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‣ A novel TBX5 missense mutation (V263M) in a family with atrial septal defects and postaxial hexodactyly

FARIA, Mario Henrique Girao; RABENHORST, Silvia Helena Barem; PEREIRA, Alexandre da Costa; KRIEGER, Jose Eduardo
Fonte: ELSEVIER IRELAND LTD Publicador: ELSEVIER IRELAND LTD
Tipo: Artigo de Revista Científica
Português
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Background: Congenital heart diseases are the most frequent birth defects and are commonly associated with skeletal malformations. Mutations in the TBX5 gene, a T-box transcription factor located on chromosome 12q24.1, have been demonstrated to be the underlying molecular alteration in individuals with different congenital cardiac disorders, notably the Holt-Oram syndrome. Methods: Six members from a two-generation family from a consanguineous couple, which had atrial septal defects associated with postaxial hexodactyly in all extremities were clinically assessed and submitted to TBX5 mutational analysis performed by direct sequencing. Results: We detected a new TBX5 missense mutation (V263M) in all four individuals studied with cardiac abnormalities. The genotype phenotype correlations in light of unusual features are extensively discussed, as well as the possible significance of these atypical findings. Conclusions: These new data extend our clinical and molecular knowledge of TBX5 gene mutations and also raise interesting questions about the phenotype heterogeneity regarding these gene alterations. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

‣ Genomic Strategy Identifies a Missense Mutation in WD-Repeat Domain 65 (WDR65) in an Individual With Van der Woude Syndrome

Rorick, Nicholas K.; Kinoshita, Akira; Weirather, Jason L.; Peyrard-Janvid, Myriam; Ferreira de Lima, Renata L. L.; Dunnwald, Martine; Shanske, Alan L.; Moretti-Ferreira, Danilo; Koillinen, Hannele; Kere, Juha; Mansilla, Maria A.; Murray, Jeffrey C.; Goud
Fonte: Wiley-Blackwell Publicador: Wiley-Blackwell
Tipo: Artigo de Revista Científica Formato: 1314-1321
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Genetic variation in the transcription factor interferon regulatory factor 6 (IRF6) causes and contributes risk for oral clefting disorders. We hypothesized that genes regulated by IRF6 are also involved in oral clefting disorders. We used five criteria to identify potential IRF6 target genes; differential gene expression in skin taken from wild-type and Irf6-deficient murine embryos, localization to the Van der Woude syndrome 2 (VWS2) locus at 1p36-1p32, overlapping expression with Irf6, presence of a conserved predicted-binding site in the promoter region, and a mutant murine phenotype that was similar to the Irf6 mutant mouse. Previously, we observed altered expression for 573 genes; 13 were located in the murine region syntenic to the VWS2 locus. Two of these genes, Wdr65 and Stratifin, met 4 of 5 criteria. Wdr65 was a novel gene that encoded a predicted protein of 1,250 amino acids with two WD domains. As potential targets for Irf6 regulation, we hypothesized that disease-causing mutations will be found in WDR65 and Stratifin in individuals with VWS or VWS-like syndromes. We identified a potentially etiologic missense mutation in WDR65 in a person with VWS who does not have an exonic mutation in IRF6. The expression and mutation data were consistent with the hypothesis that WDR65 was a novel gene involved in oral clefting. (C) 2011 Wiley-Liss...

‣ Neuroferritinopathy : missense mutation in FTL causing early-onset bilateral pallidal involvement

Maciel, P.; Cruz, V. T.; Constante, M.; Iniesta, I.; Costa, Maria do Carmo; Gallati, S.; Sousa, Nuno; Sequeiros, Jorge; Coutinho, P.; Santos, M. M.
Fonte: American Academy of Neurology Publicador: American Academy of Neurology
Tipo: Artigo de Revista Científica
Publicado em /08/2005 Português
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The authors identified a missense mutation in the FTL gene (474G>A; A96T) in a 19-year-old man with parkinsonism, ataxia, corticospinal signs, mild nonprogressive cognitive deficit, and episodic psychosis. This mutation was also present in his asymptomatic mother and younger brother, who had abnormally low levels of ferritin in the serum. The patient and his mother displayed bilateral involvement of the pallidum.; Fundação para a Ciência e a Tecnologia/Fundo Europeu de Desenvolvimento Regional (FCT)/(FEDER) - CBO/33485/99.

