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‣ Missense mutations define a restricted segment in the C-terminal domain of phytochrome A critical to its regulatory activity.

Xu, Y; Parks, B M; Short, T W; Quail, P H
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/1995 Português
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The phytochrome family of photoreceptors has dual molecular functions: photosensory, involving light signal perception, and regulatory, involving signal transfer to downstream transduction components. To define residues necessary specifically for the regulatory activity of phytochrome A (phyA), we undertook a genetic screen to identify Arabidopsis mutants producing wild-type levels of biologically defective but photochemically active and dimeric phyA molecules. Of eight such mutants identified, six contain missense mutations (including three in the same residue, glycine 727) clustered within a restricted segment in the C-terminal domain of the polypeptide. Quantitative photobiological analysis revealed retention of varying degrees of partial activity among the different alleles--a result consistent with the extent of conservation at the position mutated. Together with additional data, these results indicate that the photoreceptor subdomain identified here is critical to the regulatory activity of both phyA and phyB.

‣ Aberrant splicing and missense mutations cause steroid 21-hydroxylase [P-450(C21)] deficiency in humans: possible gene conversion products.

Higashi, Y; Tanae, A; Inoue, H; Hiromasa, T; Fujii-Kuriyama, Y
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1988 Português
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Four steroid 21-hydroxylase B [P-450(C21)B] genes (designated P.7, P.10-1, P.10-2, and P.3) from three P-450(C21)-deficient patients were isolated to analyze their structures and functions. Several base changes were observed in the sequences of the four P-450(C21)B genes as compared to that of the functional B gene. Many of these base changes were identical to those of the P-450(C21)A pseudogene. The three DNAs (P.10-1, P.10-2, and P.3) produced no P-450(C21) activity in a functional assay for P-450(C21) by the COS cell expression system, while the P.7 DNA expressed the activity. The P.10-1 and P.10-2 DNAs were shown to have a point mutation in the second intron, causing aberrant splicing. The P.3 DNA carried three clustered missense mutations in the sixth exon, which impaired P-450(C21) activity. All these critical mutations could be seen in the corresponding site of the P-450(C21)A pseudogene. These data strongly suggest the involvement of gene conversion in this genetic disease.

‣ Absence of missense mutations in activated c-myc genes in avian leukosis virus-induced B-cell lymphomas.

Hahn, M; Hayward, W S
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/1988 Português
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We have determined the nucleotide sequences of two independent DNA clones which contained the activated c-myc genes from avian leukosis virus-induced B-cell lymphomas. Neither of these c-myc genes contained missense mutations. This strongly supports the notion that the c-myc proto-oncogene in avian leukosis virus-induced B-cell lymphomas can be oncogenically activated by altered expression of the gene without a change in the primary structure of the gene product.

‣ Missense Mutations in CRELD1 Are Associated with Cardiac Atrioventricular Septal Defects

Robinson, Susan W.; Morris, Cynthia D.; Goldmuntz, Elizabeth; Reller, Mark D.; Jones, Melanie A.; Steiner, Robert D.; Maslen, Cheryl L.
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
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Atrioventricular septal defects (AVSD) are common cardiovascular malformations, occurring in 3.5/10,000 births. Although frequently associated with trisomy 21, autosomal dominant AVSD has also been described. Recently we identified and characterized the cell adhesion molecule CRELD1 (previously known as “cirrin”) as a candidate gene for the AVSD2 locus mapping to chromosome 3p25. Analysis of the CRELD1 gene from individuals with non–trisomy 21–associated AVSD identified heterozygous missense mutations in nearly 6% of this population, including mutations in isolated AVSD and AVSD associated with heterotaxy syndrome. CRELD1 is the first human gene to be implicated in the pathogenesis of isolated AVSD and AVSD in the context of heterotaxy, which provides an important step in unraveling the pathogenesis of AVSD.

‣ Missense Mutations in the Regulatory Domain of PKCγ: A New Mechanism for Dominant Nonepisodic Cerebellar Ataxia

