Task 7 (MSUD)
Contents
HGMD
Database facts
Q: What information is given?
A: Only disease causing mutations are included. HGMD lists the following mutation types:
- missense/nonsense
- splicing
- regulatory
- small deletions
- small insertions
- small indels
- gross deletions
- gross insertions/duplications
- complex rearrangements
- repeat variations
For each mutation entry the following information is given in the public version:
- accession number
- codon change
- amino acid change
- codon number
- phenotype
- reference
- comments
Q: How recent is the release?
A: Release 2013.1 is the current professional version. Entries are made publicly accessible three years after they are included. Mutations that are taken from publicly available locus-specific mutation databases are immediately added to the public version.
Q: Where does the information come from?
A: The information is extracted from articles that describe genetic diseases. So only published mutations are included.
Mutations of BCKDHA
The following mutations are listed for BCKDHA (20 June 2013):
| mutation type | number of mutations |
|---|---|
| missense/nonsense | 40 |
| splicing | 2 |
| small deletions | 4 |
| small insertions | 1 |
| small indels | 1 |
| gross deletions | 2 |
| complex rearrangements | 1 |
All reported mutations are associated with MSUD. Among the 40 mutations of category "missense/nonsense", there are 37 missense mutations listet and 3 nonsense mutations.
Definition of the mutation types:
- missense: single base substitution that leads to amino acid change
- nonsense: single base substitution that leads to a stop codon
- splicing: mutation that affects a splicing side
- small deletion: deletion of few base pairs
- small insertion: insertion of few base pairs
- small indel: insertion / deletion of few base pairs
- gross deletion: deletion of many base pairs
- complex rearrangement: insertion / deletion of many base pairs
dbSNP
Database facts
Q: What information is given?
A: Short variations in nucleotide sequence from many different organisms. It contains following information:
- mutations of different categories:
- single nucleotide variations
- indels
- short tandem repeats
- microsatellites
- additional information for rare variations
- disease relationship
- genotype information
- allele origin
- somatic or germline events
Q: How recent is the release?
A: Current version of dbSNP is build 137. dbSNP web query, ftp data and Entrez Indexing were released on Jun 26, 2012. New release of BLAST database is not yet done. The newest release of BLAST database was released on Nov 14, 2011 from build 135.
Q: Where does the information come from?
A: dbSNP is created by the cooperation of the National Human Genome Research Institute and the National Center for Biotechnology Information. It is integrated with the NCBI Genomic data. There are two sorts of content in dbSNP: submitted and computed data. During a build cycle, submitted SNPs (identified by ss#) which map to the same genomic position, are clustered to a non-redundant set of reference SNPs (refSNPs), that get a unique rs# identifier.
Mutations of BCKDHA
Totally 292 SNPs in coding region of BCKDHA were found in dbSNP. 4 mutations are nonsense (stop-gained) which introduce stop condon in the coding region. 152 mutations are missense among which 28 mutations can cause disease. 136 mutations are synonymous codons.
SNPdbe
Database facts
Q: What information is given?
A: Experimentally annotated effects of non-synonymous SNPs (nsSNP). Computationally annotated structural and functional effects of nsSNP. Association between nsSNP and diseases.
Q: How recent is the release?
A: The most recent update took place on Mar 05, 2012.
Q: Where does the information come from?
A: Experimentally annotated nsSNP from dbSNP; Variants from UniProt and PMD; Genomic data from 1000 Genome collection; predicted impacts on protein structure and function are computed with SNAP and SIFT.
Mutations of BCKDHA
102 SNPs were reported in SNPdbe for BCKDHA. Among them 8 SNPs were reported to have association to MSUD.
OMIM
Database facts
Q: What information is given?
A: In the allelic variants section of a gene entry, mutations (e. g. substitions or deletions) are given and the phenotype that they are causing. Only selected mutations are listed (see OMIM FAQ), most of which are disease associated.
Q: How recent is the release?
A: OMIM is updated daily. The entry for BCKDHA was last updated 05/23/2012.