‣ The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex development

Cunha,J.L.; Soardi,F.C.; Bernardi,R.D.; Oliveira,L.E.C.; Benedetti,C.E.; Guerra-Junior,G.; Maciel-Guerra,A.T.; de Mello,M.P.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/04/2011 Português
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Male sex determination in humans is controlled by the SRY gene, which encodes a transcriptional regulator containing a conserved high mobility group box domain (HMG-box) required for DNA binding. Mutations in the SRY HMG-box affect protein function, causing sex reversal phenotypes. In the present study, we describe a 19-year-old female presenting 46,XY karyotype with hypogonadism and primary amenorrhea that led to the diagnosis of 46,XY complete gonadal dysgenesis. The novel p.E89K missense mutation in the SRY HMG-box was identified as a de novo mutation. Electrophoretic mobility shift assays showed that p.E89K almost completely abolished SRY DNA-binding activity, suggesting that it is the cause of SRY function impairment. In addition, we report the occurrence of the p.G95R mutation in a 46,XY female with complete gonadal dysgenesis. According to the three-dimensional structure of the human SRY HMG-box, the substitution of the conserved glutamic acid residue by the basic lysine at position 89 introduces an extra positive charge adjacent to and between the positively charged residues R86 and K92, important for stabilizing the HMG-box helix 2 with DNA. Thus, we propose that an electrostatic repulsion caused by the proximity of these positive charges could destabilize the tip of helix 2...

‣ Addition of a Missense Mutation Present in the L Gene of Respiratory Syncytial Virus (RSV) cpts530/1030 to RSV Vaccine Candidate cpts248/404 Increases Its Attenuation and Temperature Sensitivity

Whitehead, Stephen S.; Firestone, Cai-Yen; Karron, Ruth A.; Crowe, James E.; Elkins, William R.; Collins, Peter L.; Murphy, Brian R.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /02/1999 Português
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Respiratory syncytial virus (RSV) cpts530/1030 is an attenuated, temperature-sensitive subgroup A vaccine candidate derived previously from cold-passaged RSV (cpRSV) by two sequential rounds of chemical mutagenesis and biological selection. Here, cpts530/1030 was shown to be highly attenuated in the upper and lower respiratory tracts of seronegative chimpanzees. However, evaluation in seropositive children showed that it retains sufficient replicative capacity and virulence to preclude its direct use as a live attenuated vaccine. Nucleotide sequence analysis of the genome of cpts530/1030 showed that it had acquired two nucleotide substitutions (compared to its cpts530 parent), both of which were in the L gene: a silent mutation at nucleotide position 8821 (amino acid 108) and a missense mutation at nucleotide position 12458 resulting in a tyrosine-to-asparagine change at amino acid 1321, herein referred to as the 1030 mutation. It also contained the previously identified 530 missense mutation at nucleotide 10060 in the L gene. The genetic basis of attenuation of cpts530/1030 was defined by the introduction of the 530 and 1030 mutations into a cDNA clone of cpRSV, from which recombinant RSV was derived and analyzed to determine the contribution of each mutation to the temperature sensitivity (ts) and attenuation (att) phenotypes of cpts530/1030. The 530 mutation...

‣ Identification of a missense mutation in one allele of a patient with Pompe disease, and use of endonuclease digestion of PCR-amplified RNA to demonstrate lack of mRNA expression from the second allele.

Zhong, N; Martiniuk, F; Tzall, S; Hirschhorn, R
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/1991 Português
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Infantile-onset glycogen storage disease type II, or Pompe disease, results from a genetic deficiency of the lysosomal enzyme acid alpha glucosidase (GAA). Sequencing of the cDNA from a cell line (GM 244) derived from a patient with Pompe disease demonstrated a T953-to-C transition that predicted a methionine-to-threonine substitution at codon 318. The basepair substitution resulted in loss of restriction-endonuclease sites for NcoI and StyI. Analysis of genomic DNA revealed both a normal and an abnormal NcoI fragment, indicating that the patient was a genetic compound. NcoI and StyI digestion of cDNA, amplified by PCR from reverse-transcribed RNA, demonstrated that greater than 95% of the GAA mRNA in GM 244 was derived from the allele carrying the missense mutation. The missense mutation was uncommon, since it was not detected in 37 additional GAA-deficient chromosomes, as determined by digestion of genomic DNA with NcoI and hybridization. The amino acid substitution predicts a new potential site for N-linked glycosylation, as well as major changes in secondary structure of the protein. We could confirm that the mutation was responsible for the enzyme deficiency by demonstrating that a hybrid minigene containing the mutation did not express GAA enzyme activity after transient gene expression. We have therefore now provided the first identification of a single-basepair missense mutation in a patient with Pompe disease and furthermore have demonstrated that the patient is a genetic compound with the second allele barely expressing mRNA.

‣ Mucopolysaccharidosis IVA: Identification of a Common Missense Mutation I113F in the N-Acetylgalactosamine-6-Sulfate Sulfatase Gene

Tomatsu, Shunji; Fukuda, Seiji; Cooper, Alan; Wraith, James E.; Rezvi, Golam Md. Maruf; Yamagishi, Atsushi; Yamada, Naoto; Kato, Zenichiro; Isogai, Kouji; Sukegawa, Kazuko; Kondo, Naomi; Suzuki, Yasuyuki; Shimozawa, Nobuyuki; Orii, Tadao
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/1995 Português
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Mucopolysaccharidosis IVA is an autosomal recessive lysosomal storage disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase. The recent isolation and characterization of cDNA and genomic sequences encoding GALNS has facilitated identification of the molecular lesions that cause MPS IVA. We identified a common missense mutation among Caucasian MPS IVA patients. The mutation was originally detected by SSCP, and successive sequencing revealed an A→T transversion at nt 393. This substitution altered the isoleucine at position 113 to phenylalanine (I113F) in the 622 amino acid GALNS protein and was associated with a severe phenotype in a homozygote. Compound heterozygotes with one I113F-allele mutation have a wide range of clinical phenotypes. Transfection experiments in GALNS-deficient fibroblasts revealed that the mutation drastically reduces the enzyme activity of GALNS. Allele-specific oligonucleotide or SSCP analysis indicated that this mutation accounted for 22.5% (9/40) of unrelated MPS IVA chromosomes from 23 Caucasian patients, including 6 consanguineous cases. Of interest, the I1e 113→Phe substitution occurred in only Caucasian MPS IVA patients and in none of the GALNS alleles of 20 Japanese patients. These findings identify a frequent missense mutation among MPS IVA patients of Caucasian ancestry...

‣ The ATM missense mutation Ser49Cys and risk of breast cancer

Stredrick, Denise L.; Garcia-Closas, Montserrat; Pineda, Marbin A.; Bhatti, Parveen; Alexander, Bruce H.; Doody, Michele M.; Lissowska, Jolanta; Peplonska, Beata; Brinton, Louise A.; Chanock, Stephen J.; Struewing, Jeffery P.; Sigurdson, Alice J.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/2006 Português
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Homozygous mutation in the ATM gene causes ataxia telangiectasia and heterozygous mutation carriers may be at increased risk of breast cancer. We studied a total of 22 ATM variants in two large population-based studies of 2856 breast cancer cases and 3344 controls from the U.S. and Poland. The missense mutation Ser49Cys (S49C), carried by approximately 2% of subjects, was more common in cases than controls in both study populations, combined odds ratio (OR) 1.69, 95% CI 1.19 – 2.40, P = 0.004. Another missense mutation at approximately 2% frequency, F858L, was associated with a significant increased risk in the U.S. study but not in Poland, combined OR of 1.44, 95% CI 0.98 – 2.11, P = 0.06. These analyses provide the most convincing evidence thus far that some missense mutations in ATM, particularly S49C, may be breast cancer susceptibility alleles. Because of their low frequency, even larger sample sizes are required to more firmly establish these associations.

‣ A missense mutation in the conserved C2B domain of otoferlin causes deafness in a new mouse model of DFNB9

Longo-Guess, Chantal; Gagnon, Leona H.; Bergstrom, David E.; Johnson, Kenneth R.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Mutations of the otoferlin gene have been shown to underlie deafness disorders in humans and mice. Analysis of genetically engineered mice lacking otoferlin have demonstrated an essential role for this protein in vesicle exocytosis at the inner hair cell afferent synapse. Here, we report on the molecular and phenotypic characterization of a new ENU-induced missense mutation of the mouse otoferlin gene designated Otofdeaf5Jcs. The mutation is a single T to A base substitution in exon 10 of Otof that causes a non-conservative amino acid change of isoleucine to asparagine in the C2B domain of the protein. Although strong immunoreactivity with an otoferlin-specific antibody was detected in cochlear hair cells of wild type mice, no expression was detected in mutant mice, indicating that the missense mutation has a severe effect on the stability of the protein and potentially its localization. Auditory brainstem response (ABR) analysis demonstrated that mice homozygous for the missense mutation are profoundly deaf, consistent with an essential role for otoferlin in inner hair cell neurotransmission. Vestibular-evoked potentials (VsEPs) of mutant mice, however, were equivalent to those of wild type mice, indicating that otoferlin is unnecessary for vestibular function even though it is highly expressed in both vestibular and cochlear hair cells.

