Mutation Databases

Christophe Béroud, CHU de Montpellier, INSERM, and Université Montpellier, Montpellier, France
Mireille Claustres, CHU de Montpellier, INSERM, and Université Montpellier, Montpellier, France

Published online: July 2007

DOI: 10.1002/9780470015902.a0005315

Full Article on Wiley Online Library

In the 1970s began the organization of medical knowledge in databases. Twenty years later, few groups understood the importance of mutations in all areas of health care and the need to create mutation databases. To classify, interpret and develop this knowledge, two complementary approaches have been developed: the collection of mutations from a large set of genes (core database) and the collection of mutations from a single gene (Locus Specific Database). During the last decades the developments of technology, especially the availability of large scale sequencing, led to the collection of tens of thousands of mutations and polymorphisms. The mass of data is now sufficient to address fundamental questions such as the predictive medicine. Concomitantly new bioinformatics tools are developed to evaluate the pathogenic impact of a given mutation or its consequence on the 3D structure of the protein and to identify cellular signals such as Exonic Splicing Enhancers and Exonic Splicing Silencers either disrupted or created by mutations. In the near future, tremendous progresses will be made to collect phenotypic information and will be of considerable importance for the development of new therapeutic strategies based on mutations such as the exon-skipping or the premature termination codon read-through.

Keywords: Locus Specific Mutation Database; LSDB; core database; mutation; mutation nomenclature; human disease

	Figure 1. Evolution of the number of publications reporting mutations in human genes.
	Figure 2. Impact of the mutation c.3735+2T>C of the LAMA2 gene on the donor splice site of exon 25 described by Allamand et al. (1997). The wild-type donor splice site (AAGgtaagc) has a consensus value of 96.87, while the mutant sequence (AAGgcaagc) has a CV of 70.03 and therefore cannot be considered as an active donor splice site. This prediction from the Universal Mutation Database (UMD tool was confirmed by experiments that established that the mutant ribonucleic acid (RNA) lacks exon 25.
	Figure 3. Impact of an unusual intronic mutation c.3845-26T>G from the FBN2 gene. Wild-type sequence of the intron #30 from the FBN2 gene (a) and mutant sequence (b). X-axis position in the intronic sequence upstream of exon #31; Y-axis consensus value of potential branch points (a CV>70 means a potential active site). Arrows indicated the position of the first nucleotide of the wild-type branch point (a) and the mutant sequence (b). The branch point and mutant sequences are displayed on the top of each figure. A dark yellow box indicates the most favourable location of a branch point sequence. The c.3845-26T>G mutation is localized upstream of the acceptor splice site and thus does not affect its effectiveness; it does not create either an alternative site. Its pathogenicity is due to the disruption of the wild-type branch point as revealed by the prediction from the UMD software. This prediction was confirmed by experiments on RNA (Maslen et al., 1997).
	Figure 4. Interactions between LSDBs and other partners. NEMB, National and Ethnic Mutation Databases; Single arrow, uni-directional flow of information; double-headed arrow, bidirectional flow of information.

References
	Aartsma-Rus A, Bremmer-Bout M, Janson AA et al. (2002) Targeted exon skipping as a potential gene correction therapy for Duchenne muscular dystrophy. Neuromuscular Disorders 1(Suppl. 12): S71–S77.
	Allamand V Sunada Y, Salih MA et al. (1997) Mild congenital muscular dystrophy in two patients with an internally deleted laminin alpha2-chain. Human Molecular Genetics 6(5): 747–752.
	Antonarakis SE (1998) Recommendations for a nomenclature system for human gene mutations. Nomenclature working group. Human Mutation 11(1): 1–3.
	Aurino S and Nigro V (2006) Readthrough strategies for stop codons in Duchenne muscular dystrophy. Acta Myologica 25(1): 5–12.
	Beaudet AL and Tsui LC (1993) A suggested nomenclature for designating mutations. Human Mutation 2(4): 245–248.
	Beroud C, Hamroun D, Collod-Beroud G et al. (2005) UMD (universal mutation database): 2005 update. Human Mutation 26(3): 184–191.
	Beroud C, Tuffery-Giraud S, Matsuo M et al. (2007) Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy. Human Mutation 28(2): 196–202.
	Cariello NF, Beroud C and Soussi T (1994) Database and software for the analysis of mutations at the human p53 gene. Nucleic Acids Research 22(17): 3549–3550.
	Claustres M, Horaitis O, Vanevski M and Cotton RG (2002) Time for a unified system of mutation description and reporting: a review of locus-specific mutation databases. Genome Research 12(5): 680–688.
	Cooper DN, Ball EV and Krawczak M (1998) The human gene mutation database. Nucleic Acids Research 26(1): 285–287.
	den Dunnen JT and Antonarakis SE (2001) Nomenclature for the description of human sequence variations. Human Genetics 109(1): 121–124.
	Fokkema IF, den Dunnen JT and Taschner PE (2005) LOVD: easy creation of a locus-specific sequence variation database using an ‘LSDB-in-a-box’ approach. Human Mutation 26(2): 63–68.
	Hoang L, Byck S, Prevost L and Scriver CR (1996) PAH Mutation Analysis Consortium Database: a database for disease-producing and other allelic variation at the human PAH locus. Nucleic Acids Research 24(1): 127–131.
	Horaitis O and Cotton RG (2004) The challenge of documenting mutation across the genome: the human genome variation society approach. Human Mutation 23(5): 447–452.
	Howard MT, Shirts BH, Petros LM et al. (2000) Sequence specificity of aminoglycoside-induced stop condon readthrough: potential implications for treatment of Duchenne muscular dystrophy. Annals of Neurology 48(2): 164–169.
	Ingram VM (1957) Gene mutations in human haemoglobin: the chemical difference between normal and sickle cell haemoglobin. Nature 180(4581): 326–328.
	Maslen C, Babcock D, Raghunath M and Steinmann B (1997) A rare branch-point mutation is associated with missplicing of fibrillin-2 in a large family with congenital contractural arachnodactyly. American Journal of Human Genetics 60(6): 1389–1398.
	book McKusick VA (1998) Mendelian Inheritance in Man. A Catalog of Human Genes and Genetic Disorders. Baltimore, MD: John Hopkins University Press.
	Patrinos GP (2006) National and ethnic mutation databases: recording populations’ genography. Human Mutations 27(9): 879–887.
	Pauling L, Itano HA, Singer SJ and Wells IC (1949) Sickle cell anemia a molecular disease. Science 110(2865): 543–548.
	Rene C, Taulan M, Iral F et al. (2005) Binding of serum response factor to cystic fibrosis transmembrane conductance regulator CArG-like elements, as a new potential CFTR transcriptional regulation pathway. Nucleic Acids Research 33(16): 5271–5290.
	Sanger F, Nicklen S and Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proceedings of the National Academy of Sciences of the USA 74(12): 5463–5467.
	Saunders RE, O’Connell NM, Lee CA, Perry DJ and Perkins SJ (2005) Factor XI deficiency database: an interactive web database of mutations, phenotypes, and structural analysis tools. Human Mutations 26(3): 192–198.
	Scriver CR, Nowacki PM and Lehvaslaiho H (1999) Guidelines and recommendations for content, structure, and deployment of mutation databases. Human Mutations 13(5): 344–350.
	Soret J, Gabut M and Tazi J (2006) SR proteins as potential targets for therapy. Progress in Molecular Subcell Biology 44: 65–87.

Article Title:	Mutation Databases
* Name:
* E-mail:
* Note:

Mutation Databases

Related Sub-Topics: