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‣ A Brazilian family with hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia

FANGANIELLO, R.D.; KIMONIS, V.E.; CÔRTE, C.C.; NITRINI, R.; PASSOS-BUENO, M.R.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica
Português
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Inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD) is a progressive and usually misdiagnosed autosomal dominant disorder. It is clinically characterized by a triad of features: proximal and distal myopathy, early onset Paget disease of bone (PDB), and frontotemporal dementia (FTD). It is caused by missense mutations in the valosin-containing protein (VCP) gene. We describe here the clinical and molecular findings of the first Brazilian family identified with IBMPFD. Progressive myopathy affecting the limb girdles was detected by clinical examination followed by muscle biopsy and creatine kinase measurement. PDB was suggested after anatomopathological bone examination and FTD was diagnosed by clinical, neuropsychological and language evaluations. Brain magnetic resonance revealed severe atrophy of the anterior temporal lobes, including the hippocampi. A R93C mutation in VCP was detected by direct sequencing screening in subject W (age 62) and in his mother. Four more individuals diagnosed with "dementia" were reported in this family. We also present a comprehensive genotype-phenotype correlation analysis of mutations in VCP in 182 patients from 29 families described in the literature and show that while IBM is a conspicuously penetrant symptom...

‣ Clinical and molecular characterization of Brazilian families with von Hippel-Lindau disease: a need for delineating genotype-phenotype correlation

GOMY, Israel; MOLFETTA, Greice Andreotti; BARRETO, Ester de Andrade; FERREIRA, Cristiane Ayres; ZANETTE, Dalila Luciola; CASALI-DA-ROCHA, Jose Claudio; SILVA JR., Wilson Araujo
Fonte: SPRINGER Publicador: SPRINGER
Tipo: Artigo de Revista Científica
Português
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von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer syndrome that predisposes to the development of a variety of benign and malignant tumours, especially cerebellar haemangioblastomas, retinal angiomas and clear-cell renal cell carcinomas (RCC). The etiology and manifestations are due to germline and somatic mutations in the VHL tumour suppressor gene. VHL disease is classified into type 1 and type 2, showing a clear genotype-phenotype correlation, as type 2 is associated with phaeochromocytoma and essentially caused by missense mutations. The aim of this study is to characterize the phenotype and genotype of families with VHL disease. Eighteen of twenty patients from ten unrelated families underwent genetic testing, nine of them fulfilled VHL disease criteria and one had an apparently sporadic cerebellar haemangioblastoma. Four different germline mutations in the VHL gene were identified: c.226_228delTTC (p.Phe76del); c.217C > T (p.Gln73X); IVS1-1 G > A and IVS2-1 G > C. The first three mutations were associated with type 1 disease and the last one with type 2B, which had never been identified in the germline. The transcriptional processing of a novel splice-site mutation was characterised. Three type 1 VHL families showed large deletions of the VHL gene...

‣ Multi-system neurological disease is common in patients with OPA1 mutations

YU-WAI-MAN, P.; GRIFFITHS, P. G.; GORMAN, G. S.; LOURENCO, C. M.; WRIGHT, A. F.; AUER-GRUMBACH, M.; TOSCANO, A.; MUSUMECI, O.; VALENTINO, M. L.; CAPORALI, L.; LAMPERTI, C.; TALLAKSEN, C. M.; DUFFEY, P.; MILLER, J.; WHITTAKER, R. G.; BAKER, M. R.; JACKSON,
Fonte: OXFORD UNIV PRESS Publicador: OXFORD UNIV PRESS
Tipo: Artigo de Revista Científica
Português
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Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal `dominant optic atrophy plus` variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44-6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29...