‣ Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation

Wang, Yongxing; Suh, Young-Ah; Fuller, Maren Y.; Jackson, James G.; Xiong, Shunbin; Terzian, Tamara; Quintás-Cardama, Alfonso; Bankson, James A.; El-Naggar, Adel K.; Lozano, Guillermina
Fonte: American Society for Clinical Investigation Publicador: American Society for Clinical Investigation
Tipo: Artigo de Revista Científica
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The transcription factor p53 is a tumor suppressor. As such, the P53 gene is frequently altered in human cancers. However, over 80% of the P53 mutations found in human cancers are missense mutations that lead to expression of mutant proteins that not only lack p53 transcriptional activity but exhibit new functions as well. Recent studies show that restoration of p53 expression leads to tumor regression in mice carrying p53 deletions. However, the therapeutic efficacy of restoring p53 expression in tumors containing p53 missense mutations has not been evaluated. Here we demonstrate that restoring wild-type p53 expression halted tumor growth in mice inheriting a p53R172H missense mutation that is equivalent to a P53 missense mutation detected in approximately 6% of human cancers. However, it did not lead to tumor regression, as was observed in mice lacking p53. We further showed that the dominant-negative effect of the mutant p53 encoded by p53R172H dampened the activity of the restored wild-type p53. We therefore conclude that in a mutant p53 background, p53 restoration has the therapeutic potential to suppress tumor progression. Our findings support using p53 restoration as a strategy to treat human cancers with P53 missense mutations and provide direction for optimizing p53 restoration in cancer therapy.

‣ Population-Based Estimate of Prostate Cancer Risk for Carriers of the HOXB13 Missense Mutation G84E

MacInnis, Robert J.; Severi, Gianluca; Baglietto, Laura; Dowty, James G.; Jenkins, Mark A.; Southey, Melissa C.; Hopper, John L.; Giles, Graham G.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 15/02/2013 Português
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The HOXB13 missense mutation G84E (rs138213197) is associated with increased risk of prostate cancer, but the current estimate of increased risk has a wide confidence interval (width of 95% confidence interval (CI) >200-fold) so the point estimate of 20-fold increased risk could be misleading. Population-based family studies can be more informative for estimating risks for rare variants, therefore, we screened for mutations in an Australian population-based series of early-onset prostate cancer cases (probands). We found that 19 of 1,384 (1.4%) probands carried the missense mutation, and of these, six (32%) had a family history of prostate cancer. We tested the 22 relatives of carriers diagnosed from 1998 to 2008 for whom we had a DNA sample, and found seven more carriers and one obligate carrier. The age-specific incidence for carriers was estimated to be, on average, 16.4 (95% CI 2.5–107.2) times that for the population over the time frame when the relatives were at risk prior to baseline. We then estimated the age and birth year- specific cumulative risk of prostate cancer (penetrance) for carriers. For example, the penetrance for an unaffected male carrier born in 1950 was 19% (95% CI 5–46%) at age 60 years, 44% (95% CI 18–74%) at age 70 years and 60% (95% CI 30–85%) at age 80 years. Our study has provided a population-based estimate of the average risk of prostate cancer for HOXB13 missense mutation G84E carriers that can be used to guide clinical practice and research. This study has also shown that the majority of hereditary prostate cancers due to the HOXB13 missense mutation are ‘sporadic’ in the sense that unselected cases with the missense mutation do not typically report having a family history of prostate cancer.

