Full text data of CSTB
CSTB
(CST6, STFB)
[Confidence: low (only semi-automatic identification from reviews)]
Cystatin-B (CPI-B; Liver thiol proteinase inhibitor; Stefin-B)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Cystatin-B (CPI-B; Liver thiol proteinase inhibitor; Stefin-B)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P04080
ID CYTB_HUMAN Reviewed; 98 AA.
AC P04080;
DT 01-NOV-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 2.
DT 22-JAN-2014, entry version 163.
DE RecName: Full=Cystatin-B;
DE AltName: Full=CPI-B;
DE AltName: Full=Liver thiol proteinase inhibitor;
DE AltName: Full=Stefin-B;
GN Name=CSTB; Synonyms=CST6, STFB;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP PROTEIN SEQUENCE.
RX PubMed=3902020; DOI=10.1016/0006-291X(85)90216-5;
RA Ritonja A., Machleidt W., Barrett A.J.;
RT "Amino acid sequence of the intracellular cysteine proteinase
RT inhibitor cystatin B from human liver.";
RL Biochem. Biophys. Res. Commun. 131:1187-1192(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=8596935; DOI=10.1126/science.271.5256.1731;
RA Pennacchio L.A., Lehesjoki A.-E., Stone N.E., Willour V.L.,
RA Virteneva K., Miao J., D'Amato E., Ramirez L., Faham J.,
RA Koskiniemi M., Warringtion J.A., Norio R., la Chapelle A., Cox D.R.,
RA Myers R.M.;
RT "Mutations in the gene encoding cystatin B in progressive myoclonus
RT epilepsy (EPM1).";
RL Science 271:1731-1734(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Bhat K.S.;
RL Submitted (MAY-1993) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10830953; DOI=10.1038/35012518;
RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T.,
RA Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y.,
RA Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K.,
RA Polley A., Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D.,
RA Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W.,
RA Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S.,
RA Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E.,
RA Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P.,
RA Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H.,
RA Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E.,
RA Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F.,
RA Lehrach H., Reinhardt R., Yaspo M.-L.;
RT "The DNA sequence of human chromosome 21.";
RL Nature 405:311-319(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP SUBCELLULAR LOCATION.
RX PubMed=11139332; DOI=10.1006/excr.2000.5085;
RA Riccio M., Di Giaimo R., Pianetti S., Palmieri P.P., Melli M.,
RA Santi S.;
RT "Nuclear localization of cystatin B, the cathepsin inhibitor
RT implicated in myoclonus epilepsy (EPM1).";
RL Exp. Cell Res. 262:84-94(2001).
RN [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS).
RX PubMed=2347312;
RA Stubbs M.T., Laber B., Bode W., Huber R., Jerala R., Lenarcic B.,
RA Turk V.;
RT "The refined 2.4 A X-ray crystal structure of recombinant human stefin
RT B in complex with the cysteine proteinase papain: a novel type of
RT proteinase inhibitor interaction.";
RL EMBO J. 9:1939-1947(1990).
RN [10]
RP VARIANT EPM1 ARG-4.
RX PubMed=9012407;
RA Lalioti M.D., Mirotsou M., Buresi C., Peitsch M.C., Rossier C.,
RA Ouazzani R., Baldy-Moulinier M., Bottani A., Malafosse A.,
RA Antonarakis S.E.;
RT "Identification of mutations in cystatin B, the gene responsible for
RT the Unverricht-Lundborg type of progressive myoclonus epilepsy
RT (EPM1).";
RL Am. J. Hum. Genet. 60:342-351(1997).
CC -!- FUNCTION: This is an intracellular thiol proteinase inhibitor.
CC Tightly binding reversible inhibitor of cathepsins L, H and B.
CC -!- SUBUNIT: Able to form dimers stabilized by noncovalent forces.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus.
