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‣ Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17

Clark, Lorraine N.; Poorkaj, Parvoneh; Wszolek, Zbigniew; Geschwind, Daniel H.; Nasreddine, Ziad S.; Miller, Bruce; Li, Diane; Payami, Haydeh; Awert, Fre; Markopoulou, Katerina; Andreadis, Athena; D’Souza, Ian; Lee, Virginia M.-Y.; Reed, Lee; Trojanowsk
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Publicado em 27/10/1998 Português
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Pallido-ponto-nigral degeneration (PPND) is one of the most well characterized familial neurodegenerative disorders linked to chromosome 17q21–22. These hereditary disorders are known collectively as frontotemporal dementia (FTD) and parkinsonism linked to chromosome 17 (FTDP-17). Although the clinical features and associated regional variations in the neuronal loss observed in different FTDP-17 kindreds are diverse, the diagnostic lesions of FTDP-17 brains are tau-rich filaments in the cytoplasm of specific subpopulations of neurons and glial cells. The microtubule associated protein (tau) gene is located on chromosome 17q21–22. For these reasons, we investigated the possibility that PPND and other FTDP-17 syndromes might be caused by mutations in the tau gene. Two missense mutations in exon 10 of the tau gene that segregate with disease, Asn279Lys in the PPND kindred and Pro301Leu in four other FTDP-17 kindreds, were found. A third mutation was found in the intron adjacent to the 3′ splice site of exon 10 in patients from another FTDP-17 family. Transcripts that contain exon 10 encode tau isoforms with four microtubule (MT)-binding repeats (4Rtau) as opposed to tau isoforms with three MT-binding repeats (3Rtau). The insoluble tau aggregates isolated from brains of patients with each mutation were analyzed by immunoblotting using tau-specific antibodies. For each of three mutations...

‣ Acute intermittent porphyria: identification and expression of exonic mutations in the hydroxymethylbilane synthase gene. An initiation codon missense mutation in the housekeeping transcript causes "variant acute intermittent porphyria" with normal expression of the erythroid-specific enzyme.

Chen, C H; Astrin, K H; Lee, G; Anderson, K E; Desnick, R J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/1994 Português
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Acute intermittent porphyria (AIP), an autosomal dominant inborn error, results from the half-normal activity of the heme biosynthetic enzyme, hydroxymethylbilane synthase (EC 4.3.1.8). Diagnosis of AIP heterozygotes is essential to prevent acute, life-threatening neurologic attacks by avoiding various precipitating factors. Since biochemical diagnosis is problematic, the identification of hydroxymethylbilane synthase mutations has facilitated the detection of AIP heterozygotes. Molecular analyses of unrelated AIP patients revealed six exonic mutations: an initiating methionine to isoleucine substitution (M1I) in a patient with variant AIP, which precluded translation of the housekeeping, but not the erythroid-specific isozyme; four missense mutations in classical AIP patients, V93F, R116W, R201W, C247F; and a nonsense mutation W283X in a classical AIP patient, which truncated the housekeeping and erythroid-specific isozymes. Each mutation was confirmed in genomic DNA from family members. The W283X lesion was found in another unrelated AIP family. Expression of each mutation in Escherichia coli revealed that R201W, C247F, and W283X had residual activity. In vitro transcription/translation studies indicated that the M1I allele produced only the erythroid-specific enzyme...

‣ Functional Analysis of RUNX2 Mutations in Japanese Patients with Cleidocranial Dysplasia Demonstrates Novel Genotype-Phenotype Correlations