‣ A Missense Mutation (Q279R) in the Fumarylacetoacetate Hydrolase Gene, Responsible for Hereditary Tyrosinemia, Acts as a Splicing Mutation

Dreumont, Natacha; Poudrier, Jacques A; Bergeron, Anne; Baklouti, Faouzi; Tanguay, Robert M; Levy, Harvey Louis
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
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Background: Tyrosinemia type I, the most severe disease of the tyrosine catabolic pathway is caused by a deficiency in fumarylacetoacetate hydrolase (FAH). A patient showing few of the symptoms associated with the disease, was found to be a compound heterozygote for a splice mutation, IVS6-1g->t, and a putative missense mutation, Q279R. Analysis of FAH expression in liver sections obtained after resection for hepatocellular carcinoma revealed a mosaic pattern of expression. No FAH was found in tumor regions while a healthy region contained enzymeexpressing nodules. Results: Analysis of DNA from a FAH expressing region showed that the expression of the protein was due to correction of the Q279R mutation. RT-PCR was used to assess if Q279R RNA was produced in the liver cells and in fibroblasts from the patient. Normal mRNA was found in the liver region where the mutation had reverted while splicing intermediates were found in nonexpressing regions suggesting that the Q279R mutation acted as a splicing mutation in vivo. Sequence of transcripts showed skipping of exon 8 alone or together with exon 9. Using minigenes in transfection assays, the Q279R mutation was shown to induce skipping of exon 9 when placed in a constitutive splicing environment. Conclusion: These data suggest that the putative missense mutation Q279R in the FAH gene acts as a splicing mutation in vivo. Moreover FAH expression can be partially restored in certain liver cells as a result of a reversion of the Q279R mutation and expansion of the corrected cells.

‣ X-linked mild non-syndromic mental retardation with neuropsychiatric problems and the missense mutation A365E in PAK3

Gedeon, A.; Nelson, J.; Gecz, J.; Mulley, J.
Fonte: Wiley-Liss Publicador: Wiley-Liss
Tipo: Artigo de Revista Científica
Publicado em //2003 Português
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We describe a family of 19 males in five generations with mild to borderline non-syndromic X-linked mental retardation (MRX). There were no clinical manifestations in the affected males other than mental impairment and relatively long ears, with neuropsychiatric problems in some cases. Linkage analysis carried out on part of the pedigree using 34 markers spanning the X chromosome localized the gene between DXS454 and DXS1001 in Xq23. The maximum two-point lod score was 3.21 at DXS1059. PAK3 is a known MRX gene mapping to the same region. The affected males and obligate carrier females were found to have a missense mutation c.1094C > A in exon 10 causing an A365E substitution in a highly conserved region of the protein. The C to A base change abolishes a PvuII restriction enzyme site providing the basis for a simple test, if required, for carrier detection and prenatal diagnosis in the extended family.; Gedeon, Agi K.; Nelson, John; Gécz, Jozef; Mulley, John C.

‣ A missense mutation in RPS6KA3 (RSK2) responsible for non-specific mental retardation

Merienne, K.; Jacquot, S.; Pannetier, S.; Zeniou, M.; Bankier, A.; Gecz, J.; Mandel, J.L.; Mulley, J.; Sassone-Corsi, P.; Hanauer, A.
Fonte: NATURE AMERICA INC Publicador: NATURE AMERICA INC
Tipo: Artigo de Revista Científica
Publicado em //1999 Português
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Studies the genetic aspects of X-linked mental retardation (XLMR). Subtypes of XLMR; Presence of RPS6KA3 missense mutation; Kinase activity of the R383 mutant.; Karine Merienne; Sylvie Jacquot; Solange Pannetier; Maria Zeniou; Agnes Bankier; Jozef Gecz; Jean-louis Mandel; John Mulley; Paolo Sassone-corsi; André Hanauer

‣ Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM

Friend, K.; Crimmins, D.; Phan, T.; Sue, C.; Colley, A.; Fung, V.; Morris, J.; Sutherland, G.; Richards, R.
Fonte: SPRINGER VERLAG Publicador: SPRINGER VERLAG
Tipo: Artigo de Revista Científica
Publicado em //1999 Português
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Mutations in the brain specific P/Q type Ca2+ channel alpha1 subunit gene, CACNA1A, have been identified in three clinically distinct disorders, viz. episodic ataxia type 2 (EA-2), familial hemiplegic migraine (FHM) and spinocerebellar ataxia 6 (SCA6). For individuals with EA-2, the mutations described thus far are presumed to result in a truncated protein product. Several different missense mutations have been identified in patients with FHM. At least two of these mutations have been identified on two different chromosome 19p13 haplotypes and thus represent recurrent mutations. In the present study, we have screened several individuals for mutations in all 47 exons in the CACNA1A gene by single-strand conformation analysis. We have characterised a novel missense mutation, G5260A, in exon 32 in a family segregating for EA-2. The consequence of this mutation is an amino acid substitution at a highly conserved position within the CACNA1A gene. This represents the first point mutation not resulting in a proposed truncated protein. Furthermore, this mutation has been detected in a family member with mild clinical signs including only migraine. Additionally, a second previously identified recurrent muta tion, C2272T, in exon 16 has been discovered in a patient with FHM.; Friend...