‣ Inactivating Mutations of the Human Luteinizing Hormone Receptor in Both Sexes

Latronico, Ana Claudia; Arnhold, Ivo J. P.
Fonte: THIEME MEDICAL PUBL INC; NEW YORK Publicador: THIEME MEDICAL PUBL INC; NEW YORK
Tipo: Artigo de Revista Científica
Português
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The human luteinizing hormone/chorionic gonadotropin receptor (LHCGR) plays a fundamental role in male and female reproductive physiology. Over the past 15 years, several homozygous or compound heterozygous loss-of-function mutations in the LHCGR gene have been described in males and females. In genetic males, mutations in LHCGR were associated with distinct degrees of impairment in pre- and postnatal testosterone secretion resulting in a phenotypic spectrum. Patients with the severe form of LH resistance have predominantly female external genitalia and absence of secondary sex differentiation at puberty. Patients with milder forms have predominantly male external genitalia with micropenis and/or hypospadias or only infertility without ambiguity. The undermasculization is associated with low basal, as well as human CG-stimulated, testosterone levels and elevated LH levels after pubertal age, without abnormal step-up in testosterone biosynthesis precursors. The testes have only slightly reduced size but mature Leydig cells are absent or scarce (Leydig cell hypoplasia). Genetic females with inactivating LHCGR mutations have female external genitalia, spontaneous breast and pubic hair development at puberty, and normal or late menarche followed by oligoamenorrhea and infertility. Estradiol and progesterone levels are normal for the early to midfollicular phase...

‣ A Brazilian family with hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia

Fanganiello,R.D.; Kimonis,V.E.; Côrte,C.C.; Nitrini,R.; Passos-Bueno,M.R.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/04/2011 Português
Relevância na Pesquisa
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Inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD) is a progressive and usually misdiagnosed autosomal dominant disorder. It is clinically characterized by a triad of features: proximal and distal myopathy, early onset Paget disease of bone (PDB), and frontotemporal dementia (FTD). It is caused by missense mutations in the valosin-containing protein (VCP) gene. We describe here the clinical and molecular findings of the first Brazilian family identified with IBMPFD. Progressive myopathy affecting the limb girdles was detected by clinical examination followed by muscle biopsy and creatine kinase measurement. PDB was suggested after anatomopathological bone examination and FTD was diagnosed by clinical, neuropsychological and language evaluations. Brain magnetic resonance revealed severe atrophy of the anterior temporal lobes, including the hippocampi. A R93C mutation in VCP was detected by direct sequencing screening in subject W (age 62) and in his mother. Four more individuals diagnosed with "dementia" were reported in this family. We also present a comprehensive genotype-phenotype correlation analysis of mutations in VCP in 182 patients from 29 families described in the literature and show that while IBM is a conspicuously penetrant symptom...

‣ Prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation

Xie,Wen-Hui; Chang,Cheng; Xu,Ying-Jia; Li,Ruo-Gu; Qu,Xin-Kai; Fang,Wei-Yi; Liu,Xu; Yang,Yi-Qing
Fonte: Faculdade de Medicina / USP Publicador: Faculdade de Medicina / USP
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2013 Português
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OBJECTIVE: The aim of this study was to evaluate the prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation (AF). METHODS: A cohort of 136 unrelated patients with idiopathic atrial fibrillation and 200 unrelated, ethnically matched healthy controls were enrolled. The coding exons and splice junctions of the Nkx2.5 gene were sequenced in 136 atrial fibrillation patients, and the available relatives of mutation carriers and 200 controls were subsequently genotyped for the identified mutations. The functional characteristics of the mutated Nkx2.5 gene were analyzed using a dual-luciferase reporter assay system. RESULTS: Two novel heterozygous Nkx2.5 mutations (p.N19D and p.F186S) were identified in 2 of the 136 unrelated atrial fibrillation cases, with a mutational prevalence of approximately 1.47%. These missense mutations co-segregated with atrial fibrillation in the families and were absent in the 400 control chromosomes. Notably, 2 mutation carriers also had congenital atrial septal defects and atrioventricular block. Multiple alignments of the Nkx2.5 protein sequences across various species revealed that the altered amino acids were completely conserved evolutionarily. Functional analysis demonstrated that the mutant Nkx2.5 proteins were associated with significantly reduced transcriptional activity compared to their wild-type counterpart. CONCLUSION: These findings associate the Nkx2.5 loss-of-function mutation with atrial fibrillation and atrioventricular block and provide novel insights into the molecular mechanism involved in the pathogenesis of atrial fibrillation. These results also have potential implications for early prophylaxis and allele-specific therapy of this common arrhythmia.