Yoshida, Taketoshi; Kanegane, Hirokazu; Osato, Motomi; Yanagida, Masatoshi; Miyawaki, Toshio; Ito, Yoshiaki; Shigesada, Katsuya
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
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Cleidocranial dysplasia (CCD) is an autosomal dominant heritable skeletal disease caused by heterozygous mutations in the osteoblast-specific transcription factor RUNX2. We have performed mutational analysis of RUNX2 on 24 unrelated patients with CCD. In 17 patients, 16 distinct mutations were detected in the coding region of RUNX2: 4 frameshift, 3 nonsense, 6 missense, and 2 splicing mutations, in addition to 1 polymorphism. The missense mutations were all clustered within the Runt domain, and their protein products were severely impaired in DNA binding and transactivation. In contrast, two RUNX2 mutants had the Runt domain intact and remained partially competent for transactivation. One criterion of CCD, short stature, was much milder in the patients with the intact Runt domain than in those without. Furthermore, a significant correlation was found between short stature and the number of supernumerary teeth. On the one hand, these genotype-phenotype correlations highlight a general, quantitative dependency, by skeleto-dental developments, on the gene dosage of RUNX2, which has hitherto been obscured by extreme clinical diversities of CCD; this gene-dosage effect is presumed to manifest on small reductions in the total RUNX2 activity...

‣ Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss.

Kelley, P M; Harris, D J; Comer, B C; Askew, J W; Fowler, T; Smith, S D; Kimberling, W J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/1998 Português
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Mutations in the connexin 26 (Cx26) gene (GJB2) are associated with the type of autosomal recessive nonsyndromic neurosensory deafness known as "DFNB1." Studies indicate that DFNB1 (13q11-12) causes 20% of all childhood deafness and may have a carrier rate as high as 2. 8%. This study describes the analysis of 58 multiplex families each having at least two affected children diagnosed with autosomal recessive nonsyndromic deafness. Twenty of the 58 families were observed to have mutations in both alleles of Cx26. Thirty-three of 116 chromosomes contained a 30delG allele, for a frequency of .284. This mutation was observed in 2 of 192 control chromosomes, for an estimated gene frequency of .01+/-.007. The homozygous frequency of the 30delG allele is then estimated at .0001, or 1/10,000. Given that the frequency of all childhood hearing impairment is 1/1,000 and that half of that is genetic, the specific mutation 30delG is responsible for 10% of all childhood hearing loss and for 20% of all childhood hereditary hearing loss. Six novel mutations were also observed in the affected population. The deletions detected cause frameshifts that would severely disrupt the protein structure. Three novel missense mutations, Val84Met, Val95Met, and Ser113Pro...

‣ Patients with autosomal nephrogenic diabetes insipidus homozygous for mutations in the aquaporin 2 water-channel gene.

van Lieburg, A. F.; Verdijk, M. A.; Knoers, V. V.; van Essen, A. J.; Proesmans, W.; Mallmann, R.; Monnens, L. A.; van Oost, B. A.; van Os, C. H.; Deen, P. M.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1994 Português
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Mutations in the X-chromosomal V2 receptor gene are known to cause nephrogenic diabetes insipidus (NDI). Besides the X-linked form, an autosomal mode of inheritance has been described. Recently, mutations in the autosomal gene coding for water-channel aquaporin 2 (AQP2) of the renal collecting duct were reported in an NDI patient. In the present study, missense mutations and a single nucleotide deletion in the aquaporin 2 gene of three NDI patients from consanguineous matings are described. Expression studies in Xenopus oocytes showed that the missense AQP2 proteins are nonfunctional. These results prove that mutations in the AQP2 gene cause autosomal recessive NDI.

‣ Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemia

Caligiuri, Michael A.; Briesewitz, Roger; Yu, Jianhua; Wang, Lisheng; Wei, Min; Arnoczky, Kristy J.; Marburger, Trent B.; Wen, Jing; Perrotti, Danilo; Bloomfield, Clara D.; Whitman, Susan P.
Fonte: American Society of Hematology Publicador: American Society of Hematology
Tipo: Artigo de Revista Científica
Publicado em 01/08/2007 Português
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The CBL ubiquitin ligase targets a variety of activated tyrosine kinases (TKs) for degradation. Many TKs are mutationally or autocrine activated and/or often overexpressed at the mRNA and protein levels in acute leukemias. We hypothesized that CBL is mutated in patients with acute myeloid leukemia (AML). Four of 12 patients and the MOLM-13 cell line harbored c-CBL mutations, either RNA splicing mutations, missense mutations, or a nucleotide insertion. Additionally, 1 of the 12 patients harbored a missense mutation in the related CBL-b gene. Each c-CBL mutation involves the structurally important α-helix within the linker region, while the mutation in CBL-b was located in the Ub-E2 protein-binding RING finger. Short-interfering RNA knockdown of mutant c-CBL present in MOLM-13 cells was growth inhibitory. In summary, novel mutations in c-CBL and CBL-b have been identified in human AML and may represent potential targets for novel therapeutics.

