostasis modulators prolong missense VHL protein activity and halt tumor progression

Yang, Chunzhang; Huntoon, Kristin; Ksendzovsky, Alexander; Zhuang, Zhengping; Lonser, Russell R.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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While missense mutations of von Hippel-Lindau disease (VHL) gene are the most common germline mutation underlying this heritable cancer syndrome, the mechanism of tumorigenesis is unknown. We found a quantitative reduction of missense mutant VHL protein (pVHL) in VHL-associated tumors associated with physiologic mRNA expression. While mutant pVHL is unstable and degraded contemporarily with translation, it retains its E3 ligase function, including hypoxia inducible factor degradation. The premature pVHL degradation is due to misfolding and imbalance of chaperonin binding. Histone deacetylase inhibitors (HDACis) can modulate this pathway by inhibiting the HDAC6-Hsp90 chaperone axis, stabilizing pVHL and restoring activity comparable to wild type protein in vitro and in animal models (786-O tumor xenografts). HDACi mediated stabilization of missense pVHL significantly attenuates the growth of 786-O rodent tumor model. These findings provide direct biologic insight into VHL-associated tumors and elucidate a new treatment paradigm for VHL.

‣ A Novel Missense Mutation in the Thyroid Peroxidase Gene, R175Q, Resulting in Insufficient Cell Surface Enzyme in Two Siblings

Kotani, Tomio; Umeki, Kazumi; Kawano, Jun-ichi; Suganuma, Tatsuo; Yamamoto, Ikuo; Aratake, Yatsuki; Ichiba, Yozo; Furujo, Mahoko
Fonte: The Japanese Society for Pediatric Endocrinology Publicador: The Japanese Society for Pediatric Endocrinology
Tipo: Artigo de Revista Científica
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Thyroid peroxidase (TPO) abnormality is one of the causes of congenital hypothyroidism. Two missense mutations were found as a compound heterozygous mutation in two siblings with congenital goitrous hypothyroidism. One of these mutations, G614A (R175Q), was a novel mutation. Characterization of the novel mutation and a cotransfection experiment with two mutated TPO mRNAs were carried out. G614A-mRNA introduced into CHO-K1 cells expressed TPO protein with the same molecular weight as that of wild-type mRNA. The R175Q-TPO was thought to possess enzyme activity. In terms of localization, a very small amount of mutated TPO was expressed on the plasma membrane of CHO-K1 cells. This plasma membrane expression of R175Q-TPO was insufficient to perform thyroid hormone synthesis, but was markedly different from R665W-TPO. When G614A- and C2083T-mRNAs were cotransfected, cell surface TPO-positive cells were only 13.1% in contrast to 54.4% for wild-type mRNA. The low positivity and intensity of cell surface TPO suggested that in the patients’ thyroids thyroid hormone synthesis was hardly performed. The congenital hypothyroidism of the patients was thought to be a result of the mutations of the TPO gene (G614A/C2083T).

‣ Mutations in SACPD-C Result in a Range of Elevated Stearic Acid Concentration in Soybean Seed

Carrero-Colón, Militza; Abshire, Nathan; Sweeney, Daniel; Gaskin, Erik; Hudson, Karen
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 20/05/2014 Português
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Soybean oil has a wide variety of uses, and stearic acid, which is a relatively minor component of soybean oil is increasingly desired for both industrial and food applications. New soybean mutants containing high levels of the saturated fatty acid stearate in seeds were recently identified from a chemically mutagenized population. Six mutants ranged in stearate content from 6–14% stearic acid, which is 1.5 to 3 times the levels contained in wild-type seed of the Williams 82 cultivar. Candidate gene sequencing revealed that all of these lines carried amino acid substitutions in the gene encoding the delta-9-stearoyl-acyl-carrier protein desaturase enzyme (SACPD-C) required for the conversion of stearic acid to oleic acid. Five of these missense mutations were in highly conserved residues clustered around the predicted di-iron center of the SACPD-C enzyme. Co-segregation analysis demonstrated a positive association of the elevated stearate trait with the SACPD-C mutation for three populations. These missense mutations may provide additional alleles that may be used in the development of new soybean cultivars with increased levels of stearic acid.