Q: Where does the information come from?
A: The information comes from published articles. For each mutation the reference article is given in the text of the allelic variants section.
Mutations of BCKDHA
For BCKDHA, there are 7 missense mutations listed and 2 deletions, where one is a 1-bp (base pair) deletion and the other 8-bp (last update of entry: 05/23/2012). All these mutations are associated with MSUD type IA (classic or intermediate form).
SNPedia
Database facts
Q: What information is given?
A: The wiki style project 'SNPedia' is open to the internet community. It contains information about effects of SNPs. Annotations from wide range of internet resources such as the dbSNP project, Ensembl or even google search are included into SNPedia. It tries to gather all SNP related information to one web site.
Q: How recent is the release?
A: Due to contribution of its user community, new updates could occur at any time point. But still it depends on the release of other SNP related resources.
Q: Where does the information come from?
A: Many different public available databases, resources about SNPs, publications about genomic studies.
Mutations of BCKDHA
Due the fact that SNPedia is not a database-like data source. Statistics over reported SNPs for BCKDHA is hard to obtain.
Mutation map
102 mutations were selected from different databases. Disease causing mutations are marked in red, mutations that do not cause disease are marked in blue.
Following table contains the SNPs that we have chosen from different databases:
| Accession.Number | Codon.number | Pathogenic | Mutation | Type | pathogenic | all |
|---|---|---|---|---|---|---|
| 17 | N/A | L17F | missense | FALSE | silent | |
| 29 | N/A | G29E | missense | FALSE | silent | |
| rs11549936 | 38 | N/A | P38H | missense | FALSE | silent |
| rs80014754 | 38 | N/A | P38P | synonymous-codon | FALSE | silent |
| rs150177278 | 41 | N/A | Q41R | missense | FALSE | silent |
| 59 | N/A | A59V | missense | FALSE | silent | |
| rs149251798 | 61 | N/A | I61M | missense | FALSE | silent |
| CM093772 | 69 | Maple syrup urine disease | Q69* | nonsense | TRUE | disease |
| rs138025447 | 70 | N/A | N70N | synonymous-codon | FALSE | silent |
| rs11549938 | 81 | N/A | M81L | missense | FALSE | silent |
| rs148571328 | 95 | N/A | H95H | synonymous-codon | FALSE | silent |
| rs11549937 | 96 | N/A | L96L | synonymous-codon | FALSE | silent |
| CM005526 | 109 | Maple syrup urine disease | M109T | missense | TRUE | disease |
| rs150700696 | 111 | N/A | L111L | synonymous-codon | FALSE | silent |
| CM021496 | 125 | Maple syrup urine disease | Q125E | missense | TRUE | disease |
| rs139678295 | 126 | N/A | R126W | missense | FALSE | silent |
| rs201638798 | 133 | N/A | N133N | synonymous-codon | FALSE | silent |
| rs146804716 | 140 | N/A | H140H | synonymous-codon | FALSE | silent |
| rs200947033 | 145 | N/A | A145A | synonymous-codon | FALSE | silent |
| CM021497 | 151 | Maple syrup urine disease | T151M | missense | TRUE | disease |
| CM082498 | 152 | Maple syrup urine disease | D152N | missense | TRUE | disease |
| CM930067 | 159 | Maple syrup urine disease | R159W | missense | TRUE | disease |
| CM984173 | 166 | Maple syrup urine disease | Y166N | missense | TRUE | disease |
| CM984174 | 167 | Maple syrup urine disease | R167Q | missense | TRUE | disease |
| 170 | N/A | P170S | missense | FALSE | silent | |
| CM930068 | 190 | Maple syrup urine disease | Q190K | missense | TRUE | disease |
| rs190610188 | 199 | N/A | R199C | missense | FALSE | silent |
| 6 | 204 | MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA | G204S | missense | TRUE | disease |
