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‣ Pompe disease in a Brazilian series: clinical and molecular analyses with identification of nine new mutations

OBA-SHINJO, Sueli M.; SILVA, Roseli da; ANDRADE, Fernanda G.; PALMER, Rachel E.; POMPONIO, Robert J.; CIOCIOLA, Kristina M.; CARVALHO, Mary S.; GUTIERREZ, Paulo S.; PORTA, Gilda; MARRONE, Carlo D.; MUNOZ, Veronica; GRZESIUK, Anderson K.; LLERENA JR., Juan
Fonte: DR DIETRICH STEINKOPFF VERLAG Publicador: DR DIETRICH STEINKOPFF VERLAG
Tipo: Artigo de Revista Científica
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Pompe disease (glycogen storage disease type II or acid maltase deficiency) is an inherited autosomal recessive deficiency of acid alpha-glucosidase (GAA), with predominant manifestations of skeletal muscle weakness. A broad range of studies have been published focusing on Pompe patients from different countries, but none from Brazil. We investigated 41 patients with either infantile-onset (21 cases) or late-onset (20 cases) disease by muscle pathology, enzyme activity and GAA gene mutation screening. Molecular analyses identified 71 mutant alleles from the probands, nine of which are novel (five missense mutations c.136T > G, c.650C > T, c.1456G > C, c.1834C > T, and c.1905C > A, a splice-site mutation c.1195-2A > G, two deletions c.18_25del and c.2185delC, and one nonsense mutation c.643G > T). Interestingly, the c.1905C > A variant was detected in four unrelated patients and may represent a common Brazilian Pompe mutation. The c.2560C > T severe mutation was frequent in our population suggesting a high prevalence in Brazil. Also, eight out of the 21 infantile-onset patients have two truncating mutations predicted to abrogate protein expression. Of the ten late-onset patients who do not carry the common late-onset intronic mutation c.-32-13T > G...

‣ Functional analysis of myosin missense mutations in familial hypertrophic cardiomyopathy.

Straceski, A J; Geisterfer-Lowrance, A; Seidman, C E; Seidman, J G; Leinwand, L A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 18/01/1994 Português
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To analyze potential functional consequences of myosin heavy chain (MHC) mutations identified in patients with familial hypertrophic cardiomyopathy (FHC), we have assessed the stability of the mutant MHCs and their ability to form thick filaments. Constructs encoding wild-type rat alpha MHC and seven corresponding FHC missense mutants were transfected into COS cells. Immunoblot analysis suggested that FHC mutations do not grossly alter protein stability. Wild-type alpha MHC transfected into COS cells forms structures previously shown to be arrays of thick filaments, which also resemble myosin structures observed early in differentiation of muscle cells. Surprisingly, up to 29% of COS cells transfected with the FHC mutants failed to form filamentous structures. To assess whether this phenotype was specific for the FHC mutants and not generalizable to any myosin mutation, COS cells were transfected with a construct encoding an MHC with a 168-amino acid deletion of the hinge/rod region. This deletion construct formed filamentous structures with the same frequency as wild-type MHC. Biochemical analysis of one FHC mutant (Arg-249-->Gln) demonstrates that the structures formed by the mutant are solubilized at a lower ionic strength than those formed by wild-type MHC. We conclude that although the FHC mutant MHC is not labile...

‣ Functional analysis of a type IIB von Willebrand disease missense mutation: increased binding of large von Willebrand factor multimers to platelets.

Cooney, K A; Lyons, S E; Ginsburg, D
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/04/1992 Português
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Type IIB von Willebrand disease is an autosomal dominant bleeding disorder characterized by the selective loss of high molecular weight von Willebrand factor (vWF) multimers in plasma, presumably due to their abnormally increased reactivity with platelets. We and others have recently identified a panel of missense mutations clustered in the platelet glycoprotein Ib binding domain of vWF from patients with type IIB von Willebrand disease. We now report functional analysis of one of the most frequent type IIB missense mutations, Arg-543----Trp (vWF R543W). vWF from a human umbilical vein endothelial cell culture heterozygous for the vWF R543W mutation showed markedly increased binding of large vWF multimers to platelets in the presence of a low dose of ristocetin compared to vWF from a normal control culture. Recombinant vWF containing the vWF R543W mutation expressed in COS-7 cells also demonstrated increased binding of large vWF multimers. Mixed multimers obtained by cotransfection of mutant and wild-type cDNAs showed partial dominance of the vWF R543W mutation. Thus these data demonstrate that the vWF R543W mutation alone is sufficient to confer increased binding of large vWF multimers to platelets in a dominant fashion and that no other factors relating to vWF posttranslational processing or secretion in endothelial cells are required for this effect.