Chen, Dong-Hui; Brkanac, Zoran; Verlinde, Christophe L. M. J.; Tan, Xiao-Jian; Bylenok, Laura; Nochlin, David; Matsushita, Mark; Lipe, Hillary; Wolff, John; Fernandez, Magali; Cimino, P. J.; Bird, Thomas D.; Raskind, Wendy H.
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
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We report a nonepisodic autosomal dominant (AD) spinocerebellar ataxia (SCA) not caused by a nucleotide repeat expansion that is, to our knowledge, the first such SCA. The AD SCAs currently comprise a group of ⩾16 genetically distinct neurodegenerative conditions, all characterized by progressive incoordination of gait and limbs and by speech and eye-movement disturbances. Six of the nine SCAs for which the genes are known result from CAG expansions that encode polyglutamine tracts. Noncoding CAG, CTG, and ATTCT expansions are responsible for three other SCAs. Approximately 30% of families with SCA do not have linkage to the known loci. We recently mapped the locus for an AD SCA in a family (AT08) to chromosome 19q13.4-qter. A particularly compelling candidate gene, PRKCG, encodes protein kinase C γ (PKCγ), a member of a family of serine/threonine kinases. The entire coding region of PRKCG was sequenced in an affected member of family AT08 and in a group of 39 unrelated patients with ataxia not attributable to trinucleotide expansions. Three different nonconservative missense mutations in highly conserved residues in C1, the cysteine-rich region of the protein, were found in family AT08, another familial case, and a sporadic case. The mutations cosegregated with disease in both families. Structural modeling predicts that two of these amino acid substitutions would severely abrogate the zinc-binding or phorbol ester–binding capabilities of the protein. Immunohistochemical studies on cerebellar tissue from an affected member of family AT08 demonstrated reduced staining for both PKCγ and ataxin 1 in Purkinje cells...

‣ Differential Behavior of Missense Mutations in the Intersubunit Contact Domain of the Human Pyruvate Kinase M2 Isozyme*S⃞

Akhtar, Kamal; Gupta, Vibhor; Koul, Anita; Alam, Neelima; Bhat, Rajiv; Bamezai, Rameshwar N. K.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em 01/05/2009 Português
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In this study, we attempted to understand the mechanism of regulation of the activity and allosteric behavior of the pyruvate kinase M2 enzyme and two of its missense mutations, H391Y and K422R, found in cells from Bloom syndrome patients, prone to develop cancer. Results show that despite the presence of mutations in the intersubunit contact domain, the K422R and H391Y mutant proteins maintained their homotetrameric structure, similar to the wild-type protein, but showed a loss of activity of 75 and 20%, respectively. Interestingly, H391Y showed a 6-fold increase in affinity for its substrate phosphoenolpyruvate and behaved like a non-allosteric protein with compromised cooperative binding. However, the affinity for phosphoenolpyruvate was lost significantly in K422R. Unlike K422R, H391Y showed enhanced thermal stability, stability over a range of pH values, a lesser effect of the allosteric inhibitor Phe, and resistance toward structural alteration upon binding of the activator (fructose 1,6-bisphosphate) and inhibitor (Phe). Both mutants showed a slight shift in the pH optimum from 7.4 to 7.0. Although this study signifies the importance of conserved amino acid residues in long-range communications between the subunits of multimeric proteins...

‣ Missense Mutations in Cancer Predisposing Genes: Can We Make Sense of Them?

Scott, Rodney J; Meldrum, Cliff J
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 15/08/2005 Português
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In the analysis of genes associated with predispositions to malignancy the causative status of mutations can be made relatively easily where it is obvious that there is a clear disruption in the coding sequence of the gene. Difficulties arise, however, if missense mutations are identified, as these are not easily categorised into genetic variants that are not associated with disease risk or into clearly causative changes that impart a significant risk of disease.

‣ Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene

Tzur, Shay; Rosset, Saharon; Shemer, Revital; Yudkovsky, Guennady; Selig, Sara; Tarekegn, Ayele; Bekele, Endashaw; Bradman, Neil; Wasser, Walter G.; Behar, Doron M.; Skorecki, Karl
Fonte: Springer-Verlag Publicador: Springer-Verlag
Tipo: Artigo de Revista Científica
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MYH9 has been proposed as a major genetic risk locus for a spectrum of nondiabetic end stage kidney disease (ESKD). We use recently released sequences from the 1000 Genomes Project to identify two western African-specific missense mutations (S342G and I384M) in the neighboring APOL1 gene, and demonstrate that these are more strongly associated with ESKD than previously reported MYH9 variants. The APOL1 gene product, apolipoprotein L-1, has been studied for its roles in trypanosomal lysis, autophagic cell death, lipid metabolism, as well as vascular and other biological activities. We also show that the distribution of these newly identified APOL1 risk variants in African populations is consistent with the pattern of African ancestry ESKD risk previously attributed to MYH9.