‣ Functional Studies of Tyrosine Hydroxylase Missense Variants Reveal Distinct Patterns of Molecular Defects in Dopa-Responsive Dystonia

Fossbakk, Agnete; Kleppe, Rune; Knappskog, Per M; Martinez, Aurora; Haavik, Jan
Fonte: BlackWell Publishing Ltd Publicador: BlackWell Publishing Ltd
Tipo: Artigo de Revista Científica
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Congenital tyrosine hydroxylase deficiency (THD) is found in autosomal-recessive Dopa-responsive dystonia and related neurological syndromes. The clinical manifestations of THD are variable, ranging from early-onset lethal disease to mild Parkinson disease-like symptoms appearing in adolescence. Until 2014, approximately 70 THD patients with a total of 40 different disease-related missense mutations, five nonsense mutations, and three mutations in the promoter region of the tyrosine hydroxylase (TH) gene have been reported. We collected clinical and biochemical data in the literature for all variants, and also generated mutant forms of TH variants previously not studied (N = 23). We compared the in vitro solubility, thermal stability, and kinetic properties of the TH variants to determine the cause(s) of their impaired enzyme activity, and found great heterogeneity in all these properties among the mutated forms. Some TH variants had specific kinetic anomalies and phenylalanine hydroxylase, and Dopa oxidase activities were measured for variants that showed signs of altered substrate binding. p.Arg233His, p.Gly247Ser, and p.Phe375Leu had shifted substrate specificity from tyrosine to phenylalanine and Dopa, whereas p.Cys359Phe had an impaired activity toward these substrates. The new data about pathogenic mechanisms presented are expected to contribute to develop individualized therapy for THD patients.

‣ PhosphoSitePlus, 2014: mutations, PTMs and recalibrations

Hornbeck, Peter V.; Zhang, Bin; Murray, Beth; Kornhauser, Jon M.; Latham, Vaughan; Skrzypek, Elzbieta
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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PhosphoSitePlus® (PSP, http://www.phosphosite.org/), a knowledgebase dedicated to mammalian post-translational modifications (PTMs), contains over 330 000 non-redundant PTMs, including phospho, acetyl, ubiquityl and methyl groups. Over 95% of the sites are from mass spectrometry (MS) experiments. In order to improve data reliability, early MS data have been reanalyzed, applying a common standard of analysis across over 1 000 000 spectra. Site assignments with P > 0.05 were filtered out. Two new downloads are available from PSP. The ‘Regulatory sites’ dataset includes curated information about modification sites that regulate downstream cellular processes, molecular functions and protein-protein interactions. The ‘PTMVar’ dataset, an intersect of missense mutations and PTMs from PSP, identifies over 25 000 PTMVars (PTMs Impacted by Variants) that can rewire signaling pathways. The PTMVar data include missense mutations from UniPROTKB, TCGA and other sources that cause over 2000 diseases or syndromes (MIM) and polymorphisms, or are associated with hundreds of cancers. PTMVars include 18 548 phosphorlyation sites, 3412 ubiquitylation sites, 2316 acetylation sites, 685 methylation sites and 245 succinylation sites.

‣ Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6

Vance, Caroline; Rogelj, Boris; Hortobágyi, Tibor; De Vos, Kurt J.; Nishimura, Agnes Lumi; Sreedharan, Jemeen; Hu, Xun; Smith, Bradley; Ruddy, Deborah; Wright, Paul; Ganesalingam, Jeban; Williams, Kelly L.; Tripathi, Vineeta; Al-Saraj, Safa; Al-Chalabi,
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 27/02/2009 Português
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is familial in 10% of cases. We have identified a missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6. In a survey of 197 familial ALS index cases, we identified two further missense mutations in eight families. Postmortem analysis of three cases with FUS mutations showed FUS-immunoreactive cytoplasmic inclusions and predominantly lower motor neuron degeneration. Cellular expression studies revealed aberrant localization of mutant FUS protein. FUS is involved in the regulation of transcription and RNA splicing and transport, and it has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration.

‣ Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy

Stromme, P.; Mangelsdorf, M.; Shaw, M.; Lower, K.; Lewis, S.; Bruyere, H.; Lutcherath, V.; Gedeon, A.; Wallace, R.; Scheffer, I.; Turner, G.; Partington, M.; Frints, S.; Fryns, J.P.; Sutherland, G.; Mulley, J.; Gecz, J.
Fonte: Nature America Inc Publicador: Nature America Inc
Tipo: Artigo de Revista Científica
Publicado em //2002 Português
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Mental retardation and epilepsy often occur together. They are both heterogeneous conditions with acquired and genetic causes. Where causes are primarily genetic, major advances have been made in unraveling their molecular basis. The human X chromosome alone is estimated to harbor more than 100 genes that, when mutated, cause mental retardation. At least eight autosomal genes involved in idiopathic epilepsy have been identified, and many more have been implicated in conditions where epilepsy is a feature. We have identified mutations in an X chromosome-linked, Aristaless-related, homeobox gene (ARX), in nine families with mental retardation (syndromic and nonspecific), various forms of epilepsy, including infantile spasms and myoclonic seizures, and dystonia. Two recurrent mutations, present in seven families, result in expansion of polyalanine tracts of the ARX protein. These probably cause protein aggregation, similar to other polyalanine and polyglutamine disorders. In addition, we have identified a missense mutation within the ARX homeodomain and a truncation mutation. Thus, it would seem that mutation of ARX is a major contributor to X-linked mental retardation and epilepsy.; Petter Strømme ; Marie E. Mangelsdorf ; Marie A. Shaw ; Karen M. Lower ; Suzanne M.e. Lewis ; Helene Bruyere ; Viggo Lütcherath ; Ági K. Gedeon ; Robyn H. Wallace ; Ingrid E. Scheffer ; Gillian Turner ; Michael Partington ; Suzanna G.m. Frints ; Jean-pierre Fryns ; Grant R. Sutherland ; John C. Mulley ; Jozef Gécz

‣ Mutations in PHF6 are associated with Börjeson-Forssman-Lehmann syndrome; Mutations in PHF6 are associated with Borjeson-Forssman-Lehmann syndrome

Lower, K.; Turner, G.; Kerr, B.; Mathews, K.; Shaw, M.; Gedeon, A.; Schelley, S.; Hoyme, H.; White, S.; Delatycki, M.; Lampe, A.; Clayton-Smith, J.; Stewart, H.; van Ravenswaay, C.; de Vries, B.; Cox, B.; Grompe, M.; Ross, S.; Thomas, P.; Mulley, J.; et a
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em //2002 Português
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Börjeson–Forssman–Lehmann syndrome (BFLS; OMIM 301900) is characterized by moderate to severe mental retardation, epilepsy, hypogonadism, hypometabolism, obesity with marked gynecomastia, swelling of subcutaneous tissue of the face, narrow palpebral fissure and large but not deformed ears. Previously, the gene associated with BFLS was localized to 17 Mb in Xq26–q27 (refs 2–4). We have reduced this interval to roughly 9 Mb containing more than 62 genes. Among these, a novel, widely expressed zinc-finger (plant homeodomain (PHD)-like finger) gene (PHF6) had eight different missense and truncation mutations in seven familial and two sporadic cases of BFLS. Transient transfection studies with PHF6 tagged with green fluorescent protein (GFP) showed diffuse nuclear staining with prominent nucleolar accumulation. Such localization, and the presence of two PHD-like zinc fingers, is suggestive of a role for PHF6 in transcription.; Karen M. Lower, Gillian Turner, Bronwyn A. Kerr, Katherine D. Mathews, Marie A. Shaw, Ági K. Gedeon, Susan Schelley, H. Eugene Hoyme, Susan M. White, Martin B. Delatycki, Anne K. Lampe, Jill Clayton-Smith, Helen Stewart, Conny M.A. van Ravenswaay, Bert B.A. de Vries, Barbara Cox, Markus Grompe, Shelley Ross...

‣ The original Lujan syndrome family has a novel missense mutation (p. N1007S) in the MED12 gene

Schwartz, C.; Tarpey, P.; Lubs, H.; Verloes, A.; May, M.; Risheg, H.; Friez, M.; Futreal, P.; Edkins, S.; Teague, J.; Briault, S.; Skinner, C.; Bauer-Carlin, A.; Simensin, R.; Joseph, S.; Jones, J.; Gecz, J.; Stratton, M.; Raymond, F.; Stevenson, R.
Fonte: British Med Journal Publ Group Publicador: British Med Journal Publ Group
Tipo: Artigo de Revista Científica
Publicado em //2007 Português
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A novel missense mutation in the mediator of RNA polymerase II transcription subunit 12 (MED12) gene has been found in the original family with Lujan syndrome and in a second family (K9359) that was initially considered to have Opitz–Kaveggia (FG) syndrome. A different missense mutation in the MED12 gene has been reported previously in the original family with FG syndrome and in five other families with compatible clinical findings. Neither sequence alteration has been found in over 1400 control X chromosomes. Lujan (Lujan–Fryns) syndrome is characterised by tall stature with asthenic habitus, macrocephaly, a tall narrow face, maxillary hypoplasia, a high narrow palate with dental crowding, a small or receding chin, long hands with hyperextensible digits, hypernasal speech, hypotonia, mild-to-moderate mental retardation, behavioural aberrations and dysgenesis of the corpus callosum. Although Lujan syndrome has not been previously considered to be in the differential diagnosis of FG syndrome, there are some overlapping clinical manifestations. Specifically, these are dysgenesis of the corpus callosum, macrocephaly/relative macrocephaly, a tall forehead, hypotonia, mental retardation and behavioural disturbances. Thus, it seems that these two X-linked mental retardation syndromes are allelic...