‣ CanPredict: a computational tool for predicting cancer-associated missense mutations

Kaminker, Joshua S.; Zhang, Yan; Watanabe, Colin; Zhang, Zemin
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Various cancer genome projects are underway to identify novel mutations that drive tumorigenesis. While these screens will generate large data sets, the majority of identified missense changes are likely to be innocuous passenger mutations or polymorphisms. As a result, it has become increasingly important to develop computational methods for distinguishing functionally relevant mutations from other variations. We previously developed an algorithm, and now present the web application, CanPredict (http://www.canpredict.org/ or http://www.cgl.ucsf.edu/Research/genentech/canpredict/), to allow users to determine if particular changes are likely to be cancer-associated. The impact of each change is measured using two known methods: Sorting Intolerant From Tolerant (SIFT) and the Pfam-based LogR.E-value metric. A third method, the Gene Ontology Similarity Score (GOSS), provides an indication of how closely the gene in which the variant resides resembles other known cancer-causing genes. Scores from these three algorithms are analyzed by a random forest classifier which then predicts whether a change is likely to be cancer-associated. CanPredict fills an important need in cancer biology and will enable a large audience of biologists to determine which mutations are the most relevant for further study.

‣ Effect of Mutation Type and Location on Clinical Outcome in 1,013 Probands with Marfan Syndrome or Related Phenotypes and FBN1 Mutations: An International Study

Faivre, L. ; Collod-Beroud, G. ; Loeys, B. L. ; Child, A. ; Binquet, C. ; Gautier, E. ; Callewaert, B. ; Arbustini, E. ; Mayer, K. ; Arslan-Kirchner, M. ; Kiotsekoglou, A. ; Comeglio, P. ; Marziliano, N. ; Dietz, H. C. ; Halliday, D. ; Be
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
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Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24–32 were associated with a more severe and complete phenotype...

‣ ETHE1 mutations are specific to ethylmalonic encephalopathy

Tiranti, V; Briem, E; Lamantea, E; Mineri, R; Papaleo, E; De Gioia, L; Forlani, F; Rinaldo, P; Dickson, P; Abu‐Libdeh, B; Cindro‐Heberle, L; Owaidha, M; Jack, R M; Christensen, E; Burlina, A; Zeviani, M
Fonte: BMJ Group Publicador: BMJ Group
Tipo: Artigo de Revista Científica
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Mutations in ETHE1, a gene located at chromosome 19q13, have recently been identified in patients affected by ethylmalonic encephalopathy (EE). EE is a devastating infantile metabolic disorder, characterised by widespread lesions in the brain, hyperlactic acidaemia, petechiae, orthostatic acrocyanosis, and high levels of ethylmalonic acid in body fluids. To investigate to what extent ETHE1 is responsible for EE, we analysed this gene in 29 patients with typical EE and in 11 patients presenting with early onset progressive encephalopathy with ethylmalonic aciduria (non‐EE EMA). Frameshift, stop, splice site, and missense mutations of ETHE1 were detected in all the typical EE patients analysed. Western blot analysis of the ETHE1 protein indicated that some of the missense mutations are associated with the presence of the protein, suggesting that the corresponding wild type amino acid residues have a catalytic function. No ETHE1 mutations were identified in non‐EE EMA patients. Experiments based on two dimensional blue native electrophoresis indicated that ETHE1 protein works as a supramolecular, presumably homodimeric, complex, and a three dimensional model of the protein suggests that it is likely to be a mitochondrial matrix thioesterase acting on a still unknown substrate. Finally...

‣ Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2

Alter, Blanche P; Rosenberg, Philip S; Brody, Lawrence C
Fonte: BMJ Group Publicador: BMJ Group
Tipo: Artigo de Revista Científica
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Patients with biallelic mutations in BRCA2 are in Fanconi anaemia group D1. We analysed the severity of the mutations in 27 cases, classified according to their association with breast cancer in heterozygotes, and their predicted functional effect. Twenty mutations were frameshifts or truncations, three involved splice sites, five were missense variants of unknown severity and two were benign polymorphisms. Five patients had VACTERL‐H association. Leukaemia was reported in 13 patients, and solid tumours in 15; 6 patients had two or more malignancies. The cumulative probability of any malignancy was 97% by age 5.2 years. IVS7+1G→A and IVS7+2T→G were associated with AML, and 886delGT and 6174delT with brain tumours. However, patients with other alleles remained at very high risk of these events. Missense mutations formed a distinct cluster in a highly conserved region of the BRCA2 protein.

‣ BMP15 mutations associated with Primary Ovarian Insufficiency cause a defective production of bioactive protein

Rossetti, Raffaella; Di Pasquale, Elisa; Marozzi, Anna; Bione, Silvia; Toniolo, Daniela; Grammatico, Paola; Nelson, Lawrence M.; Beck-Peccoz, Paolo; Persani, Luca
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /05/2009 Português
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BMP15 is selectively synthesized by oocytes as a pre-proprotein and is considered an ovarian follicle organizer whose adequate function is critical for female fertility. Missense mutations were reported in Primary Ovarian Insufficiency (POI) but their biological impact remained unexplored. Here, screening of 300 unrelated idiopathic overt POI women with primary or secondary amenorrhea led to the identification of 6 heterozygous BMP15 variations in 29 of them. All alterations are non-conservative and include one insertion of 3 nucleotides (p.L262_L263insL) and 5 missense substitutions. Except for the p.S5R located in the signal sequence, the other variants (p.R68W, p.R138H, p.L148P, p.A180T) localize in the proregion, which is essential for the processing and secretion of bioactive dimers. The mutations p.R68W, p.L148P and the novel p.R138H lead to marked reductions of mature protein production. Their biological effects, evaluated by a novel luciferase-reporter assay in a human granulosa cell line, were significantly reduced. Co-transfection experiments of defective mutants with equal amounts of wild-type BMP15 cDNA, thus reproducing the heterozygous state seen in patients, did not generate a complete recovery of wild-type activity. No or minor deleterious effects were detected for the variants p.L262_L263insL...

‣ Mutations in MUSK causing congenital myasthenic syndrome impair MuSK–Dok-7 interaction

Maselli, Ricardo A.; Arredondo, Juan; Cagney, Órla; Ng, Jarae J.; Anderson, Jennifer A.; Williams, Colette; Gerke, Bae J.; Soliven, Betty; Wollmann, Robert L.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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We describe a severe congenital myasthenic syndrome (CMS) caused by two missense mutations in the gene encoding the muscle specific receptor tyrosine kinase (MUSK). The identified MUSK mutations M605I and A727V are both located in the kinase domain of MuSK. Intracellular microelectrode recordings and microscopy studies of the neuromuscular junction conducted in an anconeus muscle biopsy revealed decreased miniature endplate potential amplitudes, reduced endplate size and simplification of secondary synaptic folds, which were consistent with postsynaptic deficit. The study also showed a striking reduction of the endplate potential quantal content, consistent with additional presynaptic failure. Expression studies in MuSK deficient myotubes revealed that A727V, which is located within the catalytic loop of the enzyme, caused severe impairment of agrin-dependent MuSK phosphorylation, aggregation of acetylcholine receptors (AChRs) and interaction of MuSK with Dok-7, an essential intracellular binding protein of MuSK. In contrast, M605I, resulted in only moderate impairment of agrin-dependent MuSK phosphorylation, aggregation of AChRs and interaction of MuSK with Dok-7. There was no impairment of interaction of mutants with either the low-density lipoprotein receptor-related protein...