| 209 | N/A | L209A | missense | FALSE | silent | |
| CM097509 | 211 | Maple syrup urine disease | T211M | missense | TRUE | disease |
| rs10404506 | 212 | N/A | I212I | synonymous-codon | FALSE | silent |
| CM984175 | 213 | Maple syrup urine disease | I213T | missense | TRUE | disease |
| rs114716391 | 215 | N/A | A215A | synonymous-codon | FALSE | silent |
| CM062450 | 216 | Maple syrup urine disease | A216V | missense | TRUE | disease |
| 8 | 219 | MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA | C219W | missense | TRUE | disease |
| 5 | 220 | MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA | R220W | missense | TRUE | disease |
| CM062451 | 220 | Maple syrup urine disease | A220V | missense | TRUE | disease |
| rs141086188 | 221 | N/A | A221T | missense | FALSE | silent |
| rs146932786 | 235 | N/A | F235F | synonymous-codon | FALSE | silent |
| 244 | N/A | G244R | missense | FALSE | silent | |
| 3 | 245 | MAPLE SYRUP URINE DISEASE, INTERMEDIATE, TYPE IA | G245R | missense | TRUE | disease |
| rs137852874 | 248 | True | G248S | missense | TRUE | disease |
| CM984176 | 249 | Maple syrup urine disease | G249S | missense | TRUE | disease |
| rs199599175 | 252 | N/A | A252T | missense | FALSE | silent |
| CM930069 | 253 | Maple syrup urine disease | A253T | missense | TRUE | disease |
| CM005527 | 254 | Maple syrup urine disease | A254D | missense | TRUE | disease |
| CM021498 | 258 | Maple syrup urine disease | C258Y | missense | TRUE | disease |
| rs137852876 | 263 | True | C263W | missense | TRUE | disease |
| CM045934 | 264 | Maple syrup urine disease | C264W | missense | TRUE | disease |
| rs137852873 | 264 | True | R264W | missense | TRUE | disease |
| 7 | 265 | MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA | T265R | missense | TRUE | disease |
| CM984177 | 265 | Maple syrup urine disease | R265W | missense | TRUE | disease |
| 265 | N/A | R265A | missense | FALSE | silent | |
| CM984178 | 267 | Maple syrup urine disease | N267S | missense | TRUE | disease |
| rs201991385 | 272 | N/A | T272T | synonymous-codon | FALSE | silent |
| rs61737367 | 279 | N/A | R279R | synonymous-codon | FALSE | silent |
| CM062452 | 283 | Maple syrup urine disease | G283D | missense | TRUE | disease |
| CM984179 | 285 | Maple syrup urine disease | A285P | missense | TRUE | disease |
| CM970163 | 287 | Maple syrup urine disease | R287* | nonsense | TRUE | disease |
| rs137852871 | 289 | True | G289R | missense | TRUE | disease |
| CM950135 | 290 | Maple syrup urine disease | G290R | missense | TRUE | disease |
| 296 | N/A | R296C | missense | FALSE | silent | |
| rs200137189 | 296 | N/A | R296H | missense | FALSE | silent |
| CM062446 | 297 | Maple syrup urine disease | R297C | missense | TRUE | disease |
| CM076017 | 297 | Maple syrup urine disease | R297H | missense | TRUE | disease |
| CM062453 | 300 | Maple syrup urine disease | G300S | missense | TRUE | disease |
| CM062449 | 302 | Maple syrup urine disease | D302A | missense | TRUE | disease |
| rs139390622 | 306 | N/A | N306N | synonymous-codon | FALSE | silent |
| 309 | N/A | T309R | missense | FALSE | silent | |
| CM984180 | 310 | Maple syrup urine disease | T310R | missense | TRUE | disease |
| rs144372407 | 313 | N/A | R313Q | missense | FALSE | silent |
| CM034725 | 314 | Maple syrup urine disease | R314* | nonsense | TRUE | disease |
| rs201109190 | 314 | N/A | R314Q | missense | FALSE | silent |
| rs284652 | 323 | N/A | F323F | synonymous-codon | FALSE | silent |
| CM930070 | 326 | Maple syrup urine disease | I326T | missense | TRUE | disease |
| CM062447 | 327 | Maple syrup urine disease | E327K | missense | TRUE | disease |
