Faculty Opinions recommendation of Missense mutations in the regulatory domain of PKC gamma: a new mechanism for dominant nonepisodic cerebellar ataxia.

The c-Myc protein is a transcription factor with an N-terminal transcriptional regulatory domain and C-terminal oligomerization and DNA-binding motifs. Previous studies have demonstrated that p107, a protein related to the retinoblastoma protein, binds to the c-Myc transcriptional activation domain and suppresses its activity. We sought to characterize the transforming activity and transcriptional properties of lymphoma-derived mutant MYC alleles. Alleles encoding c-Myc proteins with missense mutations in the transcriptional regulatory domain were more potent than wild-type c-Myc in transforming rodent fibroblasts. Although the mutant c-Myc proteins retained their binding to p107 in in vitro and in vivo assays, p107 failed to suppress their transcriptional activation activities. Many of the lymphoma-derived MYC alleles contain missense mutations that result in substitution for the threonine at codon 58 or affect sequences flanking this amino acid. We observed that in vivo phosphorylation of Thr-58 was absent in a lymphoma cell line with a mutant MYC allele containing a missense mutation flanking codon 58. Our in vitro studies suggest that phosphorylation of Thr-58 in wild-type c-Myc was dependent on cyclin A and required prior phosphorylation of Ser-62 by a p107-cyclin A-CDK complex. In contrast, Thr-58 remained unphosphorylated in two representative mutant c-Myc transactivation domains in vitro. Our studies suggest that missense mutations in MYC may be selected for during lymphomagenesis, because the mutant MYC proteins have altered functional interactions with p107 protein complexes and fail to be phosphorylated at Thr-58.

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RNA expression profiling in brains of familial hemiplegic migraine type 1 knock-in mice

Cephalalgia ◽

10.1177/0333102413502736 ◽

2013 ◽

Vol 34 (3) ◽

pp. 174-182 ◽

Cited By ~ 8

Author(s):

Boukje de Vries ◽

Else Eising ◽

Ludo AM Broos ◽

Stephany C Koelewijn ◽

Boyan Todorov ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Expression Profiles ◽

Quantitative Polymerase Chain Reaction ◽

Brain Regions ◽

Familial Hemiplegic Migraine ◽

Rna Expression ◽

Missense Mutations ◽

Wild Type ◽

Hemiplegic Migraine

Background Various CACNA1A missense mutations cause familial hemiplegic migraine type 1 (FHM1), a rare monogenic subtype of migraine with aura. FHM1 mutation R192Q is associated with pure hemiplegic migraine, whereas the S218L mutation causes hemiplegic migraine, cerebellar ataxia, seizures, and mild head trauma-induced brain edema. Transgenic knock-in (KI) migraine mouse models were generated that carried either the FHM1 R192Q or the S218L mutation and were shown to exhibit increased CaV2.1 channel activity. Here we investigated their cerebellar and caudal cortical transcriptome. Methods Caudal cortical and cerebellar RNA expression profiles from mutant and wild-type mice were studied using microarrays. Respective brain regions were selected based on their relevance to migraine aura and ataxia. Relevant expression changes were further investigated at RNA and protein level by quantitative polymerase chain reaction (qPCR) and/or immunohistochemistry, respectively. Results Expression differences in the cerebellum were most pronounced in S218L mice. Particularly, tyrosine hydroxylase, a marker of delayed cerebellar maturation, appeared strongly upregulated in S218L cerebella. In contrast, only minimal expression differences were observed in the caudal cortex of either mutant mice strain. Conclusion Despite pronounced consequences of migraine gene mutations at the neurobiological level, changes in cortical RNA expression in FHM1 migraine mice compared to wild-type are modest. In contrast, pronounced RNA expression changes are seen in the cerebellum of S218L mice and may explain their cerebellar ataxia phenotype.

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Characterization of 19 Disease-Associated Missense Mutations in the Regulatory Domain of the Cystic Fibrosis Transmembrane Conductance Regulator

Human Molecular Genetics ◽

10.1093/hmg/7.11.1761 ◽

1998 ◽

Vol 7 (11) ◽

pp. 1761-1769 ◽

Cited By ~ 45

Author(s):

A. Vankeerberghen ◽

L. Wei ◽

M. Jaspers ◽

J.-J. Cassiman ◽

B. Nilius ◽

...