‣ Mucoid-to-nonmucoid conversion in alginate-producing Pseudomonas aeruginosa often results from spontaneous mutations in algT, encoding a putative alternate sigma factor, and shows evidence for autoregulation.

DeVries, C A; Ohman, D E
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/1994 Português
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The mucoid phenotype is common among strains of Pseudomonas aeruginosa that cause chronic pulmonary infections in patients with cystic fibrosis and is due to overproduction of an exopolysaccharide called alginate. However, the mucoid phenotype is unstable in vitro, especially when the cells are incubated under low oxygen tension. Spontaneous conversion to the nonmucoid form is typically due to mutations (previously called algS) that are closely linked to the alginate regulatory gene algT, located at 68 min on the chromosome. Our sequence analysis of algT showed that its 22-kDa gene product shares homology with several alternate sigma factors in bacteria, suggesting that AlgT (also known as AlgU) interacts directly with RNA polymerase core to activate the promoters of alginate genes. AlgT showed striking sequence similarity (79%) to sigma E of Escherichia coli, an alternate sigma factor involved in high-temperature gene expression. Our analysis of the molecular basis for spontaneous conversion from mucoid to nonmucoid, in the cystic fibrosis isolate FRD, revealed that nonmucoid conversion was often due to one of two distinct missense mutations in algT that occurred at codons 18 and 29. RNase protection assays showed that spontaneous nonmucoid strains with the algT18 and algT29 alleles have a four- to fivefold reduction in the accumulation of algT transcripts compared with the wild-type mucoid strain. Likewise...

‣ Understanding missense mutations in the BRCA1 gene: An evolutionary approach

Fleming, Melissa A.; Potter, John D.; Ramirez, Christina J.; Ostrander, Gary K.; Ostrander, Elaine A.
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
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The role of missense changes in BRCA1 in breast cancer susceptibility has been difficult to establish. We used comparative evolutionary methods to identify potential functionally important amino acid sites in exon 11 and missense changes likely to disrupt gene function, aligning sequences from 57 eutherian mammals and categorizing amino acid sites by degree of conservation. We used Bayesian phylogenetic analyses to determine relationships among orthologs and identify codons evolving under positive selection. Most conserved residues occur in a region with the highest concentration of protein-interacting domains. Rapidly evolving residues are concentrated in the RAD51-interacting domain, suggesting that selection is acting most strongly on the role of BRCA1 in DNA repair. Investigation of the functional role of missense changes in breast-cancer susceptibility should focus on 38 missense changes in conserved and 3 in rapidly evolving regions of exon 11.

‣ Two Missense Mutations in the Primary Autosomal Recessive Microcephaly Gene MCPH1 Disrupt the Function of the Highly Conserved N-Terminal BRCT Domain of Microcephalin