‣ Gaucher disease in sheep

Karageorgos, L.; Lancaster, M.; Nimmo, J.; Hopwood, J.
Fonte: Kluwer Academic Publ Publicador: Kluwer Academic Publ
Tipo: Artigo de Revista Científica
Publicado em //2011 Português
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Gaucher disease, an autosomal recessive lysosomal storage disorder caused by mutations in the β-glucocerebrosidase gene, was recently discovered in sheep on a "Southdown" sheep stud in Victoria, Australia. Clinical signs include neuropathy, thickened leathery skin, and ichthyosis, with lambs unable to stand from birth. Affected lambs were found to be deficient in glucocerebrosidase activity, and mutational analysis found them to be homozygous for the missense mutations c.1142G>A (p.C381Y) and c.1400C>T (p.P467L). In addition, four silent mutations were detected (c.777C>A [p.Y259Y], c1203A>G [p.Q401Q], c.1335T>C [p.I445I], c.1464C>G [p.L488L]). The human equivalent [C342Y] to the C381Y mutation leads to an acute neuronopathic phenotype in patients. Identification of an acute neuronopathic form of Gaucher disease in sheep provides a large animal model that will enable studies of pathology and evaluation of therapies to treat this common lysosomal storage disorder.

‣ The role of Aristaless related homeobox (ARX) gene mutations in intellectual disability.

Fullston, Tod
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2012 Português
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Intellectual disability (ID) affects ~1-3% of the population, profoundly impacting the lives of affected individuals and their families. An approximate 30% excess of males with ID implicates X-chromosome genes. The most common inherited form of ID is fragile-X syndrome, affecting ~1/5,000 live male births. Another X-linked gene, the aristaless related homeobox (ARX) gene, is also frequently mutated causing X-linked ID (XLID). At least 50 pathogenic mutations spanning the ARX open reading frame (ORF) have been reported in 110 families. These mutations cause at least 10 clinically distinct pathologies, all of which include ID. These clinical entities range in severity from X-linked lissencephaly with ambiguous genitalia (XLAG) to mild ID with no other consistent clinical features. Of the known ARX mutations 60% occur in the section of the ORF that encodes for the first two tracts of uninterrupted alanine, ie polyalanine (pA) tracts. This is likely due to the extraordinarily high GC content of these regions of the gene (>97%). Two recurrent mutations (c.304ins(GCG)₇ – pA1 and c.429_452dup – pA2) arise from expansion of their respective pA tracts. The c.429_452dup mutation alone accounts for ~40% of all reported ARX mutations. To assess the frequency of ARX mutations among the intellectually disabled...

‣ Computational approaches for predicting the biological effect of p53 missense mutations: a comparison of three sequence analysis based methods

Mathe, Ewy; Olivier, Magali; Kato, Shunsuke; Ishioka, Chikashi; Hainaut, Pierre; Tavtigian, Sean V.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Prediction of the biological effect of missense substitutions has become important because they are often observed in known or candidate disease susceptibility genes. In this paper, we carried out a 3-step analysis of 1514 missense substitutions in the DNA-binding domain (DBD) of TP53, the most frequently mutated gene in human cancers. First, we calculated two types of conservation scores based on a TP53 multiple sequence alignment (MSA) for each substitution: (i) Grantham Variation (GV), which measures the degree of biochemical variation among amino acids found at a given position in the MSA; (ii) Grantham Deviation (GD), which reflects the ‘biochemical distance’ of the mutant amino acid from the observed amino acid at a particular position (given by GV). Second, we used a method that combines GV and GD scores, Align-GVGD, to predict the transactivation activity of each missense substitution. We compared our predictions against experimentally measured transactivation activity (yeast assays) to evaluate their accuracy. Finally, the prediction results were compared with those obtained by the program Sorting Intolerant from Tolerant (SIFT) and Dayhoff's classification. Our predictions yielded high prediction accuracy for mutants showing a loss of transactivation (∼88% specificity) with lower prediction accuracy for mutants with transactivation similar to that of the wild-type (67.9 to 71.2% sensitivity). Align-GVGD results were comparable to SIFT (88.3 to 90.6% and 67.4 to 70.3% specificity and sensitivity...