‣ Missense mutations in the sodium borate co-transporter SLC4A11 cause late onset Fuchs corneal dystrophy

Riazuddin, S. Amer; Vithana, Eranga N.; Seet, Li-Fong; Liu, Yangjian; Al-Saif, Amr; Koh, Li Wei; Heng, Yee Meng; Aung, Tin; Meadows, Danielle N.; Eghrari, Allen O.; Gottsch, John D.; Katsanis, Nicholas
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Homozygous mutations in the sodium-bicarbonate transporter SLC4A11 cause two early onset corneal dystrophies: congenital hereditary endothelial dystrophy (CHED) and Harboyan syndrome. More recently, four sporadic patients with late onset Fuchs corneal dystrophy (FCD), a common age-related disorder, were also reported to harbor heterozygous mutations at this locus. We therefore tested the hypothesis that SLC4A11 contributes to FCD and asked whether mutations in SLC4A11 are responsible for familial cases of late onset FCD. We sequenced SLC4A11 in 192 sporadic and small nuclear late-onset FCD families and found seven heterozygous missense novel variations that were absent from ethnically matched controls. Familial data available for one of these mutations showed segregation under a dominant model in a three-generational family. In silico analyses suggested that most of these substitutions are intolerant, while biochemical studies of the mutant protein indicated that these alleles impact the localization and/or post-translational modification of the protein. These results suggest that heterozygous in SLC4A11 are modest contributors to the pathogenesis of adult FCD, suggesting a causality continuum between FCD and CHED. Taken together with a recent model between FCD and yet another early onset corneal dystrophy...

‣ A novel mutation in FHL1 in a family with X-linked scapuloperoneal myopathy: phenotypic spectrum and structural study of FHL1 mutations

Chen, Dong-Hui; Raskind, Wendy H.; Parson, William W.; Sonnen, Joshua A.; Vu, Tiffany; Zheng, YunLin; Matsushita, Mark; Wolff, John; Lipe, Hillary; Bird, Thomas D.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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An X-linked myopathy was recently associated with mutations in the four-and-a-half-LIM domains 1 (FHL1) gene. We identified a family with late onset, slowly progressive weakness of scapuloperoneal muscles in three brothers and their mother. A novel missense mutation in the LIM2 domain of FHL1 (W122C) co-segregated with disease in the family. The phenotype was less severe than that in other reported families. Muscle biopsy revealed myopathic changes with FHL1 inclusions that were ubiquitin- and desmin-positive. This mutation provides additional evidence for X-linked myopathy caused by a narrow spectrum of mutations in FHL1, mostly in the LIM2 domain. Molecular dynamics (MD) simulations of the newly identified mutation and five previously published missense mutations in the LIM2 domain revealed no major distortions of the protein structure or disruption of zinc binding. There were, however, increases in the nonpolar, solvent-accessible surface area in one or both of two clusters of residues, suggesting that the mutant proteins have a variably increased propensity to aggregate. Review of the literature shows a wide range of phenotypes associated with mutations in FHL1. However, recognizing the typical scapuloperoneal phenotype and X-linked inheritance pattern will help clinicians arrive at the correct diagnosis.