CC -!- DISEASE: Epilepsy, progressive myoclonic 1 (EPM1) [MIM:254800]: An
CC autosomal recessive disorder characterized by severe, stimulus-
CC sensitive myoclonus and tonic-clonic seizures. The onset,
CC occurring between 6 and 13 years of age, is characterized by
CC convulsions. Myoclonus begins 1 to 5 years later. The twitchings
CC occur predominantly in the proximal muscles of the extremities and
CC are bilaterally symmetrical, although asynchronous. At first
CC small, they become late in the clinical course so violent that the
CC victim is thrown to the floor. Mental deterioration and eventually
CC dementia develop. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the cystatin family.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/CSTBID40181ch21q22.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CSTB";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; U46692; AAA99014.1; -; Genomic_DNA.
DR EMBL; L03558; AAA35727.1; -; mRNA.
DR EMBL; AF208234; AAF44059.1; -; Genomic_DNA.
DR EMBL; AP001752; BAA95541.1; -; Genomic_DNA.
DR EMBL; BC003370; AAH03370.1; -; mRNA.
DR EMBL; BC010532; AAH10532.1; -; mRNA.
DR PIR; A01278; UDHUB.
DR RefSeq; NP_000091.1; NM_000100.3.
DR UniGene; Hs.695; -.
DR PDB; 1STF; X-ray; 2.37 A; I=1-98.
DR PDB; 2OCT; X-ray; 1.40 A; A/B=1-98.
DR PDBsum; 1STF; -.
DR PDBsum; 2OCT; -.
DR ProteinModelPortal; P04080; -.
DR SMR; P04080; 1-98.
DR IntAct; P04080; 7.
DR MINT; MINT-1504629; -.
DR STRING; 9606.ENSP00000291568; -.
DR MEROPS; I25.003; -.
DR TCDB; 1.C.91.1.1; the stefin b pore-forming protein (stefin b) family.
DR PhosphoSite; P04080; -.
DR DMDM; 1706278; -.
DR PaxDb; P04080; -.
DR PeptideAtlas; P04080; -.
DR PRIDE; P04080; -.
DR DNASU; 1476; -.
DR Ensembl; ENST00000291568; ENSP00000291568; ENSG00000160213.
DR GeneID; 1476; -.
DR KEGG; hsa:1476; -.
DR UCSC; uc002zdr.4; human.
DR CTD; 1476; -.
DR GeneCards; GC21M045192; -.
DR HGNC; HGNC:2482; CSTB.
DR HPA; CAB047320; -.
DR HPA; HPA017380; -.
DR MIM; 254800; phenotype.
DR MIM; 601145; gene.
DR neXtProt; NX_P04080; -.
DR Orphanet; 308; Unverricht-Lundborg disease.
DR PharmGKB; PA26984; -.
DR eggNOG; NOG29074; -.
DR HOGENOM; HOG000294175; -.
DR HOVERGEN; HBG002292; -.
DR InParanoid; P04080; -.
DR KO; K13907; -.
DR OMA; PHENKPP; -.
DR OrthoDB; EOG7FR7JX; -.
DR PhylomeDB; P04080; -.
DR ChiTaRS; CSTB; human.
DR EvolutionaryTrace; P04080; -.
DR GeneWiki; Cystatin_B; -.
DR GenomeRNAi; 1476; -.
DR NextBio; 6061; -.
DR PRO; PR:P04080; -.
DR ArrayExpress; P04080; -.
DR Bgee; P04080; -.
DR CleanEx; HS_CST6; -.
DR CleanEx; HS_CSTB; -.
DR Genevestigator; P04080; -.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005730; C:nucleolus; IDA:HPA.
DR GO; GO:0004869; F:cysteine-type endopeptidase inhibitor activity; IDA:BHF-UCL.
DR GO; GO:0008344; P:adult locomotory behavior; IEA:Ensembl.
DR GO; GO:0042981; P:regulation of apoptotic process; IEA:Ensembl.
DR InterPro; IPR000010; Prot_inh_cystat.
DR InterPro; IPR018073; Prot_inh_cystat_CS.
DR InterPro; IPR001713; Prot_inh_stefinA.
DR Pfam; PF00031; Cystatin; 1.
DR PRINTS; PR00295; STEFINA.
DR SMART; SM00043; CY; 1.
DR PROSITE; PS00287; CYSTATIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disease mutation; Epilepsy; Nucleus;
KW Protease inhibitor; Reference proteome; Thiol protease inhibitor.
FT CHAIN 1 98 Cystatin-B.
FT /FTId=PRO_0000207136.
FT MOTIF 46 50 Secondary area of contact.
FT SITE 4 4 Reactive site.
FT MOD_RES 1 1 N-acetylmethionine.
FT VARIANT 4 4 G -> R (in EPM1).
FT /FTId=VAR_002206.
FT CONFLICT 31 31 E -> Y (in Ref. 1; AA sequence).
FT HELIX 14 31
FT STRAND 39 58
FT STRAND 60 62
FT STRAND 64 74
FT STRAND 80 89
SQ SEQUENCE 98 AA; 11140 MW; B8076220E19D0483 CRC64;
MMCGAPSATQ PATAETQHIA DQVRSQLEEK ENKKFPVFKA VSFKSQVVAG TNYFIKVHVG
DEDFVHLRVF QSLPHENKPL TLSNYQTNKA KHDELTYF
//
ID CYTB_HUMAN Reviewed; 98 AA.
AC P04080;
DT 01-NOV-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 2.
DT 22-JAN-2014, entry version 163.
DE RecName: Full=Cystatin-B;
DE AltName: Full=CPI-B;
DE AltName: Full=Liver thiol proteinase inhibitor;
DE AltName: Full=Stefin-B;
GN Name=CSTB; Synonyms=CST6, STFB;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP PROTEIN SEQUENCE.
RX PubMed=3902020; DOI=10.1016/0006-291X(85)90216-5;
RA Ritonja A., Machleidt W., Barrett A.J.;
RT "Amino acid sequence of the intracellular cysteine proteinase
RT inhibitor cystatin B from human liver.";
RL Biochem. Biophys. Res. Commun. 131:1187-1192(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=8596935; DOI=10.1126/science.271.5256.1731;
RA Pennacchio L.A., Lehesjoki A.-E., Stone N.E., Willour V.L.,
RA Virteneva K., Miao J., D'Amato E., Ramirez L., Faham J.,
RA Koskiniemi M., Warringtion J.A., Norio R., la Chapelle A., Cox D.R.,
RA Myers R.M.;
RT "Mutations in the gene encoding cystatin B in progressive myoclonus
RT epilepsy (EPM1).";
RL Science 271:1731-1734(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Bhat K.S.;
RL Submitted (MAY-1993) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10830953; DOI=10.1038/35012518;
RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T.,
RA Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y.,
RA Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K.,
RA Polley A., Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D.,
RA Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W.,
RA Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S.,
RA Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E.,
RA Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P.,
RA Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H.,
RA Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E.,
RA Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F.,
RA Lehrach H., Reinhardt R., Yaspo M.-L.;
RT "The DNA sequence of human chromosome 21.";
RL Nature 405:311-319(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP SUBCELLULAR LOCATION.
RX PubMed=11139332; DOI=10.1006/excr.2000.5085;
RA Riccio M., Di Giaimo R., Pianetti S., Palmieri P.P., Melli M.,
RA Santi S.;
RT "Nuclear localization of cystatin B, the cathepsin inhibitor
RT implicated in myoclonus epilepsy (EPM1).";
RL Exp. Cell Res. 262:84-94(2001).
RN [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS).
RX PubMed=2347312;
RA Stubbs M.T., Laber B., Bode W., Huber R., Jerala R., Lenarcic B.,
RA Turk V.;
RT "The refined 2.4 A X-ray crystal structure of recombinant human stefin
RT B in complex with the cysteine proteinase papain: a novel type of
RT proteinase inhibitor interaction.";
RL EMBO J. 9:1939-1947(1990).