Ghani-Kakhki, M.; Robinson, P.N.; Morlot, S.; Mitter, D.; Trimborn, M.; Albrecht, B.; Varon, R.; Sperling, K.; Neitzel, H.
Fonte: S. Karger AG Publicador: S. Karger AG
Tipo: Artigo de Revista Científica
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Primary microcephaly MCPH1 is an extremely rare autosomal recessive disorder associated with congenital microcephaly, mental retardation and a distinctive cellular phenotype of misregulated chromosome condensation. The MCPH1 gene encodes an 835-amino acid protein, microcephalin, which contains 1 N-terminal and 2 C-terminal BRCT (BRCA1 C-terminus) domains. BRCT domains are predominantly found in proteins involved in cell cycle control and DNA repair. Here we describe 1 novel and 1 previously reported MCPH1 missense mutation, p.Trp75Arg and p.Ser72Leu, respectively, in the N-terminal BRCT domain of microcephalin associated with severe congenital microcephaly. Both residues are entirely conserved in the MCPH1 orthologs of all vertebrate species and Drosophila. Proliferating lymphocytes of the patients with p.Trp75Arg and p.Ser72Leu show the unique cellular MCPH1 phenotype of misregulated chromosome condensation, indicating that these missense alterations disrupt the function of the N-terminal BRCT domain of the protein. Interestingly, both residues are strictly conserved in BRCT domains of BRCA1. ClustalW alignments show that the residue p.Ser72 of microcephalin corresponds to p.Ser1715 of the N-terminal BRCT domain of BRCA1, while the microcephalin residue p.Trp75 is analogous to p.Trp1718 in the N-terminal BRCT and to p.Trp1837 in C-terminal BRCT domains of BRCA1. Missense alterations for all 3 corresponding BRCA1 residues were described and are predicted to be deleterious resulting in the destabilization of the BRCA1 protein. Our data on the 2 MCPH1 missense alterations provide further evidence for the functional significance of these residues in BRCT domains.

‣ Homozygosity for Non-H1069Q Missense Mutations in ATP7B Gene and Early Severe Liver Disease: Report of Two Families and a Meta-analysis

Usta, Julnar; Daya, Hussein Abu; Halawi, Houssam; Al-Shareef, Ibraheem; El-Rifai, Omar; Malli, Ahmad H.; Sharara, Ala I.; Habib, Robert H.; Barada, Kassem
Fonte: Springer Berlin Heidelberg Publicador: Springer Berlin Heidelberg
Tipo: Artigo de Revista Científica
Publicado em 08/11/2011 Português
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Most patients with Wilson’s disease (WD) are compound heterozygote, which complicates establishing genotype–phenotype correlations. We identified five patients who presented with early and/or severe hepatic disease who are homozygous for W939C missense mutation on exon 12 of ATP7B. We therefore conducted a meta-analysis to determine the phenotype of patients homozygous for missense or nonsense mutations in all ATP7B exons.

‣ Missense mutation in mouse GALC mimics human gene defect and offers new insights into Krabbe disease

Potter, Gregory B.; Santos, Marta; Davisson, Muriel T.; Rowitch, David H.; Marks, Dan L.; Bongarzone, Ernesto R.; Petryniak, Magdalena A.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Krabbe disease is a devastating pediatric leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene. A significant subset of the infantile form of the disease is due to missense mutations that result in aberrant protein production. The currently used mouse model, twitcher, has a nonsense mutation not found in Krabbe patients, although it is similar to the human 30 kb deletion in abrogating GALC expression. Here, we identify a spontaneous mutation in GALC, GALCtwi-5J, that precisely matches the E130K missense mutation in patients with infantile Krabbe disease. GALCtwi-5J homozygotes show loss of enzymatic activity despite normal levels of precursor protein, and manifest a more severe phenotype than twitcher, with half the life span. Although neuropathological hallmarks such as gliosis, globoid cells and psychosine accumulation are present throughout the nervous system, the CNS does not manifest significant demyelination. In contrast, the PNS is severely hypomyelinated and lacks large diameter axons, suggesting primary dysmyelination, rather than a demyelinating process. Our data indicate that early demise is due to mechanisms other than myelin loss and support an important role for neuroinflammation in Krabbe disease progression. Furthermore...

