Standardizing mutation nomenclature: Why bother?

Dunnen, Johan T. den; Paalman, Mark H.

doi:10.1002/humu.10262

Cited by 175 publications

(119 citation statements)

References 4 publications

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“…All published and unpublished mutations were verified for accuracy of nucleotide composition of codons and exon/intron junctions and their location within the gene, using the GenBank sequences of the COL1A1 (AF017178, for genomic and NM_000088.3 for cDNA) and COL1A2 (AF004877.1 for genomic and NM_000089.3 for cDNA) genes. The database listed in Supplementary Tables S1-S4 complies with the nomenclature guidelines set by the Human Genome Variation Society (HSVG) [den Dunnen and Antonarakis, 2001;den Dunnen and Paalman, 2003]. After publication, the database may be accessed at www.oiprogram.nichd.nih.gov.…”

Section: Assemblyof the Database Mutationsmentioning

confidence: 99%

Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans

et al. 2007

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Osteogenesis imperfecta (OI) is a generalized disorder of connective tissue characterized by fragile bones and easy susceptibility to fracture. Most cases of OI are caused by mutations in type I collagen. We have identified and assembled structural mutations in type I collagen genes (COL1A1 and COL1A2, encoding the proα1(I) and proα2(I) chains, respectively) that result in OI. Quantitative defects causing type I OI were not included. Of these 832 independent mutations, 682 result in substitution for glycine residues in the triple helical domain of the encoded protein and 150 alter splice sites. Distinct genotype-phenotype relationships emerge for each chain. Onethird of the mutations that result in glycine substitutions in α1(I) are lethal, especially when the substituting residues are charged or have a branched side chain. Substitutions in the first 200 residues are nonlethal and have variable outcome thereafter, unrelated to folding or helix stability domains. Two exclusively lethal regions (helix positions 691-823 and 910-964) align with major ligand binding regions (MLBRs), suggesting crucial interactions of collagen monomers or fibrils with integrins, matrix metalloproteinases (MMPs), fibronectin, and cartilage oligomeric matrix protein (COMP). Mutations in COL1A2 are predominantly nonlethal (80%). Lethal substitutions are located in eight regularly spaced clusters along the chain, supporting a regional model. The lethal regions align with proteoglycan binding sites along the fibril, suggesting a role in fibrilmatrix interactions. Recurrences at the same site in α2(I) are generally concordant for outcome, unlike α1(I). Splice site mutations comprise 20% of helical mutations identified in OI patients, and may lead to exon skipping, intron inclusion, or the activation of cryptic splice sites. Splice site mutations in COL1A1 are rarely lethal; they often lead to frameshifts and the mild type I phenotype. In α2(I), lethal exon skipping events are located in the carboxyl half of the chain. Our data on genotype-phenotype relationships indicate that the two collagen chains play very different roles in matrix integrity and that phenotype depends on intracellular and extracellular events.

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Section: Assemblyof the Database Mutationsmentioning

confidence: 99%

Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans

et al. 2007

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“…11,12 Traditional amino-acid residue numbering, which excludes the first 39 amino acids of the leader sequence, has nevertheless also been provided in parentheses and designed without the prefix 'p' .…”

Section: Mutation Nomenclaturementioning

confidence: 99%

Functional analysis of 11 novel GBA alleles

et al. 2013

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Gaucher disease is the most frequent lysosomal storage disorder due to the deficiency of the acid b-glucosidase, encoded by the GBA gene. In this study, we report the structural and functional characterization of 11 novel GBA alleles. Seven single missense alleles, P159S, N188I, E235K, P245T, W312S, S366R and W381C, and two alleles carrying in cis mutations, (N188S; G265R) and (E326K; D380N), were studied for enzyme activity in transiently transfected cells. All mutants were inactive except the P159S, which retained 15% of wild-type activity. To further characterize the alleles carrying two in cis mutations, we expressed constructs bearing singly each mutation. The presence of G265R or D380N mutations completely abolished enzyme activity, while N188S and E326K mutants retained 25 and 54% of wild-type activity, respectively. Two mutations, affecting the acceptor splice site of introns 5 (c.589-1G4A) and 9 (c.1389-1G4A), led to the synthesis of aberrant mRNA. Unpredictably, family studies showed that two alleles resulted from germline or 'de novo' mutations. These results strengthen the importance of performing a complete and accurate molecular analysis of the GBA gene in order to avoid misleading conclusions and provide a comprehensive functional analysis of new GBA mutations.

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“…However, when the HLA nomenclature was adapted to include DNA sequences in 1987 , advice was sought from the HGNC at that time, as can be seen by the inclusion of an asterisk in the name to separate the gene and allele designations. Since then the IMGT/HLA and IPD databases and the HLA and KIR nomenclature systems have implemented the relevant guidelines issued by HUGO [Antonarakis and the Nomenclature Working Group, 1998;den Dunnen and Paalman, 2003]. A number of these guidelines were already implemented as standard, these included the use of a named and listed reference sequence for numbering and the use of the A of the ATG translation initiation codon as nucleotide residue 1.…”

Section: Database Structurementioning

confidence: 99%

The IMGT/HLA and IPD databases

et al. 2006

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For the Immunogenetics Special IssueThe IMGT/HLA database (www.ebi.ac.uk/imgt/hla) has provided a centralized repository for the sequences of the alleles named by the WHO Nomenclature Committee for Factors of the HLA System since 1998. Since its initial release, the database has rapidly grown in size and is recognized as the primary source of information for the study of sequences of the human major histocompatibility complex. The Immuno Polymorphism Database (IPD; www.ebi.ac.uk/ipd) is a set of specialist databases related to the study of polymorphic genes in the immune system. The IPD currently consists of four databases: IPD-KIR contains the allelic sequences of killercell immunoglobulin-like receptors; IPD-MHC is a database of sequences of the major histocompatibility complex of different species; IPD-HPA contains alloantigens expressed only on platelets (human platelet antigens or HPA); and IPD-ESTDAB provides access to the European Searchable Tumour Cell-Line Database, a cell bank of immunologically characterized melanoma cell lines.

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Standardizing mutation nomenclature: Why bother?

Cited by 175 publications

References 4 publications

Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans

Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans

Functional analysis of 11 novel GBA alleles

The IMGT/HLA and IPD databases

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