Página 41 dos resultados de 4394 itens digitais encontrados em 0.007 segundos

‣ Mutations in FN1 cause glomerulopathy with fibronectin deposits

Castelletti, Federica; Donadelli, Roberta; Banterla, Federica; Hildebrandt, Friedhelm; Zipfel, Peter F.; Bresin, Elena; Otto, Edgar; Skerka, Christine; Renieri, Alessandra; Todeschini, Marta; Caprioli, Jessica; Caruso, Rosa Maria; Artuso, Rosangela; Remuz
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Glomerulopathy with fibronectin (FN) deposits (GFND) is an autosomal dominant disease with age-related penetrance, characterized by proteinuria, microscopic hematuria, hypertension, and massive glomerular deposits of FN that lead to end-stage renal failure. The genetic abnormality underlying GFND was still unknown. We hypothesized that mutations in FN1, which encodes FN, were the cause of GFND. In a large Italian pedigree with eight affected subjects, we found linkage with GFND at the FN1 locus at 2q32. We sequenced the FN1 in 15 unrelated pedigrees and found three heterozygous missense mutations, the W1925R, L1974R, and Y973C, that cosegregated with the disease in six pedigrees. The mutations affected two domains of FN (Hep-II domain for the W1925R and the L1974R, and Hep-III domain for the Y973C) that play key roles in FN–cell interaction and in FN fibrillogenesis. Mutant recombinant Hep-II fragments were expressed, and functional studies revealed a lower binding to heparin and to endothelial cells and podocytes compared with wild-type Hep-II and an impaired capability to induce endothelial cell spreading and cytoskeletal reorganization. Overall dominant mutations in FN1 accounted for 40% of cases of GFND in our study group. These findings may help understanding the pathogenesis of proteinuria and glomerular FN deposits in GFND and possibly in more common renal diseases such as diabetic nephropathy...

‣ Insights into Oncogenic Mutations of Plexin-B1 Based on the Solution Structure of the Rho GTPase Binding Domain

Tong, Yufeng; Hota, Prasanta K.; Hamaneh, Mehdi Bagheri; Buck, Matthias
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/2008 Português
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The plexin family of transmembrane receptors are important for axon guidance, angiogenesis, but also in cancer. Recently, plexin-B1 somatic missense mutations were found in both primary tumors and metastases of breast and prostate cancers, with several mutations mapping to the Rho GTPase Binding Domain (RBD) in the cytoplasmic region of the receptor. Here we present the NMR solution structure of this domain, confirming that the protein has both a ubiquitin-like fold and surface features. Oncogenic mutations T1795A and T1802A are located in a loop region, perturb the average structure locally and have no effect on Rho GTPase binding affinity. Mutations L1815F and L1815P are located at the Rho GTPase binding site and are associated with a complete loss of binding for Rac1 and Rnd1. Both are found to disturb the conformation of the β3-β4 sheet and orientation of surrounding sidechains. The study suggests that the oncogenic behavior of the mutants can be rationalized with reference to the structure of the RhoGTPase binding domain of plexin-B1.

‣ BRCA2 gene mutations in families with aggregations of breast and stomach cancers

Jakubowska, A; Nej, K; Huzarski, T; Scott, R J; Lubiński, J
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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Stomach cancer ranks second to lung cancer in the global cancer burden. It is estimated that 25% of families meeting the criteria for hereditary diffuse gastric carcinoma (HDCG) will have germline mutations in the E-cadherin gene. Evidence suggests that stomach cancer might also be a malignant manifestation of other inherited predispositions to disease. Recently, it has been reported that the incidence of stomach cancer is significantly increased in BRCA2 gene mutation carriers. We analysed by direct sequencing the BRCA2 gene in 29 breast cancer patients derived from 29 families with an aggregation of at least one female breast cancer diagnosed before the age of 50 years and one male stomach cancer diagnosed before the age of 55 years. In all but one of these families at least one additional relative was also affected by a malignant tumour. We identified three frameshift mutations and three sequence variants – potentially missense mutations, in six unrelated patients representing 20.7% (six out of 29) of the families investigated. Our results confirm that BRCA2 gene mutations are also associated with familial aggregations of not only breast but also of stomach cancer. In comparison to the number of cancers expected in the study population compared to the general population there is an over-representation of several cancers with significant confidence intervals to suggest that the associations are real and not a selection artefact.