RN [10]
RP VARIANT EPM1 ARG-4.
RX PubMed=9012407;
RA Lalioti M.D., Mirotsou M., Buresi C., Peitsch M.C., Rossier C.,
RA Ouazzani R., Baldy-Moulinier M., Bottani A., Malafosse A.,
RA Antonarakis S.E.;
RT "Identification of mutations in cystatin B, the gene responsible for
RT the Unverricht-Lundborg type of progressive myoclonus epilepsy
RT (EPM1).";
RL Am. J. Hum. Genet. 60:342-351(1997).
CC -!- FUNCTION: This is an intracellular thiol proteinase inhibitor.
CC Tightly binding reversible inhibitor of cathepsins L, H and B.
CC -!- SUBUNIT: Able to form dimers stabilized by noncovalent forces.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus.
CC -!- DISEASE: Epilepsy, progressive myoclonic 1 (EPM1) [MIM:254800]: An
CC autosomal recessive disorder characterized by severe, stimulus-
CC sensitive myoclonus and tonic-clonic seizures. The onset,
CC occurring between 6 and 13 years of age, is characterized by
CC convulsions. Myoclonus begins 1 to 5 years later. The twitchings
CC occur predominantly in the proximal muscles of the extremities and
CC are bilaterally symmetrical, although asynchronous. At first
CC small, they become late in the clinical course so violent that the
CC victim is thrown to the floor. Mental deterioration and eventually
CC dementia develop. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the cystatin family.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/CSTBID40181ch21q22.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CSTB";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; U46692; AAA99014.1; -; Genomic_DNA.
DR EMBL; L03558; AAA35727.1; -; mRNA.
DR EMBL; AF208234; AAF44059.1; -; Genomic_DNA.
DR EMBL; AP001752; BAA95541.1; -; Genomic_DNA.
DR EMBL; BC003370; AAH03370.1; -; mRNA.
DR EMBL; BC010532; AAH10532.1; -; mRNA.
DR PIR; A01278; UDHUB.
DR RefSeq; NP_000091.1; NM_000100.3.
DR UniGene; Hs.695; -.
DR PDB; 1STF; X-ray; 2.37 A; I=1-98.
DR PDB; 2OCT; X-ray; 1.40 A; A/B=1-98.
DR PDBsum; 1STF; -.
DR PDBsum; 2OCT; -.
DR ProteinModelPortal; P04080; -.
DR SMR; P04080; 1-98.
DR IntAct; P04080; 7.
DR MINT; MINT-1504629; -.
DR STRING; 9606.ENSP00000291568; -.
DR MEROPS; I25.003; -.
DR TCDB; 1.C.91.1.1; the stefin b pore-forming protein (stefin b) family.
DR PhosphoSite; P04080; -.
DR DMDM; 1706278; -.
DR PaxDb; P04080; -.
DR PeptideAtlas; P04080; -.
DR PRIDE; P04080; -.
DR DNASU; 1476; -.
DR Ensembl; ENST00000291568; ENSP00000291568; ENSG00000160213.
DR GeneID; 1476; -.
DR KEGG; hsa:1476; -.
DR UCSC; uc002zdr.4; human.
DR CTD; 1476; -.
DR GeneCards; GC21M045192; -.
DR HGNC; HGNC:2482; CSTB.
DR HPA; CAB047320; -.
DR HPA; HPA017380; -.
DR MIM; 254800; phenotype.
DR MIM; 601145; gene.
DR neXtProt; NX_P04080; -.
DR Orphanet; 308; Unverricht-Lundborg disease.
DR PharmGKB; PA26984; -.
DR eggNOG; NOG29074; -.
DR HOGENOM; HOG000294175; -.
DR HOVERGEN; HBG002292; -.
DR InParanoid; P04080; -.
DR KO; K13907; -.
DR OMA; PHENKPP; -.
DR OrthoDB; EOG7FR7JX; -.
DR PhylomeDB; P04080; -.