Keyword(s):

Cystic Fibrosis ◽

Missense Mutations ◽

Transmembrane Conductance Regulator ◽

Regulatory Domain ◽

Transmembrane Conductance ◽

Cystic Fibrosis Transmembrane

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Human cystathionine β-synthase (CBS) contains two classes of binding sites for S-adenosylmethionine (SAM): complex regulation of CBS activity and stability by SAM

Biochemical Journal ◽

10.1042/bj20120731 ◽

2012 ◽

Vol 449 (1) ◽

pp. 109-121 ◽

Cited By ~ 60

Author(s):

Angel L. Pey ◽

Tomas Majtan ◽

Jose M. Sanchez-Ruiz ◽

Jan P. Kraus

Keyword(s):

Binding Sites ◽

Kinetic Modelling ◽

Genetic Diseases ◽

Enzyme Activation ◽

Missense Mutations ◽

Regulatory Domain ◽

Novel Approach ◽

Steady State Levels ◽

The Stability

CBS (cystathionine β-synthase) is a multidomain tetrameric enzyme essential in the regulation of homocysteine metabolism, whose activity is enhanced by the allosteric regulator SAM (S-adenosylmethionine). Missense mutations in CBS are the major cause of inherited HCU (homocystinuria). In the present study we apply a novel approach based on a combination of calorimetric methods, functional assays and kinetic modelling to provide structural and energetic insight into the effects of SAM on the stability and activity of WT (wild-type) CBS and seven HCU-causing mutants. We found two sets of SAM-binding sites in the C-terminal regulatory domain with different structural and energetic features: a high affinity set of two sites, probably involved in kinetic stabilization of the regulatory domain, and a low affinity set of four sites, which are involved in the enzyme activation. We show that the regulatory domain displays a low kinetic stability in WT CBS, which is further decreased in many HCU-causing mutants. We propose that the SAM-induced stabilization may play a key role in modulating steady-state levels of WT and mutant CBS in vivo. Our strategy may be valuable for understanding ligand effects on proteins with a complex architecture and their role in human genetic diseases and for the development of novel pharmacological strategies.

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Identifying Gene Mutations in Autosomal Recessive Cerebellar Ataxias and Extending the Mutational Spectrum in China

10.21203/rs.3.rs-577033/v1 ◽

2021 ◽

Author(s):

Xueping Chen ◽

Xiaoqin Yuan ◽

Qian-Qian Wei ◽

RuWei Ou ◽

Bei Cao ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Autosomal Recessive ◽

Gene Mutations ◽

Autosomal Recessive Inheritance ◽

Chinese Patients ◽

Missense Mutations ◽

Genetic Characteristics ◽

Targeted Next Generation Sequencing ◽

Cerebellar Ataxias ◽

Autosomal Recessive Cerebellar Ataxias

Abstract Background: Autosomal recessive cerebellar ataxias (ARCA) are heterogeneous, complex, disabling neurodegenerative diseases characterized by autosomal recessive inheritance and cerebellar ataxia. Numerous mutations are described in several populations. However, in China, few data are available concerning ARCA. In this study, we aimed to identify ARCA-associated ataxia by targeted next-generation sequencing or whole-exome sequencing in a Chinese cohort, trying to determine clinical and genetic characteristics of Chinese patients with ARCA.Results: We identified 15 different mutations in 7 unrelated patients, of which 12 were novel, including seven missense mutations, three frameshift mutations, two splicing mutations, two nonsense mutations, and one inframe deletion mutation. The most frequent gene was ATM (3 patients), followed by SACS (2 patients), SYNE1 (2 patients), and SETX (1 patient). Specifically, 1 patient harbored mutations in both ATM and SYNE1. The phenotype was mainly cerebellar ataxia in all these cases. However, peripheral neuropathy, dystonia, oculomotor abnormalities, pyramidal tract dysfunction, cognitive impairment, and epilepsy were also revealed. Patients who harbored different gene mutations showed mutational heterogeneity. Conclusions: Our results indicate that ARCA-associated gene mutations are uncommon with additional clinical features in the Chinese population, and advanced sequencing is required to aid the diagnosis of undetermined cerebellar ataxia in Chinese patients.

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Homozygous Splice Mutation in CWF19L1 in Two Brothers with Autosomal Recessive Cerebellar Ataxia

Neuropediatrics ◽

10.1055/s-0037-1603019 ◽

2017 ◽

Vol 48 (S 01) ◽

pp. S1-S45

Author(s):

A. Enderli ◽

B. Heinrich ◽

P. Joset ◽

J. De Geyter ◽

J. Scheer ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Autosomal Recessive ◽

Splice Mutation ◽

Autosomal Recessive Cerebellar Ataxia

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Platelet Activation and Aggregation Induced by Recombinant von Willebrand Factors Reproducing Four Type 2B von Willebrand Disease Missense Mutations

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614241 ◽

1998 ◽

Vol 79 (01) ◽

pp. 211-216 ◽

Cited By ~ 13

Author(s):

Lysiane Hilbert ◽

Claudine Mazurier ◽

Christophe de Romeuf

Keyword(s):