‣ WNT5A Mutations in Patients with Autosomal Dominant Robinow Syndrome

Person, Anthony D.; Beiraghi, Soraya; Sieben, Christine M.; Hermanson, Spencer; Neumann, Ann N.; Robu, Mara E.; Schleiffarth, J. Robert; Billington, Charles J.; van Bokhoven, Hans; Hoogeboom, J.; Mazzeu, Juliana F.; Petryk, Anna; Schimmenti, Lisa A.; Brun
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/2010 Português
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Robinow syndrome is a skeletal dysplasia with both autosomal dominant and autosomal recessive inheritance patterns. It is characterized by short stature, limb shortening, genital hypoplasia and craniofacial abnormalities. The etiology of dominant Robinow syndrome is unknown, however the phenotypically more severe autosomal recessive form of Robinow syndrome has been associated with mutations in the orphan tyrosine kinase receptor, ROR2, which has recently been identified as a putative WNT5A receptor. Here we show that two different missense mutations in WNT5A, which result in amino acid substitutions of highly conserved cysteines, are associated with autosomal dominant Robinow syndrome. One mutation has been found in all living affected members of the original family described by Meinhard Robinow and another in a second unrelated patient. These missense mutations result in decreased WNT5A activity in functional assays of zebrafish and Xenopus development. This work suggests that a WNT5A/ROR2 signal transduction pathway is important in human craniofacial and skeletal development, and that proper formation and growth of these structures is sensitive to variations in WNT5A function.

‣ Alleged Detrimental Mutations in the SMPD1 Gene in Patients with Niemann-Pick Disease

Rhein, Cosima; Mühle, Christiane; Kornhuber, Johannes; Reichel, Martin
Fonte: MDPI Publicador: MDPI
Tipo: Artigo de Revista Científica
Publicado em 15/06/2015 Português
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Loss-of-function mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene are associated with decreased catalytic activity of acid sphingomyelinase (ASM) and are the cause of the autosomal recessive lysosomal storage disorder Niemann-Pick disease (NPD) types A and B. Currently, >100 missense mutations in SMPD1 are listed in the Human Gene Mutation Database. However, not every sequence variation in SMPD1 is detrimental and gives rise to NPD. We have analysed several alleged SMPD1 missense mutations mentioned in a recent publication and found them to be common variants of SMPD1 that give rise to normal in vivo and in vitro ASM activity. (Comment on Manshadi et al. Int. J. Mol. Sci. 2015, 16, 6668–6676).

‣ Novel FGFR1 and KISS1R Mutations in Chinese Kallmann Syndrome Males with Cleft Lip/Palate

Xu, Hao; Niu, Yonghua; Wang, Tao; Liu, Simin; Xu, Hua; Wang, Shaogang; Liu, Jihong; Ye, Zhangqun
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
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Kallmann syndrome (KS) is characterized by isolated hypogonadotropic hypogonadism (IHH) with anosmia and is sometimes associated with cleft lip/palate (CLP). In order to describe the clinical features, genetic etiology, and treatment outcome of KS males with CLP, we performed genetic screening for 15 known causal IHH genes (KAL1, FGFR1, NELF, FGF8, CHD7, WDR11, SEMA3A, KISS1R, KISS1, PROKR2, PROK2, TAC3, TACR3, GNRH1, and GNRHR) in four KS with CLP patients and six IHH patients without CLP. Two novel heterozygous missense mutations in FGFR1, (NM_001174066): c.776G>A (p.G259E) and (NM_001174066): c.358C>T (p.R120C), were identified in a 23-year-old KS male with cleft lip and an 18-year-old KS patient with cleft lip and palate, dental agenesis, and high arched palate, respectively. These two mutations were not presented in their healthy parents and 200 normal controls. One novel heterozygous missense mutation in KISS1R, (NM_032551): c.587C>A (p.P196H), was identified in an 18-year-old KS male with cleft lip and dental agenesis who developed sperm after being treated with gonadotropin. This mutation was also presented in his healthy father and grandfather. These results have implications for the diagnosis, genetic counseling, and treatment of KS and CLP males with mutations in FGFR1 gene.

‣ Structural and functional influences of coagulation factor XIII subunit B heterozygous missense mutants