‣ Discovery of catalytically active orthologues of the Parkinson's disease kinase PINK1: analysis of substrate specificity and impact of mutations

Woodroof, Helen I.; Pogson, Joe H.; Begley, Mike; Cantley, Lewis C.; Deak, Maria; Campbell, David G.; van Aalten, Daan M. F.; Whitworth, Alexander J.; Alessi, Dario R.; Muqit, Miratul M. K.
Fonte: The Royal Society Publicador: The Royal Society
Tipo: Artigo de Revista Científica
Publicado em /11/2011 Português
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Missense mutations of the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) gene cause autosomal-recessive Parkinson's disease. To date, little is known about the intrinsic catalytic properties of PINK1 since the human enzyme displays such low kinase activity in vitro. We have discovered that, in contrast to mammalian PINK1, insect orthologues of PINK1 we have investigated—namely Drosophila melanogaster (dPINK1), Tribolium castaneum (TcPINK1) and Pediculus humanus corporis (PhcPINK1)—are active as judged by their ability to phosphorylate the generic substrate myelin basic protein. We have exploited the most active orthologue, TcPINK1, to assess its substrate specificity and elaborated a peptide substrate (PINKtide, KKWIpYRRSPRRR) that can be employed to quantify PINK1 kinase activity. Analysis of PINKtide variants reveal that PINK1 phosphorylates serine or threonine, but not tyrosine, and we show that PINK1 exhibits a preference for a proline at the +1 position relative to the phosphorylation site. We have also, for the first time, been able to investigate the effect of Parkinson's disease-associated PINK1 missense mutations, and found that nearly all those located within the kinase domain, as well as the C-terminal non-catalytic region...

‣ Discovery of Catalytically Active Orthologues of the Parkinson's Disease Kinase PINK1: Analysis of Substrate Specificity and Impact of Mutations

Woodroof, Helen I.; Pogson, Joe H.; Begley, Mike; Deak, Maria; van Aalten, Daan M. F.; Whitworth, Alexander J.; Alessi, Dario R.; Muqit, Miratul M. K.; Cantley, Lewis C.; Campbell, David G.
Fonte: The Royal Society Publicador: The Royal Society
Tipo: Artigo de Revista Científica
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Missense mutations of the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) gene cause autosomal-recessive Parkinson's disease. To date, little is known about the intrinsic catalytic properties of PINK1 since the human enzyme displays such low kinase activity in vitro. We have discovered that, in contrast to mammalian PINK1, insect orthologues of PINK1 we have investigated—namely Drosophila melanogaster (dPINK1), Tribolium castaneum (TcPINK1) and Pediculus humanus corporis (PhcPINK1)—are active as judged by their ability to phosphorylate the generic substrate myelin basic protein. We have exploited the most active orthologue, TcPINK1, to assess its substrate specificity and elaborated a peptide substrate (PINKtide, KKWIpYRRSPRRR) that can be employed to quantify PINK1 kinase activity. Analysis of PINKtide variants reveal that PINK1 phosphorylates serine or threonine, but not tyrosine, and we show that PINK1 exhibits a preference for a proline at the +1 position relative to the phosphorylation site. We have also, for the first time, been able to investigate the effect of Parkinson's disease-associated PINK1 missense mutations, and found that nearly all those located within the kinase domain, as well as the C-terminal non-catalytic region...

‣ Cancer associated missense mutations in BAP1 catalytic domain induce amyloidogenic aggregation: A new insight in enzymatic inactivation

Bhattacharya, Sushmita; Hanpude, Pranita; Maiti, Tushar Kanti
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Text
Publicado em 18/12/2015 Português
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BRCA1 associated protein 1 (BAP1) is a nuclear deubiquitinase that regulates tumor suppressor activity and widely involves many cellular processes ranging from cell cycle regulation to gluconeogenesis. Impairment of enzymatic activity and nuclear localization induce abnormal cell proliferation. It is considered to be an important driver gene, which undergoes frequent mutations in several cancers. However the role of mutation and oncogenic gain of function of BAP1 are poorly understood. Here, we investigated cellular localization, enzymatic activity and structural changes for four missense mutants of the catalytic domain of BAP1, which are prevalent in different types of cancer. These mutations triggered cytoplasmic/perinuclear accumulation in BAP1 deficient cells, which has been observed in proteins that undergo aggregation in cellular condition. Amyloidogenic activity of mutant BAP1 was revealed from its reactivity towards anti oligomeric antibody in HEK293T cells. We have also noted structural destabilization in the catalytic domain mutants, which eventually produced beta amyloid structure as indicated in atomic force microscopy study. The cancer associated mutants up-regulate heat shock response and activates transcription of genes normally co-repressed by BAP1. Overall...