‣ The fission yeast model for the lysosomal storage disorder Batten disease predicts disease severity caused by mutations in CLN3

Haines, Rebecca L.; Codlin, Sandra; Mole, Sara E.
Fonte: The Company of Biologists Limited Publicador: The Company of Biologists Limited
Tipo: Artigo de Revista Científica
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The function of the CLN3 protein, which is mutated in patients with the neurodegenerative lysosomal storage disorder Batten disease, has remained elusive since it was identified 13 years ago. Here, we exploited the Schizosaccharomyces pombe model to gain new insights into CLN3 function. We modelled all missense mutations of CLN3 in the orthologous protein Btn1p, as well as a series of targeted mutations, and assessed trafficking and the ability of the mutant proteins to rescue four distinct phenotypes of btn1Δ cells. Mutating the C-terminal cysteine residues of Btn1p caused it to be internalised into the vacuole, providing further evidence that this protein functions from pre-vacuole compartments. Mutations in the lumenal regions of the multi-spanning membrane protein, especially in the third lumenal domain which contains a predicted amphipathic helix, had the most significant impact on Btn1p function, indicating that these domains of CLN3 are functionally important. Only one mutant protein was able to rescue the cell curving phenotype (p.Glu295Lys), and since this mutation is associated with a very protracted disease progression, this phenotype could be used to predict the disease severity of novel mutations in CLN3. The ability to predict disease phenotypes in S. pombe confirms this yeast as an invaluable tool to understanding Batten disease.

‣ Phosphatase-defective LEOPARD syndrome mutations in PTPN11 gene have gain-of-function effects during Drosophila development

Oishi, Kimihiko; Zhang, Hui; Gault, William J.; Wang, Cindy J.; Tan, Cheryl C.; Kim, In-Kyong; Ying, Huiwen; Rahman, Tabassum; Pica, Natalie; Tartaglia, Marco; Mlodzik, Marek; Gelb, Bruce D.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Missense mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP-2, cause clinically similar but distinctive disorders, LEOPARD (LS) and Noonan (NS) syndromes. The LS is an autosomal dominant disorder with pleomorphic developmental abnormalities including lentigines, cardiac defects, short stature and deafness. Biochemical analyses indicated that LS alleles engender loss-of-function (LOF) effects, while NS mutations result in gain-of-function (GOF). These biochemical findings lead to an enigma that how PTPN11 mutations with opposite effects on function result in disorders that are so similar. To study the developmental effects of the commonest LS PTPN11 alleles (Y279C and T468M), we generated LS transgenic fruitflies using corkscrew (csw), the Drosophila orthologue of PTPN11. Ubiquitous expression of the LS csw mutant alleles resulted in ectopic wing veins and, for the Y279C allele, rough eyes with increased R7 photoreceptor numbers. These were GOF phenotypes mediated by increased RAS/MAPK signaling and requiring the LS mutant’s residual phosphatase activity. Our findings provide the first evidence that LS mutant alleles have GOF developmental effects despite reduced phosphatase activity, providing a rationale for how PTPN11 mutations with GOF and LOF produce similar but distinctive syndromes.