DR ChiTaRS; CSTB; human.
DR EvolutionaryTrace; P04080; -.
DR GeneWiki; Cystatin_B; -.
DR GenomeRNAi; 1476; -.
DR NextBio; 6061; -.
DR PRO; PR:P04080; -.
DR ArrayExpress; P04080; -.
DR Bgee; P04080; -.
DR CleanEx; HS_CST6; -.
DR CleanEx; HS_CSTB; -.
DR Genevestigator; P04080; -.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005730; C:nucleolus; IDA:HPA.
DR GO; GO:0004869; F:cysteine-type endopeptidase inhibitor activity; IDA:BHF-UCL.
DR GO; GO:0008344; P:adult locomotory behavior; IEA:Ensembl.
DR GO; GO:0042981; P:regulation of apoptotic process; IEA:Ensembl.
DR InterPro; IPR000010; Prot_inh_cystat.
DR InterPro; IPR018073; Prot_inh_cystat_CS.
DR InterPro; IPR001713; Prot_inh_stefinA.
DR Pfam; PF00031; Cystatin; 1.
DR PRINTS; PR00295; STEFINA.
DR SMART; SM00043; CY; 1.
DR PROSITE; PS00287; CYSTATIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disease mutation; Epilepsy; Nucleus;
KW Protease inhibitor; Reference proteome; Thiol protease inhibitor.
FT CHAIN 1 98 Cystatin-B.
FT /FTId=PRO_0000207136.
FT MOTIF 46 50 Secondary area of contact.
FT SITE 4 4 Reactive site.
FT MOD_RES 1 1 N-acetylmethionine.
FT VARIANT 4 4 G -> R (in EPM1).
FT /FTId=VAR_002206.
FT CONFLICT 31 31 E -> Y (in Ref. 1; AA sequence).
FT HELIX 14 31
FT STRAND 39 58
FT STRAND 60 62
FT STRAND 64 74
FT STRAND 80 89
SQ SEQUENCE 98 AA; 11140 MW; B8076220E19D0483 CRC64;
MMCGAPSATQ PATAETQHIA DQVRSQLEEK ENKKFPVFKA VSFKSQVVAG TNYFIKVHVG
DEDFVHLRVF QSLPHENKPL TLSNYQTNKA KHDELTYF
//
MIM
254800
*RECORD*
*FIELD* NO
254800
*FIELD* TI
#254800 MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
;;ULD;;
EPILEPSY, PROGRESSIVE MYOCLONIC 1; EPM1;;
read morePROGRESSIVE MYOCLONIC EPILEPSY; PME;;
BALTIC MYOCLONIC EPILEPSY;;
EPILEPSY, PROGRESSIVE MYOCLONIC 1A; EPM1A
*FIELD* TX
A number sign (#) is used with this entry because myoclonic epilepsy of
Unverricht and Lundborg (ULD, or EPM1) is caused by mutation in the
cystatin B gene (CSTB; 601145) on chromosome 21q22.
DESCRIPTION
Myoclonic epilepsy of Unverricht and Lundborg is an autosomal recessive
disorder characterized by onset of neurodegeneration between 6 and 13
years of age. Although it is considered a progressive myoclonic
epilepsy, it differs from other forms in that is appears to be
progressive only in adolescence, with dramatic worsening of myoclonus
and ataxia in the first 6 years after onset. The disease stabilizes in
early adulthood, and myoclonus and ataxia may even improve, and there is
minimal to no cognitive decline (summary by Ramachandran et al., 2009).
- Genetic Heterogeneity of Progressive Myoclonic Epilepsy
Progressive myoclonic epilepsy refers to a clinically and genetically
heterogeneous group of neurodegenerative disorders, usually with
debilitating symptoms, although severity varies. See also EPM1B
(612437), caused by mutation in the PRICKLE1 gene (608500); Lafora
disease (EPM2A/B; 254780), caused by mutation in either the EPM2A
(607566) or the NHLRC1 (608072) gene; EPM3 (611726), caused by mutation
in the KCTD7 gene (611725); EPM4 (254900), caused by mutation in the
SCARB2 gene (602257); EPM5 (613832), caused by mutation in the PRICKLE2
gene (608501); and EPM6 (614018), caused by mutation in the GOSR2 gene
(604027).