‣ Two novel frame shift, recurrent and de novo mutations in the ITGB2 (CD18) gene causing leukocyte adhesion deficiency in a highly inbred North African population

Fathallah, D. M; Jamal, T.; Barbouche, M. R; Bejaoui, M.; Hariz, M. Ben; Dellagi, K.
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
Publicado em //2001 Português
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We have identified four different mutations causing leukocyte adhesion deficiency (LAD) in the ITGB2 gene of patients from a highly inbred population. Two were novel single-bp deletions (1497delG and 1920delG) causing frame shift and the two others were the missense mutations G284S and R593C. In our study, the G284S was a recurrent mutation while the R593C occurred de novo. We have also characterized a novel Xba1 polymorphic site located at the 5′ end of the ITGB2 locus. Family studies showed that the 1497delG mutation segregated with this marker and the intragenic AvaII polymorphic marker, suggesting the presence of a founder effect. The observation of a heterogeneous spectrum including de novo and recurrent mutations causing LAD in a highly inbred population is rather unexpected. In view of the literature published on the molecular genetics of LAD and considering the ethnic origin of the patients studied, our findings confirm the heterogeneity of the mutations causing LAD and point out potential mutational hot spots in the ITGB2 gene.

‣ katG mutations in isoniazid-resistant Mycobacterium tuberculosis isolates recovered from Finnish patients.

Marttila, H J; Soini, H; Huovinen, P; Viljanen, M K
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/1996 Português
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katG and inhA genes from isoniazid-resistant Mycobacterium tuberculosis strains isolated in Finland were examined by PCR or sequencing. By PCR, katG was not detected in 3 of 54 strains. Sequencing of katG from 13 strains showed small point mutations or insertions; a previously described mutation causing a Ser-to-Thr change at position 315 was found in 4 strains, and there were nine new missense mutations of katG. A 209-bp segment of inhA from 17 strains was sequenced, but no mutations were observed. This result indicates that different mutations prevail in different geographical areas.

‣ Mutations within the first LSGGQ motif of Ste6p cause defects in a-factor transport and mating in Saccharomyces cerevisiae.

Browne, B L; McClendon, V; Bedwell, D M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /03/1996 Português
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Mating between the two haploid cell types (a and alpha) of the yeast Saccharomyces cerevisiae depends upon the efficient secretion and delivery of the a- and alpha-factor pheromones to their respective target cells. However, a quantitative correlation between the level of transported a-factor and mating efficiency has never been determined. a-Factor is transported by Ste6p, a member of the ATP-binding cassette (ABC) family of transporter proteins. In this study, several missense mutations were introduced in or near the conserved LSGGQ motif within the first nucleotide-binding domain of Ste6p. Quantitation of extracellular a-factor levels indicated that these mutations caused a broad range of a-factor transport defects, and those directly within the LSGGQ motif caused the most severe defects. Overall, we observed a strong correlation between the level of transported a-factor and the mating efficiency of these strains, consistent with the role of Ste6p as the a-factor transporter. The LSGGQ mutations did not cause either a significant alteration in the steady-state level of Ste6p or a detectable change in its subcellular localization. Thus, it appears that these mutations interfere with the ability of Ste6p to transport a-factor out of the MATa cell. The possible involvement of the LSGGQ motif in transporter function is consistent with the strong conservation of this sequence motif throughout the ABC transporter superfamily.

