Researching SNPs Gaucher Disease

HGMD

The Human Genome Mutation Database (HGMD)<ref name="hgmd">Stenson et al. 2009. The Human Gene Mutation Database (HGMD): 2008 Update. Genome Med</ref> is a collection of observed mutations in the human genome which are associated with various diseases. The mutations are taken from publications, both manually and automatically [1]. There is a public version with 88745 entries (9th June, 2012) and a professional version with 123565 entries. Since 2009, the public version has been extended only by few new entries such that it does no longer contain all currently known mutations [2]. The HGMD encompasses following types of mutations:

Missense

Mutations which result in another amino acid

Nonsense

Mutations which result in a stop codon

Splicing

Mutations which alter splice sites

Regulatory

Mutation which alter gene regulation

Small/gross deletions

Deletions which remove residues

Small/gross insertions

Insertions which give rise to new residues

Small indels

Insertions or deletions

Duplications

Duplication of gene fragments

Complex rearrangements

Change in the location for gene fragments

Repeat variations

Varying number of sequence copies

<xr id="tab:hgmd_number"/> lists the number of mutations available in HGMD for the gene GBA which is causing Gaucher disease. A comprehensive list of all missense/nonsense mutations can be obtained by following the respective hyperlink.

<figtable id="tab:hgmd_number">

Type	Count
Missense/nonsense	250
Splicing	15
Regulatory	0
Small deletions	26
Small insertions	13
Small indels	2
Gross deletions	3
Gross insertions/duplications	1
Complex rearrangements	15
Public total	325

Number of mutations in HGMD for GBA. </figtable>

<xr id="tab:hgmd_missense"/> shows the wildtype version of P04062 with missense/nonsense mutations highlighted in red. Since the transcript NM_001005741.1 in HGMD already referred to P04062, the amino acid positions could be used directly for creating <xr id="tab:hgmd_missense"/> without any additional translation.

<figtable id="tab:hgmd_missense">

         1          11         21         31         41         51         61         71        
Wildtype MEFSSPSREE CPKPLSRVSI MAGSLTGLLL LQAVSWASGA RPCIPKSFGY SSVVCVCNAT YCDSFDPPTF PALGTFSRYE
Missense MEFSSPSREE CPRPLSRVSI MAGSLTGLLL LQAVS!ASGA RPCIPKSFSY ISVLSVCNAT YCNSFDPPTF PALSTVSRYK
         81         91         101        111        121        131        141        151       
Wildtype STRSGRRMEL SMGPIQANHT GTGLLLTLQP EQKFQKVKGF GGAMTDAAAL NILALSPPAQ NLLLKSYFSE EGIGYNIIRV
Missense NIRSE!QMEL SMGPIQANHT GTGLPLTLQP E!!FQKANGF GGATTDAATL NILALSPPAQ NLLRKLCVSK EEIGYDISQA
         161        171        181        191        201        211        221        231       
Wildtype PMASCDFSIR TYTYADTPDD FQLHNFSLPE EDTKLKIPLI HRALQLAQRP VSLLASPWTS PTWLKTNGAV NGKGSLKGQP
Missense LVASCVFSIL TYP!EDTPHD FQLHNFSLPE ADTKLQILLS PQALQLA!CP V!PLDSS!PS LTRFKTKVEG NGKWPPEGQP
         241        251        261        271        281        291        301        311       
Wildtype GDIYHQTWAR YFVKFLDAYA EHKLQFWAVT AENEPSAGLL SGYPFQCLGF TPEHQRDFIA RDLGPTLANS THHNVRLLML
Missense EDICHQTRVR HCVKYLDACA EHKLQFWAVR A!NETPAVLL SVHHFQCQGL TPEQQ!DLTA HDLDATLANG THHNVRLPML
         321        331        341        351        361        371        381        391       
Wildtype DDQRLLLPHW AKVVLTDPEA AKYVHGIAVH WYLDFLAPAK ATLGETHRLF PNTMLFASEA CVGSKFWEQS VRLGSWDRGM
Missense DDQHLLPLHW AKVVLTDPEA AI!LHGIVVR RHLHFLDSAK AIPWKTHCLS PNTMPFASET YVGSKFGK!S LWLDF!D!GI
         401        411        421        431        441        451        461        471       
Wildtype QYSHSIITNL LYHVVGWTDW NLALNPEGGP NWVRNFVDSP IIVDITKDTF YKQPMFYHLG HFSKFIPEGS QRVGLVASQK
Missense QCRHGIIMKV LYHLVS!TA! KRDPNL!ERL IRLCTSFYSL FIVDITKHTI HQRRVVCHLD HFSEVIPEGS QGVGLVASQK
         481        491        501        511        521        531       
Wildtype NDLDAVALMH PDGSAVVVVL NRSSKDVPLT IKDPAVGFLE TISPGYSIHT YLWRRQ
Missense NDRDPVALMR PDGSPVVVMP KPSSKDVPLT IKYPAVSFPE TISPGYPTHI YLWRCR

