Mapping SNPs BCKDHA

General

Maple syrup urine disease is an autosomal recessive disorder that affects the amino acid metabolism. The disease is caused by a defect in the branched-chain alpha-keto acid dehydrogenase complex which blocks oxidative decarboxylation. The result is a rising concentration of branched-chain amino acids. MSUD is caused by mutations in the gene coding for the alpha subunit of the branched-chain keto acid dehydrogenase(BCKDHA).

Reference Sequences: Reference_Sequence_BCKDHA

HGMD

Searching for "BCKDHA" a total of 39 mutations are reported, comprised of the following mutation types:

• missense/nonsense: 33 mutations
• small deletions: 3 mutations
• small insertions: 1 mutation
• gross deletions: 1 mutation
• complex rearrangements: 1 mutation

For us the missense/nonsense mutations are the most interesting ones, as a single nucleotide change can lead to the phenotype of Maple Syrup Urine Disease.

Codon change	Amino Acid change	Codon number
gCAG-GAG	Gln-Glu	80
ACG-ATG	THr-Met	106
cCGG-TGG	Arg-Trp	114
gTAT-AAAT	Tyr-Asn	121
CGG-CAG	Arg-Gln	122
cCAG-AAG	Gln-Lys	145
ATC-ACC	Ile-Thr	168
GCG-GTG	Ala-Val	171
GCG-GTG	Ala-Val	175
cGGC-AGC	Gly-Ser	204
cGCT-ACT	Ala-Thr	208
TGC-TAC	Cys-Thr	213
cCGG-TGG	Arg-Trp	220
AAT-AGT	Asn-Ser	222
GGC-GAC	Gly-Asp	238
tGCA-CCA	Ala-Pro	240
aCGA-TGA	Arg-Term	242
cGGG-AGG	Gly-Arg	245
cCGC-TGC	Arg-Cys	252
CGC-CAC	Arg-His	252
tGGT-AGT	Gly-Ser	255
GAT-GCT	Asp-Ala	257
ACA-AGA	Thr-Arg	265
cCGA-TGA	Arg-Term	269
ATC-ACC	Ile-Thr	281
cGAG-AAG	Glu-Lys	282
gGCC-ACC	Ala-Thr	283
CGC-CAC	Arg-His	301
cCGG-TGG	Arg-Trp	318
TTC-TGC	Phe-Cys	364
cGTG-ATG	Val-Met	367
TAT-TGT	Tyr-Cys	368
cTAC-AAC	Tyr-Asn	393

dbSNP

results for the SNPs search with BCKDHA:

-all: 742

-human: 371

SNPs in human

RefSeq ID	SNP	Reference Sequence	Nucleotide Position	Nt old	Nt new	Codon pos	SilentSNP	Changed AA
rs137852876	CTTGAGTGCCCCATCATCTTCTTCTG[C/G]CGGAACAATGGCTACGCCATCTCCA	NM_000709.3	792	C	G	263	0	S
rs137852875	TGATGTGTTTGCCGTATACAACGCCA[C/G]AAAGGAGGCCCGACGGCGGGCTGTG	NM_000709.3	929	C	G	309	0	S
rs137852874	CAGCCAGTGAGGGGGACGCCCATGCC[A/G]GCTTCAACTTCGCTGCCACACTTGA	NM_000709.3	745	G	A	248	0	R
rs137852873	TTGAGTGCCCCATCATCTTCTTCTGC[C/T]GGAACAATGGCTACGCCATCTCCAC	NM_000709.3	793	C	T	264	0	Y
rs137852872	GCCCAAACCCAACCCCAACCTACTCT[G/T]CTCAGACGTGTATCAGGAGATGCCC	NM_000709.3	1226	T	G	408	0	K
rs137852871	GTGTCCCCACAGCAGCACGAGGCCCC[A/G]GGTATGGCATCATGTCAATCCGCGT	NM_000709.3	868	G	A	289	0	R
rs137852870	GCCACCTGCAGACCTACGGGGAGCAC[A/T]ACCCACTGGATCACTTCGATAAGTG	NM_000709.3	1312	T	A	437	0	W
rs114716391	CTCACCACCCTCTCATCCCCTGCAGC[G/T]GTGGGGGCGGCGTACGCAGCCAAGC	NM_000709.3	648	G	T	215	1	K
rs111855817	TGCCCTCCTGCTGCTGCGGCAGCCTG[A/G]GGCTCGGGGACTGGCTAGATCTGTG	NM_000709.3	86	G	A	28	0	R
rs80014754	CTCTGCTCTCTTCCCCAGCACCCCCC[A/C]AGGCAGCAGCAGCAGTTTTCATCTC	NM_000709.3	117	C	A	38	0	M
rs62637712	TTTTCTCTCTCTCTTTCTTTCTGTAC[C/T]TCTCTTTCCTTTTTCTTTTTTTTTC	NM_000709.3	114	C	G	37	0	B
rs61737367	TCCACGCCCACCTCTGAGCAGTATCG[C/T]GGCGATGGCATTGGTATGGGCTCTG	NM_000709.3	840	C	T	279	0	Y
rs61736656	ATTACTGGGATAAACAGGACCACCCC[A/G]TCTCCCGGCTGCGGCACTATCTGCT	NM_000709.3	1081	A	G	360	0	R
rs55940366	GCTGTGGCAGAGAACCAGCCCTTCCT[C/T]ATCGAGGCCATGACCTACAGGTGCC	NM_000709.3	975	C	T	324	0	Y
rs34956071	TAGGTGTGCTGATGTATCGGGACTAC[C/T]CCCTGGAACTATTCATGGCCCAGTG	NM_000709.3	508	C	T	169	0	Y
rs34589432	CCTCTGCTCTCTTCCCCAGCACCCCC[A/C]CAGGCAGCAGCAGCAGTTTTCATCT	NM_000709.3	116	C	A	38	0	M
rs34541442	TAGCGATCGCTGCAGCGAGGGTCTGG[A/C]GGCTAAACCGTGGTTTGAGCCAGGC	NM_000709.3	34	C	A	11	0	M
rs34492894	GTGTATCAGGAGATGCCCGCCCAGCT[C/T]CGCAAGCAGCAGGAGTCTCTGGCCC	NM_000709.3	1260	C	T	419	0	Y
rs34442879	GGGGAGTGCCGCCGCCCTGGACAACA[C/T]GGACCTGGTGTTTGGCCAGTACCGG	NM_000709.3	452	C	T	150	0	Y
rs28940288	ACTTCGGCGAGGGGGCAGCCAGTGAG[A/G]GGGACGCCCATGCCGGCTTCAACTT	NM_000709.3	730	G	A	243	0	R
rs17173144	TTGTTAGCCAAGATGGCGGTAGCGAT[C/T]GCTGCAGCGAGGGTCTGGCGGCTAA	NM_000709.3	15	C	T	4	0	Y
rs11549938	TCTCTGGAATCCCCATCTACCGCGTC[A/C]TGGACCGGCAAGGCCAGATCATCAA	NM_000709.3	244	A	C	81	0	M
rs11549937	ATCAACCCCAGCGAGGACCCCCACCT[C/G]CCGAAGGAGAAGGTGCTGAAGCTCT	NM_000709.3	291	G	C	96	0	S
rs10404506	ATCTCCTCTCCACTGGCCACGCAGAT[C/T]CCTCAGGGTGAGGATGCATGCCCTG	NM_000709.3	639	C	T	212	0	Y
rs284652	CACCTGTAGGTCATGGCCTCGATGAG[A/G]AAGGGCTGGTTCTCTGCCACAGCCC	NM_000709.3	972	C	T	323	0	R
rs4674	ATCTCCTGATACACGTCTGAGAAGAG[C/T]AGGTTGGGGTTGGGTTTGGGCTTCC	NM_000709.3	1221	A	G	406	0	Y

The dbSNP mutation positions in the amino acid sequence are relative the RefSeq entry NP_001158255.1, which is exactly the protein sequence listed in Uniprot.

Missense Mutations annotated in dbSNP

RefSeq ID	RefCodon	Mutated Codon	Reference Allele	Mutated Allele	Mutation Frame	Codon Number	Reference Residue	Mutated Residue
rs10853751	TGC	TTC	C	T	2	4	T	M
rs111855817	CGT	CAT	G	A	2	28	G	E
rs34500671	CAG	CAG	C	G	3	32	C	W
rs34589432	CTG	CAG	C	A	2	38	P	H
rs34442879	GAG	GTG	C	T	2	150	T	M
rs34956071	GGC	TGC	C	T	1	169	P	S
rs28940288	AGG	AGG	G	A	1	243	G	R
rs137852874	TAC	AAC	G	A	1	248	G	S
rs137852876	TTC	TTG	C	G	3	263	C	W
rs137852873	AAC	TAC	C	T	1	264	R	W
rs137852871	ACC	ACC	G	A	1	288	G	R
rs137852875	TCA	TGA	C	G	2	308	T	R
rs61736656	CGC	GGC	A	G	1	359	I	V
rs137852872	GAG	GGG	T	G	2	408	F	C
rs137852870	CAG	AAG	T	A	1	437	Y	N
rs11549938	ATC	CTC	A	C	1	81	M	L