‣ Mutations in lipoprotein lipase that block binding to the endothelial cell transporter GPIHBP1

Voss, Constance V.; Davies, Brandon S. J.; Tat, Shelly; Gin, Peter; Fong, Loren G.; Pelletier, Christopher; Mottler, Charlene D.; Bensadoun, André; Beigneux, Anne P.; Young, Stephen G.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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GPIHBP1, a glycosylphosphatidylinositol-anchored protein of capillary endothelial cells, shuttles lipoprotein lipase (LPL) from subendothelial spaces to the capillary lumen. An absence of GPIHBP1 prevents the entry of LPL into capillaries, blocking LPL-mediated triglyceride hydrolysis and leading to markedly elevated triglyceride levels in the plasma (i.e., chylomicronemia). Earlier studies have established that chylomicronemia can be caused by LPL mutations that interfere with catalytic activity. We hypothesized that some cases of chylomicronemia might be caused by LPL mutations that interfere with LPL's ability to bind to GPIHBP1. Any such mutation would provide insights into LPL sequences required for GPIHBP1 binding. Here, we report that two LPL missense mutations initially identified in patients with chylomicronemia, C418Y and E421K, abolish LPL's ability to bind to GPIHBP1 without interfering with LPL catalytic activity or binding to heparin. Both mutations abolish LPL transport across endothelial cells by GPIHBP1. These findings suggest that sequences downstream from LPL's principal heparin-binding domain (amino acids 403–407) are important for GPIHBP1 binding. In support of this idea, a chicken LPL (cLPL)–specific monoclonal antibody...

‣ Mitochondrial DNA Complex I and III Mutations Associated with Leber's Hereditary Optic Neuropathy

Brown, M. D.; Voljavec, A. S.; Lott, M. T.; Torroni, A.; Yang, C. C.; Wallace, D. C.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/1992 Português
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Four new missense mutations have been identified through restriction analysis and sequencing of the mitochondrial DNAs (mtDNA) from Leber's hereditary optic neuropathy (LHON) patients who lacked the previously identified 11778 mutation. Each altered a conserved amino acid and correlated with the LHON phenotype in population and phylogenetic analyses. The nucleotide pair (np) 13708 mutation (G to A, ND5 gene) changed an alanine to a threonine and was found in 6/25 (24%) of non-11778 LHON pedigrees and in 5.0% of controls, the np 15257 mutation (G to A, cytochrome b gene) changed an aspartate to an asparagine and was found in 4 of the 13708-positive pedigrees and 0.3% of controls, the np 15812 mutation (G to A, cytochrome b gene) changed a valine to a methionine and was detected in two of the 15257-positive pedigrees and 0.1% of controls and the np 5244 mutation (G to A, ND2 gene) changed a glycine to a serine and was found in one of the 15812-positive patients and none of 2103 controls. The 15257 mutation altered a highly conserved amino acid in an extramembrane domain of cytochrome b that is associated with the ligation of the low potential b(566) heme and the 5244 mutation altered a strongly evolutionarily conserved region of the ND2 polypeptide. The 13708 and 15812 mutations changed moderately conserved amino acids. Haplotype and phylogenetic analysis of the four np 15257 mtDNAs revealed that all harbored the same rare Caucasian haplotype and that the np 13708...

‣ Identification and Functional Analysis of Two Novel PAX9 Mutations

Wang, Ying; Wu, Hua; Wu, Jingfeng; Zhao, Hongshan; Zhang, Xiaoxia; Mues, Gabriele; D'Souza, Rena N.; Feng, Hailan; Kapadia, Hitesh
Fonte: S. Karger AG Publicador: S. Karger AG
Tipo: Artigo de Revista Científica
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The paired-domain transcription factor PAX9 plays a critical role in tooth development, as heterozygous mutations in PAX9 have been shown to be associated with human tooth agenesis. In this study, we report 2 novel missense mutations, gly6arg (G6R) and ser43lys (S43K), in the paired domain of PAX9 in Chinese patients with varying degrees of nonsyndromic tooth agenesis. Excluding third molars, the individual with the G6R mutation was missing 2 mandibular incisors and a maxillary premolar, while the phenotype of individuals with the S43K mutation consisted of peg-shaped upper lateral incisors and missing molars, premolars and canines. As these 2 mutations occur at highly conserved amino acids in the PAX gene family and between different species, we further analyzed the effects of the mutations on the function of the resulting proteins. Immunofluorescence and immunoblotting studies showed that the mutations did not alter nuclear localization in mammalian cells. Gel shift and super shift assays indicate that both mutant proteins bound DNA at a lower level than the normal protein, with G6R having a greater affinity for DNA than S43K. Likewise, the G6R protein was able to transcriptionally activate a Bmp4 promoter construct to a greater extent than S43K. Our finding that the severity of tooth agenesis in the patients was correlated to the DNA-binding capacity of the mutated PAX9 9proteins supports the hypothesis that DNA binding is responsible for the genetic defect.