Thomas, Anne; Biswas, Arijit; Ivaskevicius, Vytautas; Oldenburg, Johannes
Fonte: John Wiley & Sons, Ltd Publicador: John Wiley & Sons, Ltd
Tipo: Artigo de Revista Científica
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The coagulation factor XIII(FXIII) is a plasma circulating heterotetrameric protransglutaminase that acts at the end of the coagulation cascade by covalently cross-linking preformed fibrin clots (to themselves and to fibrinolytic inhibitors) in order to stabilize them against fibrinolysis. It circulates in the plasma as a heterotetramer composed of two homomeric catalytic Factor XIIIA2 (FXIIIA2) and two homomeric protective/carrier Factor XIIIB2 subunit (FXIIIB2). Congenital deficiency of FXIII is of two types: severe homozygous/compound heterozygous FXIII deficiency which results in severe bleeding symptoms and mild heterozygous FXIII deficiency which is associated with mild bleeding (only upon trauma) or an asymptomatic phenotype. Defects in the F13B gene (Factor XIIIB subunit) occur more frequently in mild FXIII deficiency patients than in severe FXIII deficiency. We had recently reported secretion-related defects for seven previously reported F13B missense mutations. In the present study we further analyze the underlying molecular pathological mechanisms as well as the heterozygous expression phenotype for these mutations using a combination of in vitro heterologous expression (in HEK293T cells) and confocal microscopy. In combination with the in vitro work we have also performed an in silico solvated molecular dynamic simulation study on previously reported FXIIIB subunit sushi domain homology models in order to predict the putative structure-functional impact of these mutations. We were able to categorize the mutations into the following functional groups that: (1) affect antigenic stability as well as binding to FXIIIA subunit...

‣ Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature

Kazenwadel, J.; Secker, G.; Liu, Y.; Rosenfeld, J.; Wildin, R.; Cuellar-Rodriguez, J.; Hsu, A.; Dyack, S.; Fernandez, C.; Chong, C.; Babic, M.; Bardy, P.; Shimamura, A.; Zhang, M.; Walsh, T.; Holland, S.; Hickstein, D.; Horwitz, M.; Hahn, C.; Scott, H.; e
Fonte: Amer Soc Hematology Publicador: Amer Soc Hematology
Tipo: Artigo de Revista Científica
Publicado em //2012 Português
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Recent work has established that heterozygous germline GATA2 mutations predispose carriers to familial myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), “MonoMAC” syndrome, and DCML deficiency. Here, we describe a previously unreported MDS family carrying a missense GATA2 mutation (p.Thr354Met), one patient with MDS/AML carrying a frameshift GATA2 mutation (p.Leu332Thrfs*53), another with MDSharboring a GATA2 splice site mutation, and 3 patients exhibiting MDS or MDS/AML who have large deletions encompassing the GATA2 locus. Intriguingly, 2 MDS/AML or “MonoMAC” syndrome patients with GATA2 deletions and one with a frameshift mutation also have primary lymphedema. Primary lymphedema occurs as a result of aberrations in the development and/or function of lymphatic vessels, spurring us to investigate whether GATA2 plays a role in the lymphatic vasculature. We demonstrate here that GATA2 protein is present at high levels in lymphatic vessel valves and that GATA2 controls the expression of genes important for programming lymphatic valve development. Our data expand the phenotypes associated with germline GATA2 mutations to include predisposition to primary lymphedema and suggest that complete haploinsufficiency or loss of function of GATA2...

‣ New mutations in MID1 provide support for loss of function as the cause of X-linked Optiz syndrome

Cox, T.; Allen, L.; Cox, L.; Hopwood, B.; Goodwin, B.; Haan, E.; Suthers, G.
Fonte: Oxford Univ Press Publicador: Oxford Univ Press
Tipo: Artigo de Revista Científica
Publicado em //2000 Português
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Opitz syndrome (OS) is a genetically heterogeneous malformation disorder. Patients with OS may present with a variable array of malformations that are indicative of a disturbance of the primary midline developmental field. Mutations in the C-terminal half of MID1, an RBCC (RING, B-box and coiled-coil) protein, have recently been shown to underlie the X-linked form of OS. Here we show that the MID1 gene spans at least 400 kb, almost twice the distance originally reported and has a minimum of six mRNA isoforms as a result of the alternative use of 5' untranslated exons. In addition, our detailed mutational analysis of MID1 in a cohort of 15 patients with OS has resulted in the identification of seven novel mutations, two of which disrupt the N-terminus of the protein. The most severe of these (E115X) is predicted to truncate the protein before the B-box motifs. In a separate patient, a missense change (L626P) was found that also represents the most C-terminal alteration reported to date. As noted with other C-terminal mutations, GFP fusion constructs demonstrated that the L626P mutant formed cytoplasmic clumps in contrast to the microtubular distribution seen with the wild-type sequence. Notably, however, both N-terminal mutants showed no evidence of cytoplasmic aggregation...