Silent mutations annotated in dbSNP

RefSeq ID	RefCodon	Mutated Codon	Reference Allele	Mutated Allele	Mutation Frame	Codon Number	Reference Residue	Mutated Residue
rs17173144	TGC	TGT	C	T	3	4	I	I
rs34541442	TTA	ATA	C	A	1	11	R	R
rs75733136	ATC	ATA	C	A	3	18	S	S
rs34169026	AGC	AGT	C	T	3	31	A	A
rs62637712	CTG	CTT	C	T	3	37	P	P
rs80014754	CTG	CTA	C	A	3	38	P	P
rs11549937	GAC	GAC	G	C	3	96	L	L
rs10404506	GAA	GAT	C	T	3	212	I	I
rs114716391	TTC	TTT	G	T	3	215	A	A
rs61737367	AAC	AAT	C	T	3	279	R	R
rs284652	ACA	ACT	C	T	3	323	F	F
rs55940366	AAG	AAT	C	T	3	324	L	L
rs4674	GCC	GCG	A	G	3	406	L	L
rs34492894	CCC	CCT	C	T	3	418	L	L

results for the gene search with BCKDHA

mRNA pos	aa position	function	mutation	aa change
54	5	synonymous	C/T	-
72	12	synonymous	C/A	-
125	29	missense	G/A	Gly/Glu
153	83	synonymous	C/G, C/T	-
155	39	missense	C/A	Pro/His
156	39	synonymous	C/A	-
238	82	missense	A/C	Met/Leu
330	97	synonymous	G/C	-
491	151	missense	C/T	Thr/Met
547	170	missense	C/T	Pro/Ser
678	213	synonymous	C/T	-
687	216	synonymous	G/T	-
769	244	missense	G/A	Gly/Arg
879	280	synonymous	C/T	-
1011	324	synonymous	C/T	-
1012	325	frame shift	C/	-
1014	325	synonymous	C/T	-
1120	361	missense	A/G	Ile/Val
1260	407	synonymous	A/G	-
1299	420	synonymous	C/T	-

Point mutations can have an influence on the amino acids or not depending on the kind of the point mutation. There are two different types: synonymous and non-synonymous mutations.

If a point mutation is synonymous it means that the change occurs only in the nucleotide sequence but not in the amino acid sequence. This is possible because of the fact that amino acids are encoded by three nucleotides (codons) and some of the amino acids are encoded by more than one possible arrangement of nucleotides. So it can happen that when there is a mutation in the nucleotide sequence there is also a change in the codon but both codons encode the same amino acid.

The other possibility is that a mutation is non-synonymous which means that the mutation has an influence on the amino acid sequence and the amino acid changes. This change can have more or less severe because amino acids have several properties. When an amino acid is replaced by an amino acid which has the same properties the change is not so grave as the change to an amino acid with completely different properties.

MAVAIAAARVWRLNRGLSQAALLLLRQPGARGLARSHPPRQQQQFSSLDDKPQFPGASAEF
IDKLEFIQPNVISGIPIYRVMDRQGQIINPSEDPHLPKEKVLKLYKSMTLLNTMDRILYE
SQRQGRISFYMTNYGEEGTHVGSAAALDNTDLVFGQYREAGVLMYRDYPLELFMAQCYGN
ISDLGKGRQMPVHYGCKERHFVTISSPLATQIPQAVGAAYAAKRANANRVVICYFGEGAA
SEGDAHAGFNFAATLECPIIFFCRNNGYAISTPTSEQYRGDGIAARGPGYGIMSIRVDGN
DVFAVYNATKEARRRAVAENQPFLIEAMTYRIGHHSTSDDSSAYRSVDEVNYWDKQDHPI
SRLRHYLLSQGWWDEEQEKAWRKQSRRKVMEAFEQAERKPKPNPNLLFSDVYQEMPAQLR
KQQESLARHLQTYGEHYPLDHFDK