Página 29 dos resultados de 4394 itens digitais encontrados em 0.009 segundos

‣ CYLD mutations in familial skin appendage tumours

SAGGAR, S.; CHERNOFF, K. A.; LODHA, S.; HOREV, L.; KOHL, S.; HONJO, R. S.; BRANDT, H. R. C.; HARTMANN, K.; CELEBI, J. T.
Fonte: B M J PUBLISHING GROUP Publicador: B M J PUBLISHING GROUP
Tipo: Artigo de Revista Científica
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Background: Germ-line mutations in CYLD are found in patients with familial skin appendage tumours. The protein product functions as a deubiquitinase enzyme, which negatively regulates NF-kappa B and c-Jun N-terminal kinase signalling. Brooke-Spiegler syndrome (BSS) is characterised by cylindromas, trichoepitheliomas and spiradenomas, whereas in familial cylindromatosis (FC) patients present with cylindromas and in multiple familial trichoepitheliomas (MFT) with trichoepitheliomas as the only skin tumour type. Although described as distinct entities, recent studies suggest that they are within the spectrum of a single entity. Objective: To investigate the mutation spectrum of CYLD and possible genotype-phenotype correlations. Methods: 25 families including 13 BSS, 3 FC, and 9 MFT families were examined and evaluated for mutations in the CYLD gene. Results: In total, 18 mutations in CYLD, including 6 novel mutations, were identified in 25 probands (72%). The mutation frequencies among distinct phenotypes were 85% for BSS, 100% for FC, and 44% for MFT. The majority of the mutations were insertions, deletions or nonsense mutations leading to formation of truncated proteins. All mutations were located between exons 9 to 20, encoding the NEMO binding site and the catalytic domain. Genotype-phenotype analysis failed to reveal a correlation between the types of mutations and their location within the gene and the patients` phenotypes and disease severity. Conclusions: This study provides further evidence on the role of CYLD in the pathogenesis of skin appendage tumours characterised by cylindromas...

‣ Alterações moleculares nos genes da activina (Activin receptor-like kinase-1-ALK-1) e endoglina (ENG) em telangiectasia hemorrágica hereditária tipo 1 e 2; Three novel mutations in the activin receptor-like kinase 1 (ALK-1) gene in hereditary hemorrhagic telangectasia type 2 in brazilian patients

Ângela Maria de Assis
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 22/02/2007 Português
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A Telangiectasia Hemorrágica Hereditária (THH) é uma desordem autossômica dominante caracterizada por epistaxe recorrente, telangiectases mucocutânea, hemorragia gastrointestinal, e malformação arteriovenosa pulmonar (PAVM), cerebral e hepática. A prevalência da doença é de 1/5000 e a mortalidade relatada da doença entre pacientes jovens quando comparado com aqueles com mais de 60 anos é de 36%. Dois genes da superfamília de receptores para TGF-β têm sido relacionados com THH, o gene da endoglina e o gene da activina (activin receptor-like-kinase). Estes genes são altamente expressos em células endoteliais e outros tecidos altamente vascularizados como pulmão e placenta. Mutações no gene da endoglina causam a THH tipo 1 que é caracterizada pela alta incidência de malformação arteriovenosa pulmonar sintomática (PAVMs). Mutações no gene da activina levam a THH tipo 2 caracterizada por epistaxe recorrente e malformação arteriovenosa gastrointestinal. Foi objetivo deste trabalho realizar uma triagem de mutações na região codificadora dos genes ALK-1 e endoglina em doze pacientes portadores de THH atendidos no Hemocentro da Unicamp. A abordagem metodológica incluiu a amplificação dos exóns dos genes da activina e endoglina seguida pela técnica de PCR/CSGE...

‣ Detection of mutations within exons 4 to 8 of the p53 tumor suppressor gene in canine mammary glands

Souza,D.M.B.; Barros,M.G.O.; Silva,J.S.C.; Silva,M.B.; Coleto,Z.F.; Jimenez,G.C.; Adrião,M.; Wischral,A.
Fonte: Universidade Federal de Minas Gerais, Escola de Veterinária Publicador: Universidade Federal de Minas Gerais, Escola de Veterinária
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/04/2012 Português
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Fifteen female canines with mammary tumors and 6 normal females were used to study mutations in exons 4 to 8 of the p53 gene. DNA samples from the tumors, respective adjacent normal mammary tissue and mammary glands from healthy animals were sequenced and analyzed for the presence of mutations. Mutations were found in 71.8% of the samples and the most frequent were missense mutations. The most attacked exons in the mammary tumor were 5, 7 and 8, with 23.4, 31.6 and 23.4% mutations, respectively. Canine mammary tumors are related to mutations in gene p53 and mutations mostly occur in the region of the protein that is linked to the DNA in the cell nucleus, which can change the functionality of the cell and propitiate tumor growth. Despite being macroscopically normal, the mammary tissue adjacent to the tumors has mutations that can lead to recurrence if not removed together with the tumor.

‣ Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma.

Diller, L; Sexsmith, E; Gottlieb, A; Li, F P; Malkin, D
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/1995 Português
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We investigated the possibility that a proportion of children with sporadic rhabdomyosarcoma (RMS) carry constitutional mutations of the p53 tumor suppressor gene. 33 patients with sporadic RMS at two large outpatient pediatric oncology clinics submitted blood samples. Genomic DNA was extracted from peripheral blood leukocytes and PCR was used to amplify exons 2-11 of the p53 gene. Amplified genomic DNA was screened for the presence of germline p53 mutations using single-strand conformation polymorphism (SSCP) analysis. The DNA sequence of those samples that showed aberrant migration of bands on SSCP analysis was determined to identify the precise nature of the gene mutations. Patient records were reviewed to assess clinical correlates of the mutant p53 carrier state. Heterozygous constitutional mutations were detected in 3/33 patient samples screened. Two of these missense mutations are located in exon 7 and one in exon 8 of the p53 gene. The presence of mutations was not correlated with tumor histology, stage, or site. However, an association between young age at diagnosis and presence of a constitutional p53 mutation was noted: 3/13 children under the age of 3 yr at diagnosis carried mutations, whereas none of 20 children over 3 yr of age at diagnosis harbored a detectable constitutional mutation. These results in children with RMS corroborates previous findings in other clinical settings suggesting that the mutant p53 carrier state may predispose individuals to malignancy at an early age. Although this study did not assess whether the mutations were preexisting or new germline alterations...

‣ Mutations in the Fumarate Hydratase Gene Cause Hereditary Leiomyomatosis and Renal Cell Cancer in Families in North America

Toro, Jorge R.; Nickerson, Michael L.; Wei, Ming-Hui; Warren, Michelle B.; Glenn, Gladys M.; Turner, Maria L.; Stewart, Laveta; Duray, Paul; Tourre, Ousman; Sharma, Nirmala; Choyke, Peter; Stratton, Pamela; Merino, Maria; Walther, McClellan M.; Linehan, W
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder characterized by smooth-muscle tumors of the skin and uterus and/or renal cancer. Although the identification of germline mutations in the fumarate hydratase (FH) gene in European families supports it as the susceptibility gene for HLRCC, its role in families in North America has not been studied. We screened for germline mutations in FH in 35 families with cutaneous leiomyomas. Sequence analysis revealed mutations in FH in 31 families (89%). Twenty different mutations in FH were identified, of which 18 were novel. Of these 20 mutations, 2 were insertions, 5 were small deletions that caused frameshifts leading to premature truncation of the protein, and 13 were missense mutations. Eleven unrelated families shared a common mutation: R190H. Eighty-one individuals (47 women and 34 men) had cutaneous leiomyomas. Ninety-eight percent (46/47) of women with cutaneous leiomyomas also had uterine leiomyomas. Eighty-nine percent (41/46) of women with cutaneous and uterine leiomyomas had a total hysterectomy, 44% at age ⩽30 years. We identified 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from four families had papillary type II renal cell carcinoma...

‣ Calpainopathy-a survey of mutations and polymorphisms.

Richard, I; Roudaut, C; Saenz, A; Pogue, R; Grimbergen, J E; Anderson, L V; Beley, C; Cobo, A M; de Diego, C; Eymard, B; Gallano, P; Ginjaar, H B; Lasa, A; Pollitt, C; Topaloglu, H; Urtizberea, J A; de Visser, M; van der Kooi, A; Bushby, K; Bakker, E; Lop
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/1999 Português
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Limb-girdle muscular dystrophy type 2A (LGMD2A) is an autosomal recessive disorder characterized mainly by symmetrical and selective atrophy of the proximal limb muscles. It derives from defects in the human CAPN3 gene, which encodes the skeletal muscle-specific member of the calpain family. This report represents a compilation of the mutations and variants identified so far in this gene. To date, 97 distinct pathogenic calpain 3 mutations have been identified (4 nonsense mutations, 32 deletions/insertions, 8 splice-site mutations, and 53 missense mutations), 56 of which have not been described previously, together with 12 polymorphisms and 5 nonclassified variants. The mutations are distributed along the entire length of the CAPN3 gene. Thus far, most mutations identified represent private variants, although particular mutations have been found more frequently. Knowledge of the mutation spectrum occurring in the CAPN3 gene may contribute significantly to structure/function and pathogenesis studies. It may also help in the design of efficient mutation-screening strategies for calpainopathies.