‣ Mechanistic Insights into Arrhythmogenic Right Ventricular Cardiomyopathy Caused by Desmocollin-2 Mutations

Gehmlich, Katja; Syrris, Petros; Peskett, Emma; Evans, Alison; Ehler, Elisabeth; Asimaki, Angeliki; Anastasakis, Aris; Tsatsopoulou, Adalena; Vouliotis, Apostolos-Ilias; Stefanadis, Christodoulos; Protonotarios, Nikos; McKenna, William J.; Saffitz, Jeffre
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Aims: Recent immunohistochemical studies observed the loss of plakoglobin (PG) from the intercalated disc (ID) as a hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC), suggesting a final common pathway for this disease. However, the underlying molecular processes are poorly understood. Methods and results: We have identified novel mutations in the desmosomal cadherin desmocollin 2 (DSC2 R203C, L229X, T275M, and G371fsX378). The two missense mutations (DSC2 R203C and T275M) have been functionally characterized, together with a previously reported frameshift variant (DSC2 A897fsX900), to examine their pathogenic potential towards PG's functions at the ID. The three mutant proteins were transiently expressed in various cellular systems and assayed for expression, processing, localization, and binding to other desmosomal components in comparison to wild-type DSC2a protein. The two missense mutations showed defects in proteolytic cleavage, a process which is required for the functional activation of mature cadherins. In both cases, this is thought to cause a reduction of functional DSC2 at the desmosomes in cardiac cells. In contrast, the frameshift variant was incorporated into cardiac desmosomes; however, it showed reduced binding to PG. Conclusion: Despite different modes of action...

‣ De novo missense mutations in the NAA10 gene cause severe non-syndromic developmental delay in males and females

Popp, Bernt; Støve, Svein I; Endele, Sabine; Myklebust, Line M; Hoyer, Juliane; Sticht, Heinrich; Azzarello-Burri, Silvia; Rauch, Anita; Arnesen, Thomas; Reis, André
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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Recent studies revealed the power of whole-exome sequencing to identify mutations in sporadic cases with non-syndromic intellectual disability. We now identified de novo missense variants in NAA10 in two unrelated individuals, a boy and a girl, with severe global developmental delay but without any major dysmorphism by trio whole-exome sequencing. Both de novo variants were predicted to be deleterious, and we excluded other variants in this gene. This X-linked gene encodes N-alpha-acetyltransferase 10, the catalytic subunit of the NatA complex involved in multiple cellular processes. A single hypomorphic missense variant p.(Ser37Pro) was previously associated with Ogden syndrome in eight affected males from two different families. This rare disorder is characterized by a highly recognizable phenotype, global developmental delay and results in death during infancy. In an attempt to explain the discrepant phenotype, we used in vitro N-terminal acetylation assays which suggested that the severity of the phenotype correlates with the remaining catalytic activity. The variant in the Ogden syndrome patients exhibited a lower activity than the one seen in the boy with intellectual disability, while the variant in the girl was the most severe exhibiting only residual activity in the acetylation assays used. We propose that N-terminal acetyltransferase deficiency is clinically heterogeneous with the overall catalytic activity determining the phenotypic severity.

‣ Identification of compound heterozygous KCNJ1 mutations (encoding ROMK) in a kindred with Bartter's syndrome and a functional analysis of their pathogenicity