‣ Structural and functional characteristics of the Val44Met insulin-like growth factor I missense mutation: Correlation with effects on growth and development

Denley, A.; Wang, C.; McNeil, K.; Walenkamp, M.; van Duyvenvoorde, H.; Wit, J.; Wallace, J.; Norton, R.; Karperien, M.; Forbes, B.
Fonte: Endocrine Soc Publicador: Endocrine Soc
Tipo: Artigo de Revista Científica
Publicado em //2005 Português
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We have previously described the phenotype resulting from a missense mutation in the IGF-I gene, which leads to expression of IGF-I with a methionine instead of a valine at position 44 (Val44Met IGF-I). This mutation caused severe growth and mental retardation as well as deafness evident at birth and growth retardation in childhood, but is relatively well tolerated in adulthood. We have conducted a biochemical and structural analysis of Val44Met IGF-I to provide a molecular basis for the phenotype observed. Val44Met IGF-I exhibits a 90-fold decrease in type 1 IGF receptor (IGF-1R) binding compared with wild-type human IGF-I and only poorly stimulates autophosphorylation of the IGF-1R. The ability of Val44Met IGF-I to signal via the extracellular signal-regulated kinase 1/2 and Akt/protein kinase B pathways and to stimulate DNA synthesis is correspondingly poorer. Binding or activation of both insulin receptor isoforms is not detectable even at micromolar concentrations. However, Val44Met IGF-I binds IGF-binding protein-2 (IGFBP-2), IGFBP-3, and IGFBP-6 with equal affinity to IGF-I, suggesting the maintenance of overall structure, particularly in the IGFBP binding domain. Structural analysis by nuclear magnetic resonance confirms retention of near-native structure with only local side-chain disruptions despite the significant loss of function. To our knowledge...

‣ The original Lujan syndrome family has a novel missense mutation (p. N1007S) in the MED12 gene

Schwartz, C.; Tarpey, P.; Lubs, H.; Verloes, A.; May, M.; Risheg, H.; Friez, M.; Futreal, P.; Edkins, S.; Teague, J.; Briault, S.; Skinner, C.; Bauer-Carlin, A.; Simensin, R.; Joseph, S.; Jones, J.; Gecz, J.; Stratton, M.; Raymond, F.; Stevenson, R.
Fonte: British Med Journal Publ Group Publicador: British Med Journal Publ Group
Tipo: Artigo de Revista Científica
Publicado em //2007 Português
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A novel missense mutation in the mediator of RNA polymerase II transcription subunit 12 (MED12) gene has been found in the original family with Lujan syndrome and in a second family (K9359) that was initially considered to have Opitz–Kaveggia (FG) syndrome. A different missense mutation in the MED12 gene has been reported previously in the original family with FG syndrome and in five other families with compatible clinical findings. Neither sequence alteration has been found in over 1400 control X chromosomes. Lujan (Lujan–Fryns) syndrome is characterised by tall stature with asthenic habitus, macrocephaly, a tall narrow face, maxillary hypoplasia, a high narrow palate with dental crowding, a small or receding chin, long hands with hyperextensible digits, hypernasal speech, hypotonia, mild-to-moderate mental retardation, behavioural aberrations and dysgenesis of the corpus callosum. Although Lujan syndrome has not been previously considered to be in the differential diagnosis of FG syndrome, there are some overlapping clinical manifestations. Specifically, these are dysgenesis of the corpus callosum, macrocephaly/relative macrocephaly, a tall forehead, hypotonia, mental retardation and behavioural disturbances. Thus, it seems that these two X-linked mental retardation syndromes are allelic...