Other disorders characterized by progressive myoclonic epilepsy include
the neuronal ceroid lipofuscinoses (see, e.g., CLN1; 256730); sialidosis
(256550); MERFF (545000); and DRPLA (125370), among others (reviews by
Ramachandran et al., 2009 and Mendonca de Siqueira, 2010).
CLINICAL FEATURES
Unverricht (1891, 1895) and Lundborg (1903) first reported a type of
progressive myoclonic epilepsy common in Finland. Onset of the disorder
occurred around age 10 years, and was characterized by progressive
myoclonus resulting in incapacitation, but only mild mental
deterioration. Histological studies of the brain showed 'degenerative'
changes without inclusion bodies. Severity and survival were variable
(Norio and Koskiniemi, 1979).
Eldridge et al. (1981, 1983) referred to this disorder as the 'Baltic
type' of myoclonic epilepsy because the descriptions first by Unverricht
and then by Lundborg were in families from Estonia and Eastern Sweden
and subsequent patients were found in Finland. Eldridge et al. (1983)
found 15 families in the United States. The 27 affected members had the
following features starting at about age 10 years: stimulus- and
photo-sensitive and occasionally violent myoclonus, usually worse upon
waking; generalized tonic-clonic seizures, sometimes associated with
absence attacks; and light-sensitive, generally synchronous,
spike-and-wave discharges on EEG that preceded clinical manifestations.
Necropsy showed marked loss of Purkinje cells of the cerebellum, but no
inclusion bodies. Phenytoin was associated with progressive motor and
intellectual deterioration, marked ataxia, and even death. Treatment
with valproic acid was associated with marked improvement. Contrary to
myoclonic epilepsy with Lafora bodies, intelligence in this form was
only slightly affected and psychotic symptoms were not found. In
addition, Lafora body disease is invariably fatal.
Kyllerman et al. (1991) described 4 sibs who demonstrated a subclinical
stage of this disorder at the age of 9 to 11 years, with visual
blackouts and polyspike electroencephalographic (EEG) activity on photic
stimulation; an early myoclonic stage at the age of 12 to 15 years, with
increasing segmental, stimulus-sensitive myoclonus, occasional nocturnal
buildup myoclonic 'cascade' seizures, slowing of EEG alpha-activity,
episodic 4-6 Hz bilateral sharp waves and polyspikes with myoclonus on
photic stimulation; and a disabling myoclonic stage at the age of 16 to
18 years, with periodic generalized myoclonus, nocturnal myoclonic
'cascade' seizures, ataxia, dysarthria, mental changes, intermittent
wheelchair dependency, and continuous EEG slow waves with polyspikes and
intense myoclonus on photic stimulation. One of the sibs died at the age
of 18 years with no apparent cause of death.
As pointed out by the Marseille Consensus Group (1990), patients with
Ramsay Hunt syndrome (159700) cannot be distinguished clinically from
patients with Unverricht-Lundborg disease. Linkage studies may help
determine whether that disorder is caused by mutation at the same locus.
Cochius et al. (1994) reported for the first time a pathologic
abnormality outside the central nervous system in patients with
Unverricht-Lundborg disease. They found membrane-bound vacuoles with
clear contents in eccrine clear cells and dark cells in 5 of 7 patients,
as well as in 1 clinically unaffected sib. Sweat gland vacuoles were not
seen in the biopsies of 8 patients with Lafora disease.
Photosensitivity, i.e., precipitation of myoclonic jerks by intermittent
photic stimulation, is a characteristic feature of progressive myoclonic
epilepsies. Mazarib et al. (2001) described an affected Arab family in
which photosensitivity was absent.
Mascalchi et al. (2002) performed MRI and proton MRS on 10 patients with
genetically confirmed EPM1 and found significant loss of bulk of the
basis pontis, medulla, and cerebellar hemispheres as well as mild
cerebral atrophy, compared to 20 healthy controls. The findings differed
in some critical features from those in olivopontocerebellar atrophy.
Mascalchi et al. (2002) concluded that their findings support the
hypothesis that the disease results from a decreased inhibitory control
of the cerebral cortex by the brainstem and cerebellum via the
thalamocortical loop.
Canafoglia et al. (2004) found different electrophysiologic profiles
representing sensorimotor cortex hyperexcitability in 8 patients with
Lafora disease (age range, 14 to 27 years) and 10 patients with
Unverricht-Lundborg disease (age range, 25 to 62 years). In general, the
ULD patients had a quasistationary disease course, rare seizures, and
little or no mental impairment, whereas the Lafora disease patients had
recurrent seizures and worsening mental status. Patients with ULD had
prominent action myoclonus clearly triggered by voluntary movements.
Lafora disease patients experienced spontaneous myoclonic jerks
associated with clear EEG paroxysms with only minor action myoclonus.
Although both groups had enlarged or giant somatosensory evoked
potentials, the pattern in the Lafora group was consistent with a
distortion of cortical circuitry. Patients with ULD had enhanced
long-loop reflexes with extremely brief cortical relay times. The
findings were consistent with an aberrant subcortical or cortical loop,
possibly short-cutting the somatosensory cortex, that may be involved in
generating the prominent action myoclonus that characterizes ULD.
Patients with Lafora disease had varied cortical relay times and delayed
and prolonged facilitation as evidenced by sustained hyperexcitability
of the sensorimotor cortex in response to afferent stimuli. The findings
were consistent with an impairment of inhibitory mechanisms in Lafora
disease.
INHERITANCE
Noad and Lance (1960) described myoclonic epilepsy with cerebellar
ataxia in several offspring of a mating of first cousins once removed,
indicating autosomal recessive inheritance.
CLINICAL MANAGEMENT
Pennacchio et al. (1996) stated that, even in chronic and severe cases,
patients with EPM1 show marked improvement when treated with the
antiepileptic drug sodium valproate; however, phenytoin, another drug
that is effective against some other forms of epilepsy, does not improve
the condition of EPM1 patients, often shows toxic effects, and, in some
cases, is fatal. They stated that the identification of mutant genes
encoding cystatin B in patients with EPM1 may help understanding of the
differential response to these 2 drugs. Furthermore, this knowledge
provides a biochemical pathway and molecular target for the treatment of
EPM1 and perhaps other forms of epilepsy. Selwa (1999) reported
significant improvement in seizures, tremors, speech and ambulation in a
40-year-old patient with Unverricht-Lundborg disease who was given
N-acetylcysteine as well as other vitamin preparations containing
antioxidants. The patient relapsed when medication was discontinued, but
improvement was sustained during a 10-month follow-up after resumption
of treatment. Improvement had previously been reported in 4 similarly
treated sibs (Hurd et al., 1996).
Edwards et al. (2002) found low glutathione levels in a patient with
Unverricht-Lundborg disease proven by DNA studies. Glutathione levels
increased during treatment with N-acetylcysteine (NAC). This increase
was mirrored by an improvement in seizures, but not in myoclonus or
ataxia. Three other patients with clinically determined
Unverricht-Lundborg disease showed a variable response and some notable
side effects during treatment with NAC, including sensorineural
deafness.
Kinrions et al. (2003) reported that levetiracetam, a piracetam analog,
markedly improved myoclonus and quality of life in a 38-year-old woman
with genetically confirmed Unverricht-Lundborg disease. Her illness
began at age 13 and had progressed to leave her wheelchair-bound,
dysarthric, and with multifocal myoclonus. Treatment with multiple
medications had been unsuccessful. The authors cited previous reports of
the effectiveness of levetiracetam in symptomatic myoclonus of various
etiologies.