‣ Diverse Functional Consequences of Mutations in the Na+/K+-ATPase α2-Subunit Causing Familial Hemiplegic Migraine Type 2*

Tavraz, Neslihan N.; Friedrich, Thomas; Dürr, Katharina L.; Koenderink, Jan B.; Bamberg, Ernst; Freilinger, Tobias; Dichgans, Martin
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em 07/11/2008 Português
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Mutations in ATP1A2, the gene coding for the Na+/K+-ATPase α2-subunit, are associated with both familial hemiplegic migraine and sporadic cases of hemiplegic migraine. In this study, we examined the functional properties of 11 ATP1A2 mutations associated with familial or sporadic hemiplegic migraine, including missense mutations (T263M, T376M, R383H, A606T, R763H, M829R, R834Q, R937P, and X1021R), a deletion mutant (del(K935-S940)ins(I)), and a frameshift mutation (S966fs). According to the Na+/K+-ATPase crystal structure, a subset of the mutated residues (Ala606, Arg763, Met829, and Arg834) is involved in important interdomain H-bond networks, and the C terminus of the enzyme, which is elongated by the X1021R mutation, has been implicated in voltage dependence and formation of a third Na+-binding site. Upon heterologous expression in Xenopus oocytes, the analysis of electrogenic transport properties, Rb+ uptake, and protein expression revealed pronounced and markedly diverse functional alterations in all ATP1A2 mutants. Abnormalities included a complete loss of function (T376M), impaired plasma membrane expression (del(K935-S940)ins(I) and S966fs), and altered apparent affinities for extracellular cations or reduced enzyme turnover (R383H...

‣ EXPRESSION AND CHARACTERIZATION OF MUTATIONS IN HUMAN VERY LONG-CHAIN ACYL-COA DEHYDROGENASE USING A PROKARYOTIC SYSTEM

Goetzman, Eric S.; Wang, Yudong; He, Miao; Mohsen, Al-Walid; Ninness, Brittani K.; Vockley, Jerry
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Very long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the first enzymatic step in the mitochondrial beta-oxidation of fatty acids 14 to 20 carbons in length. More than 100 cases of VLCAD deficiency have been reported with the disease varying from a severe, often fatal neonatal form to a mild adult-onset form. VLCAD is distinguished from matrix-soluble acyl-CoA dehydrogenases by its unique C-terminal domain, homodimeric structure, and localization to the inner mitochondrial membrane. We have for the first time expressed and purified VLCAD using a bacterial system. Recombinant VLCAD had similar biochemical properties to those reported for native VLCAD and the bacterial system was used to study six previously described disease-causing missense mutations including the two most common mild mutations (T220M, V243A), a mutation leading to the severe disease phenotype (R429W), and three mutations in the C-terminal domain (A450P, L462P, and R573W). Of particular interest was the finding that the A450P and L462P bacterial extracts had normal or increased amounts of VLCAD antigen and activity. In the pure form L462P had roughly 30% of wild type activity while A450P was normal. Using computer modeling both mutations were mapped to a predicted charged surface of VLCAD that we postulate interacts with the mitochondrial membrane. In a membrane pull down assay both mutants showed greatly reduced mitochondrial membrane association...

‣ X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment

Dibbens, Leanne M; Tarpey, Patrick S; Hynes, Kim; Bayly, Marta A; Scheffer, Ingrid E; Smith, Raffaella; Bomar, Jamee; Sutton, Edwina; Vandeleur, Lucianne; Shoubridge, Cheryl; Edkins, Sarah; Turner, Samantha J; Stevens, Claire; O’Meara, Sarah; Tofts, Cal
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.

