Marfan Database (second edition): software and database for the analysis of mutations in the human FBN1 gene (original) (raw)
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Software and database for the analysis of mutations in
1996
Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromosome 15 (FBN1) were described at first in the heritable connective tissue disorder, Marfan syndrome (MFS). More recently, FBN1 has also been shown to harbor mutations related to a spectrum of conditions phenotypically related to MFS and many mutations will have to be accumulated before genotype/phenotype relationships emerge. To facilitate mutational analysis of the FBN1 gene, a software package along with a computerized database (currently listing 63 entries) have been created. Each line represents a single FBN1 mutation. The columns contain the following information and abbreviations: Column A. File number. Column B. Exon number at which the mutation is located. Exons are numbered with respect to the translational initiation site given by Pereira et al. (35). Column C. Nucleotide position at which the mutation is located, numbered as above. Column D. Codon number at which the mutation is located, numbered as above. If the mutation spans more than one codon, e.g. there is a deletion of several bases, only the first (5′) codon is entered. Column E. Normal base sequence of the codon in which the mutation occurred. Column F. Mutated base sequence of the codon in which the mutation occurred. If the mutation is a base pair deletion or insertion this is indicated by 'del' or 'ins' followed by the number of bases deleted or inserted and the position of this deletion or insertion in the codon (a, b or c). The nucleotide position is the first that is deleted or the one preceding the insertion. For example, 'del66b' is a deletion of 66 bases including the second base of the codon; 'ins4b' is an insertion of 4 bases occurring between the second and the third base of the codon. Column G. Concerns base substitutions. It gives the base change, by convention, read from the coding strand. If the mutation predicts a premature protein-termination, the novel stop codon position is given, e.g. 'stop at 2115'. Column H. Mutation name according to Beaudet et al. (41). To designate missense mutations, the number of the amino acid position is flanked by the single letter code corresponding to the normal amino acid prior to the number, and the mutant amino acid following the number (e.g. Gly to Ala at codon 85 is designated 'G85A'). Nonsense mutations are designated similarly to missense mutations except that X is used to indicate any termination codon (e.g. Tyr to stop at codon 76 is designated 'Y76X'). Frameshift, insertion and deletion mutations are designated by the nucleotide number followed by 'ins' for insertion or 'del' for deletion. The nucleotide position is the first that is deleted or the one preceding it in the case of insertions. Exact nucleotides are indicated for two or less bases (e.g. 441delA). For three or more bases, the insertion or deletion is specified by the size of the change (e.g. 852del22 indicates a 22 bp deletion starting from nucleotide 852). Splicing mutations are designated by a plus (+) or minus (-) nucleotide relative to the first or last base at the nearest exon (711+1G→T is a G to T substitution in the first base of the intron following the exon that ends at nucleotide 711). Column I. Wild type amino acid. Column J. Mutant amino acid. Deletion and insertion mutations which result in a frameshift are designated by 'Frameshift'. Nonsense mutations are designated by 'stop'. Column K. Protein domain in which the mutation occurs. Each motif group is numbered separately and according to their position with respect to the amino terminal end of the protein, e.g. 'cb EGF-like' (for calcium-binding EGF-like motifs) #1 to 43, 'EGF-like' (for non calcium-binding EGF-like motifs) #1 to 4, '8-cys' (for '8-cysteine' motifs) # 1 to 7, 'Hybrid motifs' # 1 to 2 (35). Columns L-Q. Diagnostic manifestations in the systems listed by Beighton et al. (42). In all these columns, '?' indicates either lack of or unspecified data until more precise information is available. Column L. Presence (+) or absence (-) of skeletal manifestations. Column M. Presence (+) or absence (-) of ocular manifestations. Column N. Presence (+) or absence (-) of cardiovascular manifestations. Column O. Presence (+) or absence (-) of pulmonary manifestations. Column P. Presence (+) or absence (-) of manifestations in skin and integument. Column Q. Presence (+) or absence (-) of manifestations in central nervous system. Column R. Reference number indicating the publication in which the mutation is described. Full citations (authors, year, tittle, volume, pages) are provided with the database. If the same mutation has been reported for the same patient in different papers only one entry is made. If the same mutation has been reported for unrelated patients, a separate entry is made for each patient. Note: The present version of the database cannot accommodate two mutational events in a given allele therefore the compound deletion reported by Nijbroek et al. (23), i.e. del3901-4; 3908-9 d is not included.
Update of the UMD- FBN1 mutation database and creation of an FBN1 polymorphism database
Human Mutation, 2003
Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromosome 15 (FBN1) were first described in the heritable connective disorder, Marfan syndrome (MFS). FBN1 has also been shown to harbor mutations related to a spectrum of conditions phenotypically related to MFS, called ''type-1 fibrillinopathies.'' In 1995, in an effort to standardize the information regarding these mutations and to facilitate their mutational analysis and identification of structure/function and phenotype/genotype relationships, we created a human FBN1 mutation database, UMD-FBN1. This database gives access to a software package that provides specific routines and optimized multicriteria research and sorting tools. For each mutation, information is provided at the gene, protein, and clinical levels. This tool is now a worldwide reference and is frequently used by teams working in the field; more than 220,000 interrogations have been made to it since January 1998. The database has recently been modified to follow the guidelines on mutation databases of the HUGO Mutation Database Initiative (MDI) and the Human Genome Variation Society (HGVS), including their approved mutation nomenclature. The current update shows 559 entries, of which 421 are novel. UMD-FBN1 is accessible at www.umd.be/. We have also recently developed a FBN1 polymorphism database in order to facilitate diagnostics.