‣ The deleterious effect of missense mutations on pre-mRNA splicing

Gonçalves, Vânia; Jordan, Peter
Fonte: Nova Science Publishers Inc Publicador: Nova Science Publishers Inc
Tipo: Parte de Livro
Publicado em //2011 Português
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The presence of missense mutations detected during genetic testing makes it difficult to classify their pathogenic effect. It is possible that the predicted amino acid change affects protein function; however, it is also possible that a missense mutation does not act at the protein level but rather at the nucleotide level by interfering with the correct assembly of the pre-mRNA splicing machinery. In this chapter we describe that short 6 to 9 nucleotides-containing sequence motifs act as exonic splicing regulatory elements. They are specifically recognized by corresponding splicing factors, which then assist in the recognition of the conserved splice site motifs by the spliceosome. Many examples show that a point mutation in these exonic splicing regulatory elements is sufficient to change splicing factor binding, which impairs inclusion of an exon during the splicing reaction. Thus, the molecular consequence of a missense mutation can be exon skipping and thus cause a frameshift in the messenger RNA that results in a premature stop codon and loss of function of the affected allele. Although several bioinformatic tools exist to predict splicing factor binding to mRNA, this effect of a missense mutation on splicing cannot yet be accurately predicted by sequence analysis alone. In order to determine whether a missense mutation has a deleterious effect on splicing of the corresponding mRNA...

‣ Novel NR5A1 Missense Mutation in Premature Ovarian Failure: Detection in Han Chinese Indicates Causation in Different Ethnic Groups

Jiao, Xue; Qin, Yingying; Li, Guangyu; Zhao, Shidou; You, Li; Ma, Jinlong; Simpson, Joe Leigh; Chen, Zi-Jiang
Fonte: FIU Digital Commons Publicador: FIU Digital Commons
Tipo: Artigo de Revista Científica Formato: application/pdf
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Background The etiology of most premature ovarian failure (POF) cases is usually elusive. Although genetic causes clearly exist and a likely susceptible region of 8q22.3 has been discovered, no predominant explanation exists for POF. More recently, evidences have indicated that mutations in NR5A1 gene could be causative for POF. We therefore screened for mutations in the NR5A1 gene in a large cohort of Chinese women with non-syndromic POF. Methods Mutation screening of NR5A1 gene was performed in 400 Han Chinese women with well-defined 46,XX idiopathic non-syndromic POF and 400 controls. Subsequently, functional characterization of the novel mutation identified was evaluated in vitro. Results A novel heterozygous missense mutation [c.13T>G (p.Tyr5Asp)] in NR5A1 was identified in 1 of 384 patients (0.26%). This mutation impaired transcriptional activation on Amh, Inhibin-a, Cyp11a1and Cyp19a1 gene, as shown by transactivation assays. However, no dominant negative effect was observed, nor was there impact on protein expression and nuclear localization. Conclusions This novel mutation p.Tyr5Asp, in a novel non-domain region, is presumed to result in haploinsufficiency. Irrespectively, perturbation in NR5A1 is not a common explanation for POF in Chinese.

‣ HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin

Levitch, Denise; Kauwe, John S. K.; Goate, Alison M.; Liscic, Rajka M.; Grinberg, Lea Tenenholz; Hinrichs, Anthony L.; Morris, John C.; Gitcho, Michael; Pastor, Pau; Armendariz, Javier; Norton, Joanne; Behrens Pellegrino, María Isabel; Taylor-Reinwald, L
Fonte: WILEY-LISS, DIV JOHN WILEY & SONS Publicador: WILEY-LISS, DIV JOHN WILEY & SONS
Tipo: Artículo de revista
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Relevância na Pesquisa
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Objective: Familial autosomal dominant frontotemporal dementia with ubiquitin-positive, tau-negative inclusions in the brain linked to 17q21-22 recently has been reported to carry null mutations in the progranulin gene (PGRN). Hereditary dysphasic disinhibition dementia (HDDD) is a frontotemporal dementia with prominent changes in behavior and language deficits. A previous study found significant linkage to chromosome 17 in a HDDD family (HDDD2), but no mutation in the MAPT gene. Longitudinal follow-up has enabled us to identify new cases and to further characterize the dementia in this family. The goals of this study were to develop research criteria to classify the different clinical expressions of dementia observed in this large kindred, to identify the causal mutation in affected individuals and correlate this with phenotypic characteristics in this pedigree, and to assess the neuropathological characteristics using immunohistochemical techniques. Methods: In this study we describe a detailed clinical, pathological and mutation analysis of the HDDD2 kindred. Results: Neuropathologically, HDDD2 represents a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U). We developed research classification criteria and identified three distinct diagnostic thresholds...