‣ Identification of CANT1 Mutations in Desbuquois Dysplasia

Huber, Céline; Oulès, Bénédicte; Bertoli, Marta; Chami, Mounia; Fradin, Mélanie; Alanay, Yasemin; Al-Gazali, Lihadh I.; Ausems, Margreet G.E.M.; Bitoun, Pierre; Cavalcanti, Denise P.; Krebs, Alexander; Le Merrer, Martine; Mortier, Geert; Shafeghati,
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em 13/11/2009 Português
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Desbuquois dysplasia is a severe condition characterized by short stature, joint laxity, scoliosis, and advanced carpal ossification with a delta phalanx. Studying nine Desbuquois families, we identified seven distinct mutations in the Calcium-Activated Nucleotidase 1 gene (CANT1), which encodes a soluble UDP-preferring nucleotidase belonging to the apyrase family. Among the seven mutations, four were nonsense mutations (Del 5′ UTR and exon 1, p.P245RfsX3, p.S303AfsX20, and p.W125X), and three were missense mutations (p.R300C, p.R300H, and p.P299L) responsible for the change of conserved amino acids located in the seventh nucleotidase conserved region (NRC). The arginine substitution at position 300 was identified in five out of nine families. The specific function of CANT1 is as yet unknown, but its substrates are involved in several major signaling functions, including Ca2+ release, through activation of pyrimidinergic signaling. Importantly, using RT-PCR analysis, we observed a specific expression in chondrocytes. We also found electron-dense material within distended rough endoplasmic reticulum in the fibroblasts of Desbuquois patients. Our findings demonstrate the specific involvement of a nucleotidase in the endochondral ossification process.

‣ Recurrent mutations of the STAT6 DNA binding domain in primary mediastinal B-cell lymphoma

Ritz, Olga; Guiter, Chrystelle; Castellano, Flavia; Dorsch, Karola; Melzner, Julia; Jais, Jean-Philippe; Dubois, Gwendoline; Gaulard, Philippe; Möller, Peter; Leroy, Karen
Fonte: American Society of Hematology Publicador: American Society of Hematology
Tipo: Artigo de Revista Científica
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Primary mediastinal B-cell lymphoma (PMBL) is a separate entity of aggressive B-cell lymphoma, characterized by a constitutive activation of janus kinase - signal transducer and activator of transcription (JAK - STAT) signaling pathway, also observed in Hodgkin lymphoma. Although many cancers exhibit constitutive JAK - STAT pathway activation, mutations of STAT genes have not been reported in neoplasms. Here, we show that MedB-1 PMBL-derived and L1236 Hodgkin-derived cell lines and 20 of 55 (36%) PMBL cases harbor heterozygous missense mutations in STAT6 DNA binding domain, whereas no mutation was found in 25 diffuse large B-cell lymphoma samples. In 3 cases, somatic origin was indicated by the absence of the mutations in the non tumoral tissue. The pattern of STAT6 mutations was different from the classical features of somatic hypermutations. The mutant STAT6 proteins showed a decreased DNA binding ability in transfected HEK cells, but no decrease in expression of STAT6 canonical target genes was observed in PMBL cases with a mutated STAT6 gene. Although the oncogenic properties of STAT6 mutant proteins remain to be determined, their recurrent selection in PMBL strongly argues for their involvement in the pathogenesis of this aggressive B-cell lymphoma.

‣ Disease mutations in Rab7 result in unregulated nucleotide exchange and inappropriate activation

McCray, Brett A.; Skordalakes, Emmanuel; Taylor, J. Paul
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Rab GTPases are molecular switches that orchestrate vesicular trafficking, maturation and fusion by cycling between an active, GTP-bound form, and an inactive, GDP-bound form. The activity cycle is coupled to GTP hydrolysis and is tightly controlled by regulatory proteins. Missense mutations of the GTPase Rab7 cause a dominantly inherited axonal degeneration known as Charcot-Marie-Tooth type 2B through an unknown mechanism. We present the 2.8 Å crystal structure of GTP-bound L129F mutant Rab7 which reveals normal conformations of the effector binding regions and catalytic site, but an alteration to the nucleotide binding pocket that is predicted to alter GTP binding. Through extensive biochemical analysis, we demonstrate that disease-associated mutations in Rab7 do not lead to an intrinsic GTPase defect, but permit unregulated nucleotide exchange leading to both excessive activation and hydrolysis-independent inactivation. Consistent with augmented activity, mutant Rab7 shows significantly enhanced interaction with a subset of effector proteins. In addition, dynamic imaging demonstrates that mutant Rab7 is abnormally retained on target membranes. However, we show that the increased activation of mutant Rab7 is counterbalanced by unregulated...