Srivastava, Shalabh; Li, Dimin; Edwards, Noel; Hynes, Ann-M; Wood, Katrina; Al-Hamed, Mohamed; Wroe, Anna C; Reaich, David; Moochhala, Shabbir H; Welling, Paul A; Sayer, John A
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
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A multiplex family was identified with biochemical and clinical features suggestive of Bartter's syndrome (BS). The eldest sibling presented with developmental delay and rickets at 4 years of age with evidence of hypercalciuria and hypokalemia. The second sibling presented at 1 year of age with urinary tract infections, polyuria, and polydipsia. The third child was born after a premature delivery with a history of polyhydramnios and neonatal hypocalcemia. Following corrective treatment she also developed hypercalciuria and a hypokalemic metabolic alkalosis. There was evidence of secondary hyperreninemia and hyperaldosteronism in all three siblings consistent with BS. Known BS genes were screened and functional assays of ROMK (alias KCNJ1, Kir1.1) were carried out in Xenopus oocytes. We detected compound heterozygous missense changes in KCNJ1, encoding the potassium channel ROMK. The S219R/L220F mutation was segregated from father and mother, respectively. In silico modeling of the missense mutations suggested deleterious changes. Studies in Xenopus oocytes revealed that both S219R and L220F had a deleterious effect on ROMK-mediated potassium currents. Coinjection to mimic the compound heterozygosity produced a synergistic decrease in channel function and revealed a loss of PKA-dependent stabilization of PIP2 binding. In conclusion...

‣ Naturally occurring missense mutation in the polymerase gene terminating hepatitis B virus replication.

Blum, H E; Galun, E; Liang, T J; von Weizsäcker, F; Wands, J R
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/1991 Português
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A hepatitis B virus (HBV) genome was cloned from human liver. Numerous mutations in all viral genes define this HBV DNA as a mutant, divergent from all known HBV DNA sequences. Functional analyses of this mutant demonstrated a defect blocking viral DNA synthesis. The genetic basis of this defect was identified as a single missense mutation in the 5' region of the viral polymerase gene, resulting in the inability to package pregenomic RNA into core particles. The replication defect could be trans-complemented by a full-length wild-type, but not by a full-length mutant or 3'-truncated wild-type, polymerase gene construct. Our findings indicate a critical role of the 5' polymerase gene region in the life cycle of the virus and suggest that introducing missense mutations in this region can be a strategy to terminate viral replication in vivo.

‣ Mutations Partially Inactivating the Lactose Repressor of Escherichia coli

Shineberg, B.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1974 Português
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After treatment with N-methyl-N′-nitro-N-nitrosoguanidine, 133 independent mutants of a haploid strain of Escherichia coli able to use phenyl-β-galactoside as a carbon source were obtained. The galactoside was specific in selecting for mutants with increases in their uninduced levels of β-galactosidase. Virtually all mutants (37 in a subsample of 38) carried mutations in the lac repressor gene. There were two classes of repressor mutants. As well as the commonly identified class of mutants with completely inactivated repressors, there was a frequent class of mutants (21/37) whose repressors were partially inactivated. Most of these (15/21) repressed β-galactosidase synthesis 4 to 50 times less than wild type, but were more numerous in the lower part of this range. Their β-galactosidase was inducible to levels characteristic of the parent strain. The repressor activities were diverse and stably expressed under routine growth conditions. The decreased activity did not result from the formation of temperature-sensitive repressors. None of the mutants with completely inactivated repressors appeared to carry UAG or UGA chain-terminating codons. On the assumption that the partially defective repressor mutants carried missense mutations...

‣ Análisis mutacional del gen Homeobox de segmento muscular 1 (MSX1) en chilenos con fisuras orales

Vieira,Alexandre R; Castillo Taucher,Silvia; Aravena,Teresa; Astete,Carmen; Sanz,Patricia; Tastets,María Eugenia; Monasterio,Luis; Murray,Jeffrey C
Fonte: Sociedad Médica de Santiago Publicador: Sociedad Médica de Santiago
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/07/2004 Português
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Background: Mutations of the MSX1 gene may contribute to nonsyndromic forms of cleft lip and/or cleft palate. Aim: To search for mutations of MSX1 coding regions, including one highly conserved non-coding region in the single intron, among Chilean patients with cleft lip/palate. Patients and Methods: We studied 45 patients with cleft lip/palate and their parents. Oral mucosa samples were obtained with a swab. DNA was extracted and amplified by PCR. Results: Two missense mutations (G16D and G34A) were identified in this study that may be useful for future admixture studies. The G16D mutation appears to disrupt a possible splicing site and may contribute to clefting in this population. Conclusions: Rare MSX1 mutations are found in some cases of cleft lip and/or cleft palate but others remain to be found most likely in other regulatory regions of the gene (Rev Méd Chile 2004; 132: 816-22)