‣ Identification of Novel Missense Mutations of Cardiac Ryanodine Receptor Gene in Exercise-Induced Sudden Death at Autopsy

Creighton, Wendy; Virmani, Renu; Kutys, Robert; Burke, Allen
Fonte: American Society for Investigative Pathology Publicador: American Society for Investigative Pathology
Tipo: Artigo de Revista Científica
Publicado em /02/2006 Português
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Mutations in the cardiac ryanodine type 2 receptor (RyR2) gene are associated with catecholaminergic polymorphic ventricular tachycardia. We hypothesized that these mutations could be detected at autopsy in cases of exercise-triggered sudden death. Fourteen sudden death patients, eight males and six females, were studied at autopsy based on apparent sudden cardiac death, without significant anatomical abnormalities. The coding regions of arrhythmia genes were amplified by polymerase chain reaction and directly sequenced. Three novel RyR2 mutations, R414C, F2331S, and R2401L, were identified in three unrelated patients (two males and one female; mean age at death, 12 ± 2 years), all performing strenuous activity at the time of death or collapse. These mutations were located in highly conserved regions where arrhythmia-linked RyR2 mutations clustered. Although G269S in the KVLQT1 gene was detected in a female with known family history of syncope and sudden cardiac death, no other mutations were found in any of the 14 cases, and no other mutations was found in 200 controls. The absence of structural cardiac disease in physical activity-induced sudden death and the finding of three novel RyR2 mutations suggest that mutation screening in such cases should include RyR2.

‣ Overexpression of bax Associated with Mutations in the Loop-Sheet-Helix Motif of p53

Huang, Cheng-long; Kohno, Nobuoki; Inufusa, Haruhiko; Kodama, Ken; Taki, Toshihiko; Miyake, Masayuki
Fonte: American Society for Investigative Pathology Publicador: American Society for Investigative Pathology
Tipo: Artigo de Revista Científica
Publicado em /09/1999 Português
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Recent investigations have revealed that mutations of the loop-sheet-helix motif of p53 is a significant factor for a poor prognosis in patients with non-small-cell lung cancer (NSCLC). To clarify this mechanism, bcl-2 and bax expression were evaluated in relation to mutations of p53. Tumor tissues of 203 patients with NSCLC were analyzed. Immunohistochemistry was performed to evaluate bcl-2 and bax expression, and polymerase chain reaction single-strand conformation polymorphism following direct sequencing was performed to investigate p53 status. A total of 79 carcinomas were bcl-2 positive, 146 carcinomas were bax positive, and 72 carcinomas had missense mutations of p53. There was no difference in bcl-2 expression in relation to p53 status. On the other hand, tumors with structural mutations of p53 had significantly lower expression of bax than those with wild-type p53 (P = 0.0026). In contrast, tumors with mutations of the loop-sheet-helix motif of p53 had significantly higher expression of bax than those with wild-type p53 (P = 0.0236). The frequency of a bcl-2/bax ratio of ≥1 was significantly lower in tumors with mutations of the loop-sheet-helix motif than that in tumors with wild-type p53 (P = 0.0240). The bcl-2/bax ratio status was a significant factor for a prognosis in patients with NSCLC (P = 0.0083). Mutations of the loop-sheet-helix motif of p53 were correlated with overexpression of bax...

‣ Spectrum of mutations in the COL4A5 collagen gene in X-linked Alport syndrome.