Platelet Aggregation ◽

Platelet Activation ◽

Von Willebrand Disease ◽

Platelet Glycoprotein ◽

Missense Mutations ◽

Inhibit Platelet Aggregation ◽

Wild Type ◽

A1 Domain ◽

Von Willebrand ◽

Willebrand Factor

SummaryType 2B of von Willebrand disease (vWD) refers to qualitative variants with increased affinity of von Willebrand factor (vWF) for platelet glycoprotein Ib (GPIb). All the mutations responsible for type 2B vWD have been located in the A1 domain of vWF. In this study, various recombinant von Willebrand factors (rvWF) reproducing four type 2B vWD missense mutations were compared to wild-type rvWF (WT-rvWF) for their spontaneous binding to platelets and their capacity to induce platelet activation and aggregation. Our data show that the multimeric pattern of each mutated rvWF is similar to that of WT-rvWF but the extent of spontaneous binding and the capacity to induce platelet activation and aggregation are more important for the R543Q and V553M mutations than for the L697V and A698V mutations. Both the binding of mutated rvWFs to platelets and platelet aggregation induced by type 2B rvWFs are inhibited by monoclonal anti-GPIb and anti-vWF antibodies, inhibitors of vWF binding to platelets in the presence of ristocetin, as well as by aurin tricarboxylic acid. On the other hand, EDTA and a monoclonal antibody directed against GPIIb/IIIa only inhibit platelet aggregation. Furthermore, the incubation of type 2B rvWFs with platelets, under stirring conditions, results in the decrease in high molecular weight vWF multimers in solution, the extent of which appears correlated with that of plasma vWF from type 2B vWD patients harboring the corresponding missense mutation. This study supports that the binding of different mutated type 2B vWFs onto platelet GPIb induces various degrees of platelet activation and aggregation and thus suggests that the phenotypic heterogeneity of type 2B vWD may be related to the nature and/or location of the causative point mutation.

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A Novel Mutation Glyl672→Arg in Type 2A and a Homozygous Mutation in Type 2B von Willebrand Disease

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650564 ◽

1996 ◽

Vol 76 (02) ◽

pp. 253-257 ◽

Cited By ~ 14

Author(s):

Takeshi Hagiwara ◽

Hiroshi Inaba ◽

Shinichi Yoshida ◽

Keiko Nagaizumi ◽

Morio Arai ◽

...

Keyword(s):

Missense Mutation ◽

Novel Mutation ◽

Point Mutations ◽

Japanese Patients ◽

Von Willebrand Disease ◽

Homozygous Mutation ◽

Missense Mutations ◽

Reaction Products ◽

Type 3 ◽

Von Willebrand

SummaryGenetic materials from 16 unrelated Japanese patients with von Willebrand disease (vWD) were analyzed for mutations. Exon 28 of the von Willebrand factor (vWF) gene, where point mutations have been found most frequent, was screened by various restriction-enzyme analyses. Six patients were observed to have abnormal restriction patterns. By sequence analyses of the polymerase chain-reaction products, we identified a homozygous R1308C missense mutation in a patient with type 2B vWD; R1597W, R1597Q, G1609R and G1672R missense mutations in five patients with type 2A; and a G1659ter nonsense mutation in a patient with type 3 vWD. The G1672R was a novel missense mutation of the carboxyl-terminal end of the A2 domain. In addition, we detected an A/C polymorphism at nucleotide 4915 with HaeIII. There was no particular linkage disequilibrium of the A/C polymorphism, either with the G/A polymorphism at nucleotide 4391 detected with Hphl or with the C/T at 4891 detected with BstEll.

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Mutation Spectrum in Patients with Wiskott-Aldrich Syndrome and X-linked Thrombocytopenia: Identification of Twelve Different Mutations in the WASP Gene

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650318 ◽

1996 ◽

Vol 75 (04) ◽

pp. 546-550 ◽

Cited By ~ 21

Author(s):

Marianne Schwartz ◽

Albert Békássy ◽

Mikael Donnér ◽

Thomas Hertel ◽

Stefan Hreidarson ◽

...

Keyword(s):

Base Pair ◽

Hot Spot ◽

Missense Mutations ◽

Nucleotide Substitutions ◽

Exon 2 ◽

Wiskott Aldrich Syndrome ◽

Base Pair Deletion ◽

Reliable Diagnosis ◽

Wasp Gene ◽

Detection Of Mutations

SummaryTwelve different mutations in the WASP gene were found in twelve unrelated families with Wiskott-Aldrich syndrome (WAS) or X-linked thrombocytopenia (XLT). Four frameshift, one splice, one nonsense mutation, and one 18-base-pair deletion were detected in seven patients with WAS. Only missense mutations were found in five patients diagnosed as having XLT. One of the nucleotide substitutions in exon 2 (codon 86) results in an Arg to Cys replacement. Two other nucleotide substitutions in this codon, R86L and R86H, have been reported previously, both giving rise to typical WAS symptoms, indicating a mutational hot spot in this codon. The finding of mutations in the WASP gene in both WAS and XLT gives further evidence of these syndromes being allelic. The relatively small size of the WASP gene facilitates the detection of mutations and a reliable diagnosis of both carriers and affected fetuses in families with WAS or XLT.

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