Task 7 (MSUD)

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

Histogram of different types of SNPs reported in 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	213	N/A	I213I	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