‣ TIN2 Protein Dyskeratosis Congenita Missense Mutants Are Defective in Association with Telomerase*

Yang, Dong; He, Quanyuan; Kim, Hyeung; Ma, Wenbin; Songyang, Zhou
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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Dyskeratosis congenita (DC) is a progressive and heterogeneous congenital disorder that affects multiple systems and is characterized by bone marrow failure and a triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia. One common feature for all DC patients is abnormally short telomeres and defects in telomere biology. Most of the known DC mutations have been found to affect core components of the telomerase holoenzyme. Recently, multiple mutations in the gene encoding the telomeric protein TIN2 have been identified in DC patients with intact telomerase genes, but the molecular mechanisms underlying TIN2 mutation-mediated DC remain unknown. Here, we demonstrate that ectopic expression of TIN2 with DC missense mutations in human cells led to accelerated telomere shortening, similar to the telomere phenotypes found in DC patients. However, this telomere shortening was not accompanied by changes in total telomerase activity, localization of TIN2, or telomere end protection status. Interestingly, we found TIN2 to participate in the TPP1-dependent recruitment of telomerase activity. Furthermore, DC mutations in TIN2 led to its decreased ability to associate with TERC and telomerase activity. Taken together, our data suggest that TIN2 mutations in DC may compromise the telomere recruitment of telomerase...

‣ Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma

Hedayati, Mehdi; Zarif Yeganeh, Marjan; Sheikhol Eslami, Sara; Rezghi Barez, Shekoofe; Hoghooghi Rad, Laleh; Azizi, Fereidoun
Fonte: SAGE-Hindawi Access to Research Publicador: SAGE-Hindawi Access to Research
Tipo: Artigo de Revista Científica
Publicado em 13/06/2011 Português
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Medullary thyroid carcinoma occurs in both sporadic (75%) and hereditary (25%) forms. The missense mutations of RET proto-oncogene in MTC development have been well demonstrated. To investigate the spectrum of predominant RET germline mutations in exons 10, 11, and 16 in hereditary MTC in Iranian population, 217 participants were included. Genomic DNAs were extracted from the leukocytes using the standard Salting Out/Proteinase K method. Mutation detection was performed through PCR-RFLP and DNA sequencing. In 217 participants, 43 missense mutations were identified in exons 10 (6%), 11 (13%), and 16 (0.9%). Moreover, a novel germline mutation was detected in exon 11 (S686N). Also four different polymorphisms were found in intron 16 in eight patients. The obtained data showed the frequency profile of RET mutations in Iranian individuals with MTC (19.8%). The most frequent mutation in our population was C634G whereas in most population it was C634R. Altogether, these results underline the importance of the genetic background of family members of any patient with MTC.

‣ Whole Exome Sequencing in a Random Sample of North American Women with Leiomyomas Identifies MED12 Mutations in Majority of Uterine Leiomyomas

McGuire, Megan M.; Yatsenko, Alexander; Hoffner, Lori; Jones, Mirka; Surti, Urvashi; Rajkovic, Aleksandar
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 12/03/2012 Português
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Uterine leiomyomas (uterine fibroids) arise from smooth muscle tissue in the majority of women by age 45. It is common for these clonal tumors to develop from multiple locations within the uterus, leading to a variety of symptoms such as pelvic pain, abnormal uterine bleeding, and infertility. We performed whole exome sequencing on genomic DNA from five pairs of leiomyomas and corresponding normal myometrium to determine genetic variations unique to leiomyomas. Whole exome sequencing revealed that the gene encoding transcription factor MED12 (Mediator complex subunit 12) harbored heterozygous missense mutations caused by single nucleotide variants in highly conserved codon 44 of exon 2 in two of five leiomyomas. Sanger re-sequencing of MED12 among these five leiomyomas confirmed the two single nucleotide variants and detected a 42 base-pair deletion within exon 2 of MED12 in a third leiomyoma. MED12 was sequenced in an additional 143 leiomyomas and 73 normal myometrial tissues. Overall, MED12 was mutated in 100/148 (67%) of the genotyped leiomyomas: 79/148 (53%) leiomyomas exhibited heterozygous missense single nucleotide variants, 17/148 (11%) leiomyomas exhibited heterozygous in-frame deletions/insertion-deletions, 2/148 (1%) leiomyomas exhibited intronic heterozygous single nucleotide variants affecting splicing...