‣ Feline Congenital Erythropoietic Porphyria: Two Homozygous UROS Missense Mutations Cause the Enzyme Deficiency and Porphyrin Accumulation

Clavero, Sonia; Bishop, David F; Giger, Urs; Haskins, Mark E; Desnick, Robert J
Fonte: ScholarOne Publicador: ScholarOne
Tipo: Artigo de Revista Científica
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The first feline model of human congenital erythropoietic porphyria (CEP) due to deficient uroporphyrinogen III synthase (URO-synthase) activity was identified by its characteristic clinical phenotype, and confirmed by biochemical and molecular genetic studies. The proband, an adult domestic shorthair cat, had dark-red urine and brownish discolored teeth with red fluorescence under ultraviolet light. Biochemical studies demonstrated markedly increased uroporphyrinogen I in urine and plasma (2,650- and 10,700-fold greater than wild type, respectively), whereas urinary 5-aminolevulinic acid and porphobilinogen were lower than normal. Erythrocytic URO-synthase activity was <1% of mean wild-type activity, confirming the diagnosis and distinguishing it from feline phenocopies having acute intermittent porphyria. Sequencing of the affected cat’s UROS gene revealed two missense mutations, c.140C>T (p.S47F) in exon 3 and c.331G>A (p.G111S) in exon 6, both of which were homozygous, presumably owing to parental consanguinity. Neither was present in 100 normal cat alleles. Prokaryotic expression and thermostability studies of the purified monomeric wild-type, p.S47F, p.G111S, and p.S47F/G111S enzymes showed that the p.S47F enzyme had 100% of wild-type specific activity but ~50% decreased thermostability...

‣ Missense mutations to the TSC1 gene cause tuberous sclerosis complex

Nellist, Mark; van den Heuvel, Diana; Schluep, Diane; Exalto, Carla; Goedbloed, Miriam; Maat-Kievit, Anneke; van Essen, Ton; van Spaendonck-Zwarts, Karin; Jansen, Floor; Helderman, Paula; Bartalini, Gabriella; Vierimaa, Outi; Penttinen, Maila; van den End
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene on chromosome 9q34 or the TSC2 gene on chromosome 16p13.3. The TSC1 and TSC2 gene products, TSC1 and TSC2, interact to form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). Here we investigate the effects of putative TSC1 missense mutations identified in individuals with signs and/or symptoms of TSC on TSC1–TSC2 complex formation and mTOR signalling. We show that specific amino-acid substitutions close to the N-terminal of TSC1 reduce steady-state levels of TSC1, resulting in the activation of mTOR signalling and leading to the symptoms of TSC.

‣ Genotype–Phenotype Correlations of Pheochromocytoma in Two Large von Hippel–Lindau (VHL) Type 2A Kindreds With Different Missense Mutations

Nielsen, Sarah M.; Rubinstein, Wendy S.; Thull, Darcy L.; Armstrong, Michaele J.; Feingold, Eleanor; Stang, Michael T.; Gnarra, James R.; Carty, Sally E.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/2011 Português
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Von Hippel–Lindau (VHL) disease type 2A is an inherited tumor syndrome characterized by predisposition to pheochromocytoma (pheo), retinal hemangioma (RA), and central nervous system hemangioblastoma (HB). Specific VHL subtypes display genotype–phenotype correlations but, unlike other familial syndromes such as MEN-2, the phenotype in VHL has not yet been stratified at the codon level. Over decades, we have managed two very large VHL type 2A regional kindreds with nearly adjacent but distinct VHL missense mutations. We determined the phenotype of Family 2 and compared the clinical and pathologic parameters of pheo between 30 members of Family 1 (Y112H mutation) and 33 members of Family 2 (Y98H mutation) with mean follow-up of 15.5 and 12.1 years, respectively (P=0.24). In Family 2, pheo was the most frequent VHL manifestation (79%) and all pheo diagnoses occurred by age 50. Age at first diagnosis was younger in Family 2 than in Family 1 (mean 19.7 vs. 28.8 years; P=0.02). Pheo expressivity differed by genotype: Family 1 pheo was more likely to be multifocal (P=0.04), as well as malignant (P<0.01) and lethal (P=0.02). Family 1 pheo was also more likely to secrete vanillylmandelic acid (VMA) alone (P=0.05). This analysis of 130 pheochromocytomas in 63 VHL type 2A patients demonstrates that mutation-specific malignancy and expression patterns exist within the VHL type 2A subtype...

‣ Band 3 Missense Mutations and Stomatocytosis: Insight into the Molecular Mechanism Responsible for Monovalent Cation Leak

Barneaud-Rocca, Damien; Pellissier, Bernard; Borgese, Franck; Guizouarn, Hélène
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
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Missense mutations in the erythroid band 3 protein (Anion Exchanger 1) have been associated with hereditary stomatocytosis. Features of cation leaky red cells combined with functional expression of the mutated protein led to the conclusion that the AE1 point mutations were responsible for Na+ and K+ leak through a conductive mechanism. A molecular mechanism explaining mutated AE1-linked stomatocytosis involves changes in AE1 transport properties that become leaky to Na+ and K+. However, another explanation suggests that point-mutated AE1 could regulate a cation leak through other transporters. This short paper intends to discuss these two alternatives.