‣ 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, M.J.; C
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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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...

‣ Cancer-associated Mutations Activate the Nonreceptor Tyrosine Kinase Ack1*

Prieto-Echagüe, Victoria; Gucwa, Azad; Craddock, Barbara P.; Brown, Deborah A.; Miller, W. Todd
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Ack1 is a nonreceptor tyrosine kinase that participates in tumorigenesis, cell survival, and migration. Relatively little is known about the mechanisms that regulate Ack1 activity. Recently, four somatic missense mutations of Ack1 were identified in cancer tissue samples, but the effects on Ack1 activity, and function have not been described. These mutations occur in the N-terminal region, the C-lobe of the kinase domain, and the SH3 domain. Here, we show that the cancer-associated mutations increase Ack1 autophosphorylation in mammalian cells without affecting localization and increase Ack1 activity in immune complex kinase assays. The cancer-associated mutations potentiate the ability of Ack1 to promote proliferation and migration, suggesting that point mutation is a mechanism for Ack1 deregulation. We propose that the C-terminal Mig6 homology region (MHR) (residues 802–990) participates in inhibitory intramolecular interactions. The isolated kinase domain of Ack1 interacts directly with the MHR, and the cancer-associated E346K mutation prevents binding. Likewise, mutation of a key hydrophobic residue in the MHR (Phe820) prevents the MHR-kinase interaction, activates Ack1, and increases cell migration. Thus, the cancer-associated mutation E346K appears to destabilize an autoinhibited conformation of Ack1...

‣ GCAP1 mutations associated with autosomal dominant cone dystrophy

Jiang, Li; Baehr, Wolfgang
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em //2010 Português
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We discuss the heterogeneity of autosomal dominant cone and cone-rod dystrophies (adCD, and adCORD, respectively). As one of the best characterized adCD genes, we focus on the GUCA1A gene encoding guanylate cyclase activating protein 1 (GCAP1), a protein carrying three high affinity Ca2+ binding motifs (EF hands). GCAP1 senses changes in cytoplasmic free [Ca2+] and communicates these changes to GC1, by either inhibiting it (at high free [Ca2+]), or stimulating it (at low free [Ca2+]). A number of missense mutations altering the structure and Ca2+ affinity of EF hands have been discovered. These mutations are associated with a gain of function, producing dominant cone and cone rod dystrophy phenotypes. In this article we review these mutations and describe the consequences of specific mutations on GCAP1 structure and GC stimulation.

‣ Mutations in Caenorhabditis elegans eIF2β Permit Translation Initiation From Non-AUG Start Codons

Zhang, Yinhua; Maduzia, Lisa L.
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /05/2010 Português
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Recognition of the AUG start codon on mRNAs during translation initiation in eukaryotes occurs in a preinitiation complex that includes small ribosomal subunits and multiple translation initiation factors. The complexity of this process and the lack of appropriate tools have prevented its genetic study in multicellular organisms. Here we describe a genetic system in the nematode Caenorhabditis elegans to study how the AUG start codon is selected. We have generated a sensitive reporter assay that allows for the isolation of mutants with reduced fidelity to recognize the AUG start codon. Two mutants were identified to have dominant missense mutations in iftb-1, which encodes the β-subunit of eIF2 (eIF2β). Both mutations occur in a conserved region located outside of the C2–C2 zinc finger domain where yeast SUI3 mutations are localized in Saccharomyces cerevisiae eIF2β. C. elegans iftb-1, as well as mutant eIF2βs carrying the equivalent SUI3 mutations, are able to initiate translation at non-AUG codons that retain two potential base-pairing interactions with the anticodon of the initiator methionyl tRNA. These analyses further support the critical role of eIF2β in start codon selection, and two functional domains within eIF2β are likely involved...