‣ Mutations in DLC-1's (deleted in liver cancer 1) focal adhesion targeting region attenuate their expression and function

Liao, Yi-Chun; Shih, Yi-Ping; Lo, Su Hao
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/10/2008 Português
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Deleted in liver cancer-1 (DLC-1) is a RhoGAP domain containing tumor suppressor that is often down-regulated in various cancer types. Previously, we have demonstrated that DLC-1 is recruited to focal adhesions by binding to the SH2 (Src homology 2) domains of tensins and the focal adhesion localization is critical for DLC-1's tumor suppression activity. To investigate whether mutations in the focal adhesion targeting (FAT) region might occur and attenuate DLC-1's expression, localization, and function, we have first mapped the FAT region to the amino acid residues from 201 to 500, and then sequenced cDNAs and genomic DNAs encoding the FAT region from cancer patients. Several missesne and nonsense mutations were detected. All missense mutations were further examined for the potential effect on DLC-1's function. Although these mutations did not appear to affect DLC-1's focal adhesion localization, the activities of suppressing tumor cell growth were impaired in two mutants: T301K and S308I. In consistent with the fact that the RhoGAP activity of DLC-1 is essential for inhibiting tumor cell growth, the RhoGAP activities were significantly reduced in these mutants, suggesting that the FAT region also contains a regulatory element for its C-terminal RhoGAP domain. Our studies have demonstrated that mutations in DLC-1 may lead to loss of function and contribute to the tumorigenesis...

‣ Novel TMEM67 Mutations and Genotype-phenotype Correlates in Meckelin-related Ciliopathies

Iannicelli, Miriam; Brancati, Francesco; Mougou-Zerelli, Soumaya; Mazzotta, Annalisa; Thomas, Sophie; Elkhartoufi, Nadia; Travaglini, Lorena; Gomes, Céline; Ardissino, Gian Luigi; Bertini, Enrico; Boltshauser, Eugen; Castorina, Pierangela; D'Arrigo, Stef
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /05/2010 Português
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Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.

‣ Pathogenity of some limb girdle muscular dystrophy mutations can result from reduced anchorage to myofibrils and altered stability of calpain 3

Ermolova, Natalia; Kudryashova, Elena; DiFranco, Marino; Vergara, Julio; Kramerova, Irina; Spencer, Melissa J.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Calpain 3 (CAPN3) is a muscle-specific, calcium-dependent proteinase that is mutated in Limb Girdle Muscle Dystrophy type 2A. Most pathogenic missense mutations in LGMD2A affect CAPN3's proteolytic activity; however, two mutations, D705G and R448H, retain activity but nevertheless cause muscular dystrophy. Previously, we showed that D705G and R448H mutations reduce CAPN3s ability to bind to titin in vitro. In this investigation, we tested the consequence of loss of titin binding in vivo and examined whether this loss can be an underlying pathogenic mechanism in LGMD2A. To address this question, we created transgenic mice that express R448H or D705G in muscles, on wild-type (WT) CAPN3 or knock-out background. Both mutants were readily expressed in insect cells, but when D705G was expressed in skeletal muscle, it was not stable enough to study. Moreover, the D705G mutation had a dominant negative effect on endogenous CAPN3 when expressed on a WT background. The R448H protein was stably expressed in muscles; however, it was more rapidly degraded in muscle extracts compared with WT CAPN3. Increased degradation of R448H was due to non-cysteine, cellular proteases acting on the autolytic sites of CAPN3, rather than autolysis. Fractionation experiments revealed a significant decrease of R448H from the myofibrillar fraction...

‣ Novel germline mutations in the PTEN tumour suppressor gene found in women with multiple cancers

De Vivo, I.; Gertig, D.; Nagase, S.; Hankinson, S.; O'Brien, R.; Speizer, F.; Parsons, R.; Hunter, D.
Fonte: BMJ Group Publicador: BMJ Group
Tipo: Artigo de Revista Científica
Publicado em /05/2000 Português
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Germline mutations in PTEN can predispose people to Cowden syndrome (CS) and Bannayan-Ruvalcaba-Riley (BRR) syndrome, rare, autosomal dominantly inherited neoplastic disorders. To determine whether germline mutations in PTEN contribute to genetic predisposition to multiple primary tumours within the general population, we conducted a nested case-control study, among 32 826 members of the prospective Nurses' Health Study cohort; cases were women with more than one primary tumour at different anatomical sites. We screened all nine exons of PTEN and flanking intronic splice sites for all 103 eligible cases using SSCP and sequencing. We observed two novel germline heterozygous missense mutations in exon 5 in five of the cases; three were V119L and two were V158L. Neither mutation was observed in 115 controls free of diagnosed cancer (p=0.02). Both mutants showed partial tumour suppressor activity when compared to wild type PTEN when transfected into a PTEN null breast cancer cell line. The phenotype was cell line specific suggesting that genetic background affects growth suppression activity of the mutants. These data provide evidence that germline mutations in PTEN may be a more frequent predisposing factor for cancers in women than previously suggested.


Keywords: population based; tumour suppressor; multiple cancers; germline mutations

‣ Platinum: a database of experimentally measured effects of mutations on structurally defined protein-ligand complexes

Pires, Douglas E. V.; Blundell, Tom L.; Ascher, David B.
Fonte: OUP on behalf of Nucleic Acids Research Publicador: OUP on behalf of Nucleic Acids Research
Tipo: Article; published version
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This is the final published version. It first appeared at http://nar.oxfordjournals.org/content/43/D1/D387.; Drug resistance is a major challenge for the treatment of many diseases and a significant concern throughout the drug development process. The ability to understand and predict the effects of mutations on protein?ligand affinities and their roles in the emergence of resistance would significantly aid treatment and drug design strategies. In order to study and understand the impacts of missense mutations on the interaction of ligands with the proteome, we have developed Platinum (http://structure.bioc.cam.ac.uk/platinum). This manually curated, literature-derived database, comprising over 1000 mutations, associates for the first time experimental information on changes in affinity with three-dimensional structures of protein?ligand complexes. To minimize differences arising from experimental techniques and to directly compare binding affinities, Platinum considers only changes measured by the same group and with the same amino-acid sequence used for structure determination, providing a direct link between protein structure, how a ligand binds and how mutations alter the affinity of the ligand of the protein. We believe Platinum will be an invaluable resource for understanding the effects of mutations that give rise to drug resistance...