‣ In-Frame Deletion and Missense Mutations of the C-Terminal Helicase Domain of SMARCA2 in Three Patients with Nicolaides-Baraitser Syndrome

Wolff, D.; Endele, S.; Azzarello-Burri, S.; Hoyer, J.; Zweier, M.; Schanze, I.; Schmitt, B.; Rauch, A.; Reis, A.; Zweier, C.
Fonte: S. Karger AG Publicador: S. Karger AG
Tipo: Artigo de Revista Científica
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Using high-resolution molecular karyotyping with SNP arrays to identify candidate genes for etiologically unexplained intellectual disability, we identified a 32-kb de novo in-frame deletion of the C-terminal helicase domain of the SMARCA2 gene in a patient with severe intellectual disability, epilepsy, sparse hair, prominent joints, and distinct facial anomalies. Sequencing of the gene in patients with a similar phenotype revealed de novo missense mutations in this domain in 2 further patients, pointing to a crucial role of the SMARCA2 C-terminal helicase domain. The clinical features observed in all 3 patients are typical of Nicolaides-Baraitser syndrome, an only rarely reported syndrome with mainly moderate to severe intellectual disability. Notably, one of our patients with a p.Gly1132Asp mutation showed typical morphological features but an exceptional good development with borderline overall IQ and learning difficulties, thus expanding the phenotypic spectrum of Nicolaides-Baraitser syndrome.

‣ Missense Mutations in Cytochrome c Maturation Genes Provide New Insights into Rhodobacter capsulatus cbb3-Type Cytochrome c Oxidase Biogenesis

Ekici, Seda; Jiang, Xinpei; Koch, Hans-Georg; Daldal, Fevzi
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /01/2013 Português
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The Rhodobacter capsulatus cbb3-type cytochrome c oxidase (cbb3-Cox) belongs to the heme-copper oxidase superfamily, and its subunits are encoded by the ccoNOQP operon. Biosynthesis of this enzyme is complex and needs dedicated biogenesis genes (ccoGHIS). It also relies on the c-type cytochrome maturation (Ccm) process, which requires the ccmABCDEFGHI genes, because two of the cbb3-Cox subunits (CcoO and CcoP) are c-type cytochromes. Recently, we reported that mutants lacking CcoA, a major facilitator superfamily type transporter, produce very small amounts of cbb3-Cox unless the growth medium is supplemented with copper. In this work, we isolated “Cu-unresponsive” derivatives of a ccoA deletion strain that exhibited no cbb3-Cox activity even upon Cu supplementation. Molecular characterization of these mutants revealed missense mutations in the ccmA or ccmF gene, required for the Ccm process. As expected, Cu-unresponsive mutants lacked the CcoO and CcoP subunits due to Ccm defects, but remarkably, they contained the CcoN subunit of cbb3-Cox. Subsequent construction and examination of single ccm knockout mutants demonstrated that membrane insertion and stability of CcoN occurred in the absence of the Ccm process. Moreover, while the ccm knockout mutants were completely incompetent for photosynthesis...

‣ Missense Mutations Linked to Friedreich Ataxia Have Different but Synergistic Effects on Mitochondrial Frataxin Isoforms*

Li, Hongqiao; Gakh, Oleksandr; Smith, Douglas Y.; Ranatunga, Wasantha K.; Isaya, Grazia
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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Background: Missense mutations in frataxin contribute to Friedreich ataxia pathophysiology with undefined mechanisms.

‣ Nephrin missense mutations: induction of endoplasmic reticulum stress and cell surface rescue by reduction in chaperone interactions

Drozdova, Tetyana; Papillon, Joan; Cybulsky, Andrey V
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
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Nephrin, an important component of the podocyte filtration slit diaphragm, plays a key role in the maintenance of glomerular permselectivity. Mutations in nephrin lead to proteinuria and congenital nephrotic syndrome. Nephrin undergoes posttranslational modifications in the endoplasmic reticulum (ER) prior to export to the plasma membrane. We examined the effects of human nephrin disease-associated missense mutations on nephrin folding in the ER and on cellular trafficking in cultured cells. Compared with wild-type (WT) nephrin, the mutants showed impaired glycosylation and enhanced association with the ER chaperone, calnexin, as well as accumulation in the ER. Nephrin mutants demonstrated enhanced ubiquitination, and they underwent ER-associated degradation. Certain nephrin mutants did not traffic to the plasma membrane. Expression of nephrin mutants resulted in the stimulation of the activating transcription factor-6 pathway of the unfolded protein response, and an increase in the ER chaperone, Grp94. We treated cells with castanospermine (an inhibitor of glucosidase I) in order to decrease the association of nephrin mutants with calnexin. Castanospermine increased plasma membrane expression of nephrin mutants; however, full glycosylation and signaling activity of the mutants were not restored. Modulation of ER quality control mechanisms represents a potential new approach to development of therapies for proteinuric kidney disease...