Human Mutation, 2005
Communicated by Mireille Claustres Marfan Syndrome (MFS) is an autosomal dominant disorder of the connective tissue due to mutations of Fibrillin-1 gene (FBN1) in more than 90% of cases and Transforming Growth Factor-Beta-Receptor2 gene (TGFB2R) in a minority of cases. Genotyping is relevant for diagnosis and genotype-phenotype correlations. We describe the FBN1 genotypes and related phenotypes of 81 patients who were referred to our attention for MFS or Marfan-like phenotypes. Patients underwent multidisciplinary pertinent evaluation in the adult or paediatric setting, according to their age. The diagnosis relied on Ghent criteria. To optimise DHPLC analysis of the FBN1 gene, all coding regions of the gene were directly sequenced in 19 cases and 10 controls: heterozygous amplicons were used as true positives. DHPLC sensitivity was 100%. Then, DHPLC was used to screen 62 other cases. We identified 74 FBN1 mutations in 81 patients: 64 were novel and 17 known. Of the 81 mutations, 41 were missense (50.6%), 27, either nonsense or frameshift mutations and predicted a premature termination codon (PTC) (33%), 11 affected splice sites (13.6%), and two predicted in-frame deletions (2.5%). Most mutations (67.9%) occurred in cbEGF-like modules. Genotype was clinically relevant for early diagnosis and conclusion of the diagnostic work-up in patients with incomplete or atypical phenotypes.
Bovolenta et al. Human Mutation Mar;33(3):572-81. doi: 10.1002/humu.22017
Duchenne and Becker muscular dystrophies are caused by mutations in the dystrophin gene. Both the enormous size of this gene and heterogeneous set of causative mutations behind these pathologies may hamper and even prevent accurate molecular diagnosis. Often RNA analysis is required not only to identify mutations escaping MLPA/CGH or exon sequencing but also to validate the functional effect of novel variations that may affect the exon composition of the DMD gene. We present the design and experimental validation of a new, simple, and easy-to-use platform we call FluiDMD. This platform is based on the Applied Biosystems 7900HT TaqMan R low-density array technology and is able to define the fullexon composition, profile the dystrophin isoforms present, establish changes in mRNA decay, and potentially identify all deletions/duplications and splicing affecting mutations contemporaneously. Moreover, we demonstrate that this system accurately detects the pathogenic effect of all dystrophin mutations belonging to any category, thereby highlighting the functional validation capacity of this system. The high efficacy and sensitivity of this tool in detecting mutations in the dystrophin transcript can be exploited in a variety of cells/tissues, in particular skin, which is harvested by causing minimum patient discomfort. We therefore propose FluiDMD as a validated diagnostic biomarker for molecular profiling of dystrophinopathies. Hum Mutat 33:572-581, 2012. C 2011 Wiley Periodicals, Inc. KEY WORDS: diagnostic biomarker; DMD mutations; fluidic cards; RNA analysis C 2011 WILEY PERIODICALS, INC.
Human Mutation, 2009
Approximately half of gene lesions responsible for human inherited diseases are due to an amino acid substitution, showing that this mutational mechanism plays a large role in diseases. Distinguishing neutral sequence variations from those responsible for the phenotype is of major interest in human genetics. Because in vitro validation of mutations is not always possible in diagnostic settings, indirect arguments must be accumulated to define whether a missense variation is causative. To further differentiate neutral variants from pathogenic nucleotide substitutions, we developed a new tool, UMD-Predictor s . This tool provides a combinatorial approach that associates the following data: localization within the protein, conservation, biochemical properties of the mutant and wild-type residues, and the potential impact of the variation on mRNA. To evaluate this new tool, we compared it to the SIFT, PolyPhen, and SNAP software, the BLOSUM62 and Yu's Biochemical Matrices. All tools were evaluated using variations from well-validated datasets extracted from four UMD-LSDB databases (UMD-FBN1, UMD-FBN2, UMD-TGFBR1, and UMD-TGFBR2) that contain all published mutations of the corresponding genes, that is, 1,945 mutations, among which 796 different substitutions corresponding to missense mutations. Our results show that the UMD-Predictor s algorithm is the most efficient tool to predict pathogenic mutations in this context with a positive predictive value of 99.4%, a sensitivity of 95.4%, and a specificity of 92.2%. It can thus enhance the interpretation of variations in these genes, and could easily be applied to any other disease gene through the freely available UMD s generic software (http://www.umd.be). Hum Mutat 30, 952-959,
Funato_et_al-2005-Human_Mutation.pdf
The basic helix-loop-helix protein Twist, a transcriptional repressor, is essential for embryogenesis in both invertebrates and vertebrates. Haploinsufficiency of the human TWIST1 gene, which causes the craniosynostosis disorder Saethre-Chotzen syndrome (SCS), is related to failure to repress transcription of CDKN1A (which encodes p21/WAF1/CIP1), promoting osteoblast differentiation. We have examined the functional significance of natural TWIST1 variants present in craniosynostosis patients and in their healthy relatives. Both deletion and duplication variants of the glycine-rich tract Gly 5 AlaGly 5 inhibited E2A (E12/E47)dependent transcription of CDKN1A to a similar degree as wild-type protein, indicating that the length of this glycine tract is not critical for efficient transcriptional repression. We also evaluated a newly identified heterozygous TWIST1 variant (c.115C>G, encoding p.Arg39Gly), located within a putative nuclear localization signal (NLS), that was present in a child with mild SCS and her clinically unaffected father and grandmother. Unlike wild-type protein, this mutant required cotransfected E12 to localize to the nucleus, indicating that the NLS, including amino acid 39, is essential for nuclear localization; inhibition of E2Adependent transcription of CDKN1A occurred normally. This analysis further dissects the structure-function relationships of TWIST and corroborates with phenotypic observations of disease expressivity. Hum Mutat 25:550-556, 2005. r r 2005 Wiley-Liss, Inc.