Knebelmann, B.; Breillat, C.; Forestier, L.; Arrondel, C.; Jacassier, D.; Giatras, I.; Drouot, L.; Deschênes, G.; Grünfeld, J. P.; Broyer, M.; Gubler, M. C.; Antignac, C.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/1996 Português
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Alport syndrome is a mainly X-linked hereditary disease of basement membranes that is characterized by progressive renal failure, deafness, and ocular lesions. It is associated with mutations of the COL4A5 gene located at Xq22 and encoding the alpha5 chain of type IV collagen. We have screened 48 of the 51 exons of the COL4A5 gene by SSCP analysis and have identified 64 mutations and 10 sequence variants among 131 unrelated Alport syndrome patients. This represents a mutation-detection rate of 50%. There were no hot-spot mutations and no recurrent mutations in our population. The identified mutations were 6 nonsense mutations, 12 frameshift mutations, 17 splice-site mutations, and 29 missense mutations, 27 of the latter being glycine substitutions in the collagenous domain. Two of these occurred on the same allele in one patient and segregated with the disease in the family. We showed that some of the glycine substitutions could be associated with the lack of immunological expression of the alpha3(IV)-alpha5(IV) collagen chains in the glomerular basement membrane.

‣ Paroxysmal extreme pain disorder mutations within the D3/S4–S5 linker of Nav1.7 cause moderate destabilization of fast inactivation

Jarecki, Brian W; Sheets, Patrick L; Jackson II, James O; Cummins, Theodore R
Fonte: Blackwell Science Inc Publicador: Blackwell Science Inc
Tipo: Artigo de Revista Científica
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Single-point missense mutations in the peripheral neuronal voltage-gated sodium channel Nav1.7 are implicated in the painful inherited neuropathy paroxysmal extreme pain disorder (PEPD). The Nav1.7 PEPD mutations are located in regions of the channel suggested to play important roles in fast inactivation. PEPD mutations in the putative inactivation gate have been reported to significantly impair fast inactivation, resulting in pronounced persistent currents. However, PEPD mutations in the S4–S5 linker of domain 3 (D3/S4–S5) had not been characterized and the roles of specific residues in this linker in channel gating are unclear. We functionally characterized two of the D3/S4–S5 PEPD mutations (V1298F and V1299F) and compared their effects on gating to an adjacent non-PEPD mutation (V1300F) and the I1461T PEPD mutation, located in the putative inactivation gate. The primary effect of the V1298F and V1299F mutations is to shift the voltage dependence of fast inactivation by ∼20 mV in the depolarizing direction. We observed a similar effect with the PEPD mutation I1461T. Interestingly, while all three PEPD mutations increased persistent currents, the relative amplitudes (∼6% of peak) were much smaller than previously reported for the I1461T mutation. In contrast...

‣ PHEX Gene Mutations and Genotype-Phenotype Analysis of Korean Patients with Hypophosphatemic Rickets

Song, Hae-Ryong; Park, Joo-Won; Cho, Dae-Yeon; Yang, Jae Hyuk; Yoon, Hye-Ran; Jung, Sung-Chul
Fonte: The Korean Academy of Medical Sciences Publicador: The Korean Academy of Medical Sciences
Tipo: Artigo de Revista Científica
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X-linked hypophosphatemic rickets (XLH) results from mutations in the PHEX gene. Mutational analysis of the PHEX gene in 15 unrelated Korean patients with hypophosphatemic rickets revealed eight mutations, including five novel mutations, in nine patients: two nonsense mutations, two missense mutations, one insertion, and three splicing acceptor/donor site mutations. Of these, c.64G>T, c.1699C>T, c.466_467 insAC, c.1174-1G>A, and c.1768+5G>A were novel mutations. To analyze the correlation between genotype and phenotype, phenotypes were compared between groups with and without a mutation, in terms of mutation location, mutation type, and sex. Skeletal disease tended to be more severe in the group with a mutation in the C-terminal half of the PHEX gene, but no genotype-phenotype correlation was detected in other comparisons. Further extensive studies of the PHEX gene mutations and analyses of the genotype-phenotype relationships are required to understand PHEX function and the pathogenesis of XLH.