‣ Novel three missense mutations observed in Von Hippel-Lindau gene in a patient reported with renal cell carcinoma

Kumar, Pasupuleti Santhosh; Venkatesh, Katari; Srikanth, Lokanathan; Sarma, Potukuchi Venkata Gurunadha Krishna; Reddy, Akkamgari Ramprasad; Subramanian, Srinivasan; Phaneendra, Bobbidi Venkata
Fonte: Medknow Publications & Media Pvt Ltd Publicador: Medknow Publications & Media Pvt Ltd
Tipo: Artigo de Revista Científica
Publicado em //2013 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 tumors, especially cerebellar hemangioblastomas, retinal angiomas and clear-cell renal cell carcinomas (RCC). We have identified of VHL gene using immunohistochemistry in a patient who was diagnosed for RCC. In order to understand the involvement of mutation in the VHL gene exon 1 was amplified and sequenced (accession number: JX 401534). The sequence analysis revealed the presence of novel missense mutations c.194 C>T, c.239 G>A, c.278 G>A, c.319 C>G, c. 337 C > G leading to the following variations p.Ala 65 Val, p.Gly 80 Asp, p.Gly 93 Glu, p.Gln 107 Glu, p.Gln 113 Glu in the protein.

‣ In Silico Analysis of Missense Mutations in LPAR6 Reveals Abnormal Phospholipid Signaling Pathway Leading to Hypotrichosis

Raza, Syed Irfan; Muhammad, Dost; Jan, Abid; Ali, Raja Hussain; Hassan, Mubashir; Ahmad, Wasim; Rashid, Sajid
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 13/08/2014 Português
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Autosomal recessive hypotrichosis is a rare genetic irreversible hair loss disorder characterized by sparse scalp hair, sparse to absent eyebrows and eyelashes, and sparse axillary and body hair. The study, presented here, established genetic linkage in four families showing similar phenotypes to lysophosphatidic acid receptor 6 (LPAR6) gene on chromosome 13q14.11-q21.32. Subsequently, sequence analysis of the gene revealed two previously reported missense mutations including p.D63V in affected members of one and p.I188F in three other families. Molecular modeling and docking analysis was performed to investigate binding of a ligand oleoyl-L-alpha-lysophosphatidic acid (LPA) to modeled protein structures of normal and mutated (D63V, G146R, I188F, N248Y, S3T, L277P) LPAR6 receptors. The mutant receptors showed a complete shift in orientation of LPA at the binding site. In addition, hydropathy analysis revealed a significant change in the membrane spanning topology of LPAR6 helical segments. The present study further substantiated involvement of LPAR6-LPA signaling in the pathogenesis of hypotrichosis/woolly hair and provided additional insight into the molecular mechanism of hair development.

‣ The Contribution of Missense Mutations in Core and Rim Residues of Protein–Protein Interfaces to Human Disease

David, Alessia; Sternberg, Michael J.E.
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em 28/08/2015 Português
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Missense mutations at protein–protein interaction sites, called interfaces, are important contributors to human disease. Interfaces are non-uniform surface areas characterized by two main regions, “core” and “rim”, which differ in terms of evolutionary conservation and physicochemical properties. Moreover, within interfaces, only a small subset of residues (“hot spots”) is crucial for the binding free energy of the protein–protein complex.

‣ Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance

Tischfield, M.; Baris, H.; Wu, C.; Rudolph, G.; van Maldergem, L.; He, W.; Chan, W.M.; Andrews, C.; Demer, J.; Robertson, R.; Mackey, D.; Ruddle, J.; Bird, T.; Gottlob, I.; Pieh, C.; Traboulsi, E.; Pomeroy, S.; Hunter, D.; Soul, J.; Newlin, A.; et al.
Fonte: Cell Press Publicador: Cell Press
Tipo: Artigo de Revista Científica
Publicado em //2010 Português
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We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.; Max A. Tischfield, Hagit N. Baris, Chen Wu, Guenther Rudolph, Lionel Van Maldergem, Wei He, Wai-Man Chan...