GBA protein sequence P04062. Red: missense/nonsense mutations annotated in HGMD. </figtable>

dbSNP

• 47 Synonymous mutations
• 92 Missense mutations

           1          11         21         31         41         51         61         71        
Wildtype   MEFSSPSREE CPKPLSRVSI MAGSLTGLLL LQAVSWASGA RPCIPKSFGY SSVVCVCNAT YCDSFDPPTF PALGTFSRYE
Missense   MEFSSPSREE CPRPSGGVSV MAGSLTGLLL LQAVSWASGA CPCIPESFGY SSVVCVCNAT YYESFDPRTF PALGTLSCYK
Synonymous MEFSSPSREE CPKPLSRVSI MAGSLTGLLL LQAVSWASGA RPCIPKSFGY SSVVCVCNAT YCDSFDPPTF PALGTFSRYE
           81         91         101        111        121        131        141        151       
Wildtype   STRSGRRMEL SMGPIQANHT GTGLLLTLQP EQKFQKVKGF GGAMTDAAAL NILALSPPAQ NLLLKSYFSE EGIGYNIIRV
Missense   SRSSGQWMEL STGPIQANYT GTGLLLTLQP EQKFQKVKGF GGAMTDAAAL NILALSPPAQ NLLLKSYFSE EGIGYKISWV
Synonymous STRSGRRMEL SMGPIQANHT GTGLLLTLQP EQKFQKVKGF GGAMTDAAAL NILALSPPAQ NLLLKSYFSE EGIGYNIIRV
           161        171        181        191        201        211        221        231       
Wildtype   PMASCDFSIR TYTYADTPDD FQLHNFSLPE EDTKLKIPLI HRALQLAQRP VSLLASPWTS PTWLKTNGAV NGKGSLKGQP
Missense   LIASCVFSIL TYIYEDTPHD FQLHNFSLPE EDTKLNILLN PRALQLAQRP ISLLASPWTS LTRLKTKVEE NGKESLKGQP
Synonymous PMASCDFSIR TYTYADTPDD FQLHNFSLPE EDTKLKIPLI HRALQLAQRP VSLLASPWTS PTWLKTNGAV NGKGSLKGQP
           241        251        261        271        281        291        301        311       
Wildtype   GDIYHQTWAR YFVKFLDAYA EHKLQFWAVT AENEPSAGLL SGYPFQCLGF TPEHQRDFIA RDLGPTLANS THHNVRLLML
Missense   EDICHQTWAR YLVKFLDAYA EHKLQFWAVR AENEPSAGLL NGYPFQCLGF TPEHQRDFIA HDLDRTLANG THHNVRLLML
Synonymous GDIYHQTWAR YFVKFLDAYA EHKLQFWAVT AENEPSAGLL SGYPFQCLGF TPEHQRDFIA RDLGPTLANS THHNVRLLML
           321        331        341        351        361        371        381        391       
Wildtype   DDQRLLLPHW AKVVLTDPEA AKYVHGIAVH WYLDFLAPAK ATLGETHRLF PNTMLFASEA CVGSKFWEQS VRLGSWDRGM
Missense   DDQHLLLPQW AKVVLTDPEA AICVYGIAVH WYLDFLDPAK ATLGETHHLF PNTMLFASEA CVGSKFWEQS VQLGSWDQGI
Synonymous DDQRLLLPHW AKVVLTDPEA AKYVHGIAVH WYLDFLAPAK ATLGETHRLF PNTMLFASEA CVGSKFWEQS VRLGSWDRGM
           401        411        421        431        441        451        461        471       
Wildtype   QYSHSIITNL LYHVVGWTDW NLALNPEGGP NWVRNFVDSP IIVDITKDTF YKQPMFYHLG HFSKFIPEGS QRVGLVASQK
Missense   QCSHRIIMNL LYHVVGCTAW NIALNPKGGL IWVRTSVESP TIVDITKETL YKQPILCHLG HFSKFIPEGS QRVGLVASPK
Synonymous QYSHSIITNL LYHVVGWTDW NLALNPEGGP NWVRNFVDSP IIVDITKDTF YKQPMFYHLG HFSKFIPEGS QRVGLVASQK
           481        491        501        511        521        531       
Wildtype   NDLDAVALMH PDGSAVVVVL NRSSKDVPLT IKDPAVGFLE TISPGYSIHT YLWRRQ
Missense   NNLDAVALMR PDGSAVVVVL NRSFKDVPPT IKEPAVGFLE TISPGYSIHI YLWCHQ
Synonymous NDLDAVALMH PDGSAVVVVL NRSSKDVPLT IKDPAVGFLE TISPGYSIHT YLWRRQ