‣ Recurrent KRAS Codon 146 Mutations in Human Colorectal Cancer

Edkins, Sarah; O’Meara, Sarah; Parker, Adrian; Stevens, Claire; Reis, Marcelo; Jones, Siân; Greenman, Chris; Davies, Helen; Dalgliesh, Gillian; Forbes, Simon; Hunter, Chris; Smith, Raffaella; Stephens, Philip; Goldstraw, Peter; Nicholson, Andrew; Chan,
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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An activating point mutation in codon 12 of the HRAS gene was the first somatic point mutation identified in a human cancer and established the role of somatic mutations as the common driver of oncogenesis. Since then, there have been over 11,000 mutations in the three RAS (HRAS, KRAS and NRAS) genes in codons 12, 13 and 61 reported in the literature. We report here the identification of recurrent somatic missense mutations at alanine 146, a highly conserved residue in the guanine nucleotide binding domain. In two independent series of colorectal cancers from Hong Kong and the United States we detected KRAS A146 mutations in 7/126 and 2/94 cases, respectively, giving a combined frequency of 4%. We also detected KRAS A146 mutations in 2/40 (5%) colorectal cell lines, including the NCI-60 colorectal cancer line HCC2998. Codon 146 mutations thus are likely to make an equal or greater contribution to colorectal cancer than codon 61 mutations (4.2% in our combined series, 1% in the literature). Lung adenocarcinomas and large cell carcinomas did not show codon 146 mutations. We did, however, identify a KRAS A146 mutation in the ML-2 acute myeloid leukemia cell line and an NRAS A146 mutation in the NALM-6 B-cell acute lymphoblastic leukemia line...

‣ Nav1.7 mutations associated with paroxysmal extreme pain disorder, but not erythromelalgia, enhance Navβ4 peptide-mediated resurgent sodium currents

Theile, Jonathan W; Jarecki, Brian W; Piekarz, Andrew D; Cummins, Theodore R
Fonte: Blackwell Science Inc Publicador: Blackwell Science Inc
Tipo: Artigo de Revista Científica
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Inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD) are inherited pain syndromes predominantly caused by missense mutations in the peripheral neuronal voltage-gated sodium channel (Nav) isoform Nav1.7. While both IEM and PEPD mutations increase neuronal excitability, IEM mutations primarily enhance activation and PEPD mutations impair inactivation. In addition, one PEPD mutation, Nav1.7-I1461T, has been shown to increase resurgent sodium currents in dorsal root ganglion (DRG) neurons. Because resurgent currents have been implicated in increased neuronal excitability, we asked whether (1) additional PEPD mutations located within the putative inactivation gate and docking sites and (2) IEM mutations might also increase these unusual currents. Resurgent currents are generated following open-channel block at positive potentials by an endogenous blocking particle and subsequent expulsion of this blocker upon repolarization to moderately negative potentials. Here we used a mimetic of the putative blocking particle, the Navβ4 peptide, to determine if enhanced resurgent currents are induced by three distinct PEPD mutations and two IEM mutations in stably transfected HEK293 cells. We demonstrate that (1) Nav1.7-mediated resurgent currents are observed in HEK293 cells with the Navβ4 peptide in the recording pipette...

‣ Frequent Heterogeneous Missense Mutations of GGAP2 in Prostate Cancer: Implications for Tumor Biology, Clonality and Mutation Analysis

Cai, Yi; Wang, Jianghua; Ren, Chengxi; Ittmann, Michael
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 28/02/2012 Português
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Prostate cancer is the most common visceral malignancy in Western men and a major cause of cancer deaths. Increased activation of the AKT and NFkB pathways have been identified as critical steps in prostate cancer initiation and progression. GGAP2 (GTP-binding and GTPase activating protein 2) is a multidomain protein that contains an N-terminal Ras homology domain (GTPase), followed by a PH domain, a C-terminal GAP domain and an ankyrin repeat domain. GGAP2 can directly activate signaling via both the AKT and NFkB pathways and acts as a node of crosstalk between these pathways. Increased GGAP2 expression is present in three quarters of prostate cancers. Mutations of GGAP2 have been reported in cell lines from other malignancies. We therefore analyzed 84 prostate cancer tissues and 43 benign prostate tissues for somatic mutations in GGAP2 by direct sequencing of individual clones derived from the GAP and GTPase domains of normal and tumor tissue. Overall, half of cancers contained mutant GAP domain clones and in 20% of cancers, 30% or more of clones were mutant in the GAP domain. Surprisingly, the mutations were heterogeneous and nonclonal, with multiple different mutations being present in many tumors. Similar findings were observed in the analysis of the GTPase domain. Mutant GGAP2 proteins had significantly higher transcriptional activity using AP-1 responsive reporter constructs when compared to wild-type protein. Furthermore...