‣ Amino acid 572 in TMC1: hot spot or critical functional residue for dominant mutations causing hearing impairment

Hilgert, Nele; Monahan, Kelly; Kurima, Kiyoto; Li, Cindy; Friedman, Rick A; Griffith, Andrew J; Van Camp, Guy
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Two different missense mutations, p.D572N and p.D572H, affecting the same nucleotide and codon of the TMC1 gene were earlier reported to cause autosomal dominant hearing impairment at locus DFNA36 in two North American families. No other dominant mutations of human TMC1 have been published. We ascertained a third North American family segregating autosomal dominant nonsyndromic hearing impairment at the DFNA36 locus. We identified the p.D572N mutation of TMC1 co-segregating with hearing loss in our study family. A comparative haplotype analysis of linked single nucleotide polymorphisms and short tandem repeats in the two families segregating p.D572N was not consistent with a founder effect. These findings can be explained in two ways. Either nucleotide 1714 is a hot spot for mutations or, alternatively, missense mutations at this site confer a specific pathogenic gain-of-function or dominant-negative effect.

‣ Association of mutations in the zona pellucida binding protein 1 (ZPBP1) gene with abnormal sperm head morphology in infertile men

Yatsenko, Alexander N.; O'Neil, Derek S.; Roy, Angshumoy; Arias-Mendoza, Paola A.; Chen, Ruihong; Murthy, Lata J.; Lamb, Dolores J.; Matzuk, Martin M.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Nearly 7% of men are afflicted by male infertility worldwide, and genetic factors are suspected to play a significant role in the majority of these patients. Although sperm morphology is an important parameter measured in the semen analysis, only a few genetic causes of teratozoospermia are currently known. The objective of this study was to define the association between alterations in the genes encoding the Golgi-associated PDZ- and coiled-coil motif containing protein (GOPC), the protein interacting with C kinase 1 (PICK1) and the acrosomal protein zona pellucida binding protein 1 (ZPBP1/sp38) with abnormal sperm head morphology in infertile men. Previous reports demonstrated that mice lacking Gopc, Pick1 and Zpbp1 are infertile due to abnormal head morphology. Herein, using our validated RNA-based method, we studied spermatozoal cDNA encoding the human GOPC, PICK1 and ZPBP1 genes in 381 teratozoospermic and 240 controls patients via direct sequencing. Among these genes, we identified missense and splicing mutations in the sperm cDNA encoding ZPBP1 in 3.9% (15/381) of men with abnormal sperm head morphology. These mutations were not observed in 240 matched controls and the dbSNP database (χ2 = 9.3, P = 0.002). In contrast, statistically significant and functionally relevant mutations were not discovered in the GOPC and PICK1 genes. In our study ZPBP1 mutations are associated with abnormal sperm head morphology...

‣ Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI.

Burwinkel, B; Bakker, H D; Herschkovitz, E; Moses, S W; Shin, Y S; Kilimann, M W
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/1998 Português
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Deficiency of glycogen phosphorylase in the liver gives rise to glycogen-storage disease type VI (Hers disease; MIM 232700). We report the identification of the first mutations in PYGL, the gene encoding the liver isoform of glycogen phosphorylase, in three patients with Hers disease. These are two splice-site mutations and two missense mutations. A mutation of the 5' splice-site consensus of intron 14 causes the retention of intron 14 and the utilization of two illegitimate 5' splice sites, whereas a mutation of the 3' splice-site consensus of intron 4 causes the skipping of exon 5. Two missense mutations, N338S and N376K, both cause nonconservative replacements of amino acids that are absolutely conserved even in yeast and bacterial phosphorylases. We also report corrections of the PYGL coding sequence, sequence polymorphisms, and a partial PYGL gene structure with introns in the same positions as in PYGM, the gene of the muscle isoform of phosphorylase. Our findings demonstrate that PYGL mutations cause Hers disease, and they may improve laboratory diagnosis of deficiencies of the liver phosphorylase system.