‣ Analysis of the Tyrosine Kinome in Melanoma Reveals Recurrent Mutations in ERBB4

Prickett, Todd D.; Agrawal, Neena S.; Wei, Xiaomu; Yates, Kristin E.; Lin, Jimmy C.; Wunderlich, John; Cronin, Julia C.; Cruz, Pedro; ; Rosenberg, Steven A.; Samuels, Yardena
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Tyrosine phosphorylation is important in signaling pathways underlying tumorigenesis. A mutational analysis of the Protein Tyrosine Kinase (PTK) gene family in cutaneous metastatic melanoma identified 30 somatic mutations in the kinase domain of 19 PTKs. The whole of the coding region of these 19 PTKs was further evaluated for somatic mutations in a total of 79 melanoma samples. This analysis revealed novel ERBB4 mutations in 19% of melanoma patients and that an additional two kinases (FLT1 and PTK2B) are mutated in 10% of melanomas. Seven missense mutations in the most commonly altered PTK (ERBB4) were examined and found to increase kinase activity and transformation ability. Melanoma cells expressing mutant ERBB4 had reduced cell growth after shRNA–mediated knockdown of ERBB4 or treatment with the ERBB inhibitor lapatinib. These studies might lead to personalized therapeutics specifically targeting the kinases that are mutationally altered in individual melanomas.

‣ Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies

Zimoń, Magdalena; Baets, Jonathan; Auer-Grumbach, Michaela; Berciano, José; Garcia, Antonio; Lopez-Laso, Eduardo; Merlini, Luciano; Hilton-Jones, David; McEntagart, Meriel; Crosby, Andrew H.; Barisic, Nina; Boltshauser, Eugen; Shaw, Christopher E.; Land
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Hereditary neuropathies form a heterogeneous group of disorders for which over 40 causal genes have been identified to date. Recently, dominant mutations in the transient receptor potential vanilloid 4 gene were found to be associated with three distinct neuromuscular phenotypes: hereditary motor and sensory neuropathy 2C, scapuloperoneal spinal muscular atrophy and congenital distal spinal muscular atrophy. Transient receptor potential vanilloid 4 encodes a cation channel previously implicated in several types of dominantly inherited bone dysplasia syndromes. We performed DNA sequencing of the coding regions of transient receptor potential vanilloid 4 in a cohort of 145 patients with various types of hereditary neuropathy and identified five different heterozygous missense mutations in eight unrelated families. One mutation arose de novo in an isolated patient, and the remainder segregated in families. Two of the mutations were recurrent in unrelated families. Four mutations in transient receptor potential vanilloid 4 targeted conserved arginine residues in the ankyrin repeat domain, which is believed to be important in protein–protein interactions. Striking phenotypic variability between and within families was observed. The majority of patients displayed a predominantly...

‣ Mutations in the SPTLC2 Subunit of Serine Palmitoyltransferase Cause Hereditary Sensory and Autonomic Neuropathy Type I

Rotthier, Annelies; Auer-Grumbach, Michaela; Janssens, Katrien; Baets, Jonathan; Penno, Anke; Almeida-Souza, Leonardo; Van Hoof, Kim; Jacobs, An; De Vriendt, Els; Schlotter-Weigel, Beate; Löscher, Wolfgang; Vondráček, Petr; Seeman, Pavel; De Jonghe, Pe
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em 08/10/2010 Português
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Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy associated with progressive distal sensory loss and severe ulcerations. Mutations in the first subunit of the enzyme serine palmitoyltransferase (SPT) have been associated with HSAN-I. The SPT enzyme catalyzes the first and rate-limiting step in the de novo sphingolipid synthesis pathway. However, different studies suggest the implication of other genes in the pathology of HSAN-I. Therefore, we screened the two other known subunits of SPT, SPTLC2 and SPTLC3, in a cohort of 78 HSAN patients. No mutations were found in SPTLC3, but we identified three heterozygous missense mutations in the SPTLC2 subunit of SPT in four families presenting with a typical HSAN-I phenotype. We demonstrate that these mutations result in a partial to complete loss of SPT activity in vitro and in vivo. Moreover, they cause the accumulation of the atypical and neurotoxic sphingoid metabolite 1-deoxy-sphinganine. Our findings extend the genetic heterogeneity in HSAN-I and enlarge the group of HSAN neuropathies associated with SPT defects. We further show that HSAN-I is consistently associated with an increased formation of the neurotoxic 1-deoxysphinganine, suggesting a common pathomechanism for HSAN-I.