‣ Structure–phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia

Haider, Shozeb; Islam, Barira; D’Atri, Valentina; Sgobba, Miriam; Poojari, Chetan; Sun, Li; Yuen, Tony; Zaidi, Mone; New, Maria I.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Mutations in the cytochrome p450 (CYP)21A2 gene, which encodes the enzyme steroid 21-hydroxylase, cause the majority of cases in congenital adrenal hyperplasia, an autosomal recessive disorder. To date, more than 100 CYP21A2 mutations have been reported. These mutations can be associated either with severe salt-wasting or simple virilizing phenotypes or with milder nonclassical phenotypes. Not all CYP21A2 mutations have, however, been characterized biochemically, and the clinical consequences of these mutations remain unknown. Using the crystal structure of its bovine homolog as a template, we have constructed a humanized model of CYP21A2 to provide comprehensive structural explanations for the clinical manifestations caused by each of the known disease-causing missense mutations in CYP21A2. Mutations that affect membrane anchoring, disrupt heme and/or substrate binding, or impair stability of CYP21A2 cause complete loss of function and salt-wasting disease. In contrast, mutations altering the transmembrane region or conserved hydrophobic patches cause up to a 98% reduction in enzyme activity and simple virilizing disease. Mild nonclassical disease can result from interference in oxidoreductase interactions, salt-bridge and hydrogen-bonding networks...

‣ X-linked, COL4A5 hypomorphic Alport mutations such as G624D and P628L may only exhibit thin basement membrane nephropathy with microhematuria and late onset kidney failure

Pierides, A; Voskarides, K; Kkolou, M; Hadjigavriel, M; Deltas, C
Fonte: SOCIETY OF "FRIENDS OF HIPPOKRATIA JOURNAL" Publicador: SOCIETY OF "FRIENDS OF HIPPOKRATIA JOURNAL"
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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Alport syndrome (ATS) results from X-linked, COL4A5 mutations (85%) or from autosomal recessive homozygous or compound heterozygous COL4A3/A4 mutations (15%), associated with alternate thinning and thickening as well as splitting and lamellation of the glomerular basement membranes. In contrast, familial microhematuria with thin basement membranes is thought to result from heterozygous COL4A3/A4 mutations. This absolute separation may not always be true. Renal biopsies and molecular genetics were used to study microhematuric families in the Hellenic population we serve. The COL4A5 gene was studied by PCR and direct re-sequencing for new mutations, while PCR-RFLP was used to identify more carriers of known COL4A5 and COL4A3/A4 mutations. Molecular genetics in two undiagnosed microhematuric Cypriot families, revealed COL4A5 mutation P628L indicating X-linked ATS. Of nine males, seven developed end stage kidney disease (ESKD) between 31 and 56, while two are well at 51 and 57, exhibiting microhematuria and thin basement membrane nephropathy (TBMN). COL4A5 mutation G624D was also identified in six Greek families. Seventy five members had DNA tests and 37 proved positive. Four positive males developed ESKD at 61, 51, 50 and 39 years, while the remaining and all females showed only microhematuria. A literature search revealed eight papers with six similar hypomorphic COL4A5 mutations presenting as phenocopies of TBMN. In conclusion...

‣ The Genotype and Phenotype of Patients with Gonadotropin Releasing Hormone Receptor Mutations

Kim, Hyung-Goo; Pedersen-White, Jennifer; Bhagavath, Balasubramanian; Layman, Lawrence C.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Human mutations in the gonadotropin releasing hormone receptor (GNRHR) gene cause autosomal recessive, normosmic idiopathic hypogonadotropic hypogonadism (IHH). At least 19 different mutations have been identified in this G-protein coupled receptor, which consist mostly of missense mutations. The Gln106Arg and Arg262Gln mutations comprise nearly half of the identified alleles. Most mutations impair ligand binding and all compromise cell signaling events. Some of the mutations also adversely affect activation of gonadotropin subunit or Gnrhr gene promoters. Interestingly, a number of the mutant GnRHRs can be rescued in vitro from misfolding and degradation within the cell by the addition of a GnRHR antagonist IN3. Most affected patients have compound heterozygous GNRHR mutations that may cause either complete IHH (no evidence of puberty) or incomplete IHH (partial evidence of puberty), although some genotypes are associated with mild disease in some families and severe disease in others. GNRHR mutations also appear to cause constitutional delay of puberty, and one genotype (homozygosity for Gln106Arg) may be reversible in patients with IHH. Mutations in the human GNRHR have contributed greatly to the understanding of normosmic IHH, as well as the structure and function of the GnRHR.