| CM076018 | 328 | Maple syrup urine disease | A328T | missense | TRUE | disease |
| 337 | N/A | S337D | missense | FALSE | silent | |
| rs146300600 | 343 | N/A | A343V | missense | FALSE | silent |
| 345 | N/A | R345C | missense | FALSE | silent | |
| rs139556493 | 345 | N/A | S345L | missense | FALSE | silent |
| CM062448 | 346 | Maple syrup urine disease | R346H | missense | TRUE | disease |
| rs144276456 | 346 | N/A | S346S | synonymous-codon | FALSE | silent |
| rs185688419 | 356 | N/A | Q356R | missense | FALSE | silent |
| rs61736656 | 359 | N/A | I359V | missense | FALSE | silent |
| CM984181 | 363 | Maple syrup urine disease | R363W | missense | TRUE | disease |
| 4 | 364 | MAPLE SYRUP URINE DISEASE, INTERMEDIATE, TYPE IA. MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA, INCLUDED | F364C | missense | TRUE | disease |
| rs190202447 | 382 | N/A | R382R | synonymous-codon | FALSE | silent |
| 1 | 393 | MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA | Y393N | missense | TRUE | disease |
| rs145595627 | 401 | N/A | P401P | synonymous-codon | FALSE | silent |
| 403 | N/A | P403R | missense | FALSE | silent | |
| rs137852872 | 407 | True | F407C | missense | TRUE | disease |
| 408 | N/A | F408C | missense | FALSE | silent | |
| CM950136 | 409 | Maple syrup urine disease | F409C | missense | TRUE | disease |
| CM032853 | 412 | Maple syrup urine disease | V412M | missense | TRUE | disease |
| CM082499 | 413 | Maple syrup urine disease | Y413H | missense | TRUE | disease |
| CM940169 | 413 | Maple syrup urine disease | Y413C | missense | TRUE | disease |
| rs34492894 | 419 | N/A | L419L | synonymous-codon | FALSE | silent |
| rs141991700 | 422 | N/A | Q422K | missense | FALSE | silent |
| rs137852870 | 436 | True | Y436N | missense | TRUE | disease |
| CM890022 | 438 | Maple syrup urine disease | Y438N | missense | TRUE | disease |
Discussion
- SNPs are very frequent in human genome.
- Many missense mutations also lead to disease, because a mutation is a random event, which in most cases will lead to a loss of function.
- Nonsense mutations seem to be even more severe. All reported nonsense mutations in BCKDHA are disease causing. The only case, where a nonsense mutation could be neutral, is if the mutation is near the end of the protein, which is unlikely for a random SNP.
- There are disease causing mutations widespread almost over the whole length of the protein. So not only mutations at functionally important sites like binding sites or catalytic centres can cause disease, but also mutations that occur somewhere in the protein and might change its whole structure, which also disturbs the function.
- The databases have different focuses:
- OMIM and HGMD list only disease causing SNPs
- SNPdbe adds information about functional effects of non-synonymous SNPs
- dbSNP aims to collect all known SNPs
References
- Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), 2013. OMIM
- Stenson et al (2003). The Human Gene Mutation Database (HGMD®): 2003 Update. Hum Mutat(2003) 21:577-581. HGMD
- Kitts A, Sherry S. The Single Nucleotide Polymorphism Database (dbSNP) of Nucleotide Sequence Variation. 2002 Oct 9 [Updated 2011 Feb 2]. In: McEntyre J, Ostell J, editors. The NCBI Handbook [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2002-. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK21088/
- dbSNP
- Schaefer C, Meier A, Rost B, Bromberg Y (2012). SNPdbe: Constructing an nsSNP functional impacts database. Bioinformatics; 28(4):601-602. SNPdbe
- Cariaso M, Lennon G. SNPedia: a wiki supporting personal genome annotation, interpretation and analysis. Nucleic Acids Research 2011; doi: 10.1093/nar/gkr798. SNPedia