‣ Prodynorphin Mutations Cause the Neurodegenerative Disorder Spinocerebellar Ataxia Type 23

Bakalkin, Georgy; Watanabe, Hiroyuki; Jezierska, Justyna; Depoorter, Cloë; Verschuuren-Bemelmans, Corien; Bazov, Igor; Artemenko, Konstantin A.; Yakovleva, Tatjana; Dooijes, Dennis; Van de Warrenburg, Bart P.C.; Zubarev, Roman A.; Kremer, Berry; Knapp, P
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em 12/11/2010 Português
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Spinocerebellar ataxias (SCAs) are dominantly inherited neurodegenerative disorders characterized by progressive cerebellar ataxia and dysarthria. We have identified missense mutations in prodynorphin (PDYN) that cause SCA23 in four Dutch families displaying progressive gait and limb ataxia. PDYN is the precursor protein for the opioid neuropeptides, α-neoendorphin, and dynorphins A and B (Dyn A and B). Dynorphins regulate pain processing and modulate the rewarding effects of addictive substances. Three mutations were located in Dyn A, a peptide with both opioid activities and nonopioid neurodegenerative actions. Two of these mutations resulted in excessive generation of Dyn A in a cellular model system. In addition, two of the mutant Dyn A peptides induced toxicity above that of wild-type Dyn A in cultured striatal neurons. The fourth mutation was located in the nonopioid PDYN domain and was associated with altered expression of components of the opioid and glutamate system, as evident from analysis of SCA23 autopsy tissue. Thus, alterations in Dyn A activities and/or impairment of secretory pathways by mutant PDYN may lead to glutamate neurotoxicity, which underlies Purkinje cell degeneration and ataxia. PDYN mutations are identified in a small subset of ataxia families...

‣ RUNX2 mutations in Taiwanese patients with cleidocranial dysplasia

Lin, Wei-De; Lin, Shuan-Pei; Wang, Chung-Hsing; Tsai, Yushin; Chen, Chih-Ping; Tsai, Fuu-Jen
Fonte: Sociedade Brasileira de Genética Publicador: Sociedade Brasileira de Genética
Tipo: Artigo de Revista Científica
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Cleidocranial dysplasia (CCD) is an autosomal dominant human skeletal disorder comprising hypoplastic clavicles, wide cranial sutures, supernumerary teeth, short stature, and other skeletal abnormalities. It is known that mutations in the human RUNX2 gene mapped at 6p21 are responsible for CCD. We analyzed the mutation patterns of the RUNX2 gene by direct sequencing in six Taiwanese index cases with typical CCD. One of the patients was a familial case and the others were sporadic cases. Sequencing identified four mutations. Three were caused by single nucleotide substitutions, which created a nonsense (p.R391X), two were missense mutations (p.R190W, p.R225Q), and the forth was a novel mutation (c.1119delC), a one-base deletion. Real time quantitative PCR adapted to determine copy numbers of the promoter, all exons and the 3’UTR region of the RUNX2 gene detected the deletion of a single allele in a sporadic case. The results extend the spectrum of RUNX2 mutations in CCD patients and indicate that complete deletions of the RUNX2 gene should be considered in those CCD patients lacking a point mutation detected by direct sequencing.