‣ Novel GATA5 loss-of-function mutations underlie familial atrial fibrillation

Gu, Jian-Yun; Xu, Jia-Hong; Yu, Hong; Yang, Yi-Qing
Fonte: Universidade de São Paulo. Faculdade de Medicina Publicador: Universidade de São Paulo. Faculdade de Medicina
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; ; Formato: application/pdf
Publicado em 01/12/2012 Português
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OBJECTIVE: This study aimed to identify novel GATA5 mutations that underlie familial atrial fibrillation. METHODS: A total of 110 unrelated patients with familial atrial fibrillation and 200 unrelated, ethnically matched healthy controls were recruited. The entire coding region of the GATA5 gene was sequenced in 110 atrial fibrillation probands. The available relatives of the mutation carriers and 200 controls were subsequently genotyped for the identified mutations. The functional effect of the mutated GATA5 was characterized using a luciferase reporter assay system. RESULTS: Two novel heterozygous GATA5 mutations (p.Y138F and p.C210G) were identified in two of the 110 unrelated atrial fibrillation families. These missense mutations cosegregated with AF in the families and were absent in the 400 control chromosomes. A cross-species alignment of GATA5 protein sequence showed that the altered amino acids were completely conserved evolutionarily. A functional analysis revealed that the mutant GATA5 proteins were associated with significantly decreased transcriptional activation when compared with their wild-type counterpart. CONCLUSION: The findings expand the spectrum of GATA5 mutations linked to AF and provide novel insights into the molecular mechanism involved in the pathogenesis of atrial fibrillation...

‣ Defective importin beta recognition and nuclear import of the sex-determining factor SRY are associated with XY sex-reversing mutations

Harding, Ruth E; Layfield, R; Mitchell, Claire; Forwood, Jade; John, Anna; Briggs, Lyndall; McDowall, Sharon; Jans, David A
Fonte: National Academy of Sciences (USA) Publicador: National Academy of Sciences (USA)
Tipo: Artigo de Revista Científica
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The architectural transcription factor SRY (sex-determining region of the Y chromosome) plays a key role in sex determination as indicated by the fact that mutations in SRY are responsible for XY gonadal dysgenesis in humans. Although many SRY mutations reduce DNA-binding/bending activity, it is not clear how SRY mutations that do not affect interaction with DNA contribute to disease. The SRY high-mobility group domain harbors two nuclear localization signals (NLSs), and here we examine SRY from four XY females with missense mutations in these signals. In all cases, mutant SRY protein is partly localized to the cytoplasm, whereas wild-type SRY is strictly nuclear. Each NLS can independently direct nuclear transport of a carrier protein in vitro and in vivo, with mutations in either affecting the rate and extent of nuclear accumulation. The N-terminal NLS function is independent of the conventional NLS-binding importins (IMPs) and requires unidentified cytoplasmic transport factors, whereas the C-terminal NLS is recognized by IMPβ. The SRY-R133W mutant shows reduced IMPβ binding as a direct consequence of the sex-reversing C-terminal NLS mutation. Of the N-terminal NLS mutants examined, SRY-R62G unexpectedly shows a marked reduction in IMPβ binding...

‣ Novel Compound Heterozygous CBS Mutations Cause Homocystinuria in a Han Chinese Family

Gong, Bo; Liu, Liping; Li, Zhiwei; Ye, Zimeng; Xiao, Ying; Zeng, Guangqun; Shi, Yi; Wang, Yumeng; Feng, Xiaoyun; Li, Xiulan; Hao, Fang; Liu, Xiaoqi; Qu, Chao; Li, Yuanfeng; Mu, Guoying; Yang, Zhenglin
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Text
Publicado em 15/12/2015 Português
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The cystathionine β-synthase (CBS) gene has been shown to be related to homocystinuria. This study was aimed to detect the mutations in CBS in a Han Chinese family with homocystinuria. A four-generation family from Shandong Province of China was recruited in this study. All available members of the family underwent comprehensive medical examinations. Genomic DNA was collected from peripheral blood of all the participants. The coding sequence of CBS was amplified by polymerase chain reaction (PCR), followed by direct DNA sequencing. Among all the family members, three affected individuals showed typical clinical features of homocystinuria. Two novel compound heterozygous mutations in the CBS gene, c.407T > C (p. L136P) and c.473C > T (p.A158V), were identified by sequencing analysis in this family. Both of the two missense mutations were detected in the three patients. Other available normal individuals, including the patients’ parents, grand parents, her younger sister and brother in this family either carried one of the two mutations, or none. In addition, the two mutations were not found in 600 ethnically matched normal controls. This study provides a mutation spectrum of CBS resulting in homocystinuriain a Chinese population...