‣ Identification of speckle-type POZ protein somatic mutations in African American prostate cancer

Buckles, Eric; Qian, Chiping; Tadros, Andrew; Majumdar, Sumana; Cvitanovic, Jennifer; Zabaleta, Jovanny; Estrada, John; Wilson, John; Liu, Wanguo
Fonte: Medknow Publications & Media Pvt Ltd Publicador: Medknow Publications & Media Pvt Ltd
Tipo: Artigo de Revista Científica
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The speckle-type POZ protein (SPOP) is a tumor suppressor in prostate cancer (PCa). SPOP somatic mutations have been reported in up to 15% of PCa of those of European descent. However, the genetic roles of SPOP in African American (AA)-PCa are currently unknown. We sequenced the SPOP gene to identify somatic mutations in 49 AA prostate tumors and identified three missense mutations (p.Y87C, p.F102S, and p.G111E) in five AA prostate tumors (10%) and one synonymous variant (p.I106I) in one tumor. Intriguingly, all of mutations and variants clustered in exon six, and all of the mutations altered conserved amino acids. Moreover, two mutations (p.F102S and p.G111E) have only been identified in AA-PCa to date. Quantitative real-time polymerase chain reaction analysis showed a lower level of SPOP expression in tumors carrying SPOP mutations than their matched normal prostate tissues. In addition, SPOP mutations and novel variants were detected in 5 of 27 aggressive PCa and one of 22 less aggressive PCa (P < 0.05). Further studies with increased sample size are needed to validate the clinicopathological significance of these SPOP mutations in AA-PCa.

‣ Systematic Mapping of Protein Mutational Space by Prolonged Drift Reveals the Deleterious Effects of Seemingly Neutral Mutations

Rockah-Shmuel, Liat; Tóth-Petróczy, Ágnes; Tawfik, Dan S.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 14/08/2015 Português
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Systematic mappings of the effects of protein mutations are becoming increasingly popular. Unexpectedly, these experiments often find that proteins are tolerant to most amino acid substitutions, including substitutions in positions that are highly conserved in nature. To obtain a more realistic distribution of the effects of protein mutations, we applied a laboratory drift comprising 17 rounds of random mutagenesis and selection of M.HaeIII, a DNA methyltransferase. During this drift, multiple mutations gradually accumulated. Deep sequencing of the drifted gene ensembles allowed determination of the relative effects of all possible single nucleotide mutations. Despite being averaged across many different genetic backgrounds, about 67% of all nonsynonymous, missense mutations were evidently deleterious, and an additional 16% were likely to be deleterious. In the early generations, the frequency of most deleterious mutations remained high. However, by the 17th generation, their frequency was consistently reduced, and those remaining were accepted alongside compensatory mutations. The tolerance to mutations measured in this laboratory drift correlated with sequence exchanges seen in M.HaeIII’s natural orthologs. The biophysical constraints dictating purging in nature and in this laboratory drift also seemed to overlap. Our experiment therefore provides an improved method for measuring the effects of protein mutations that more closely replicates the natural evolutionary forces...

‣ The distribution and characteristics of LDL receptor mutations in China: A systematic review

Jiang, Long; Sun, Li-Yuan; Dai, Yan-Fang; Yang, Shi-Wei; Zhang, Feng; Wang, Lu-Ya
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em 26/11/2015 Português
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Familial hypercholesterolemia (FH) is a common and serious dominant genetic disease, and its main pathogenic gene is the low-density lipoprotein receptor (LDLR) gene. This study aimed to perform a systematic review of LDLR mutations in China. Using PubMed, Embase, Wanfang (Chinese), the Chinese National Knowledge Infrastructure (Chinese), and the Chinese Biological and Medical database (Chinese), public data were limited to December 2014. The Medical Subject Headings terms and the following key words were used: “familial hypercholesterolemia”, “Chinese”, “China”, “Hong Kong”, and “Taiwan”. A total of 74 studies including 295 probands with 131 LDLR mutations were identified. Most of the mutations were located in exon 4 of LDLR and approximately 60% of the mutations were missense mutations. Thirty new mutations that were not recorded in the LDLR databases were found. In silico analysis revealed that most of the mutations were pathogenic. The primary LDLR mutations were C308Y, H562Y, and A606T, and all of the mutations had functional significance. Prevalence data suggest that there are nearly 3.8 million FH patients in China, although reported numbers are much smaller, suggesting that FH is widely misunderstood. This systematic review provides information that is specific to China for inclusion in the international FH database.