MAPPING
Lehesjoki et al. (1991) demonstrated close linkage between the EPM1
locus and 3 markers on distal chromosome 21. The loci BCEI (113710) and
D21S154 gave the highest positive lod scores of 5.49 and 4.25,
respectively, at zero recombination. The third locus, D21S112, gave a
lod score of 6.91 at a recombination fraction of 0.034. No evidence of
heterogeneity was found in the 12 families studied. Multipoint lod
scores calculated against a fixed map of the 3 marker loci gave a
maximum 4-point lod score of 10.08 at a location of the disease gene at
6.0 cM distal to locus BCEI and 0.8 cM proximal to D21S154. Both of
these markers had previously been localized to 21q22.3. Lehesjoki et al.
(1992) refined the localization of EPM1 by linkage analysis between the
disease phenotype and 9 DNA markers in 13 Finnish families. A maximum
multipoint lod score of 11.04 was reached at loci D21S154/PFKL (171860),
which had previously been mapped to 21q22.3. Lehesjoki et al. (1993)
narrowed the assignment of EPM1 to an interval of approximately 7 cM,
between loci D21S212 and CD18, by analyzing crossover events in
multiplex families. They refined the localization further by applying
linkage disequilibrium mapping in 38 Finnish families, consisting of 12
with multiple affected children and 26 with a single affected child. In
this way, they were able to conclude that EPM1 resides within 0.3 cM of
PFKL, D21S25, and D21S154. This represents a likely physical distance of
300 kb or less. In a family reported by Eldridge et al. (1983), of mixed
Italian and Irish ancestry, living in the United States, Lehesjoki et
al. (1993) again found linkage to markers in the distal part of
chromosome 21. Crossover events in the family helped refine the gene
localization by placing EPM1 between CBS (613381) and D21S112.
Uncertainty has existed about the relationship between
Unverricht-Lundborg disease, also referred to as Baltic myoclonus, and
Mediterranean myoclonus, formerly considered to be a subgroup of the
Ramsay Hunt syndrome. Lehesjoki et al. (1994) studied 7 phenotypically
homogeneous Mediterranean myoclonus families, using DNA markers from the
genetically defined EPM1 region on chromosome 21. No recombination
between the disease phenotype and the markers studied was detected.
Within the EPM1 region, the highest lod score was 5.07 (at theta = 0.00)
for PFKL. Significant allelic association between the disease mutation
and PFKL was detected, suggesting a founder effect in Mediterranean
myoclonus. However, haplotype data from 4 marker loci residing within
300 kb of each other and of EPM1 suggested the occurrence of more than 1
mutation.
Using linkage disequilibrium and recombination breakpoint mapping with
Finnish EPM1 patients, Pennacchio et al. (1996) refined the location of
the EPM1 gene to a region between markers D21S2040 and D21S1259. This
region was entirely encompassed in a 750-kb bacterial clone contig
generated by sequence tagged site content mapping and walking. A
detailed restriction map of the contig determined that the distance
between the DNA markers defining the boundaries of EPM1 was about 175
kb.
HETEROGENEITY
Carr et al. (2007) reported 2 large families from the Western Cape
province of South Africa with generalized tonic-clonic seizures and
myoclonus. The mean age at onset was 20 years (range 13 to 31).
Myoclonus predominantly affected the trunk and upper limbs but was also
observed in the lower limbs. Hand tremor became apparent on posture
holding. Additional features included nystagmus, abnormal pursuit,
dysarthria, hyperreflexia, cerebellar ataxia, and cerebellar atrophy. A
number of patients also had progressive cognitive impairment, resulting
in dementia in some. EEG studies were abnormal in the majority of
patients, with polyspike and wave activity and/or clear epileptogenic
activity. Postmortem examination of 1 patient showed cerebellar atrophy
and cerebellar neuronal loss. Several patients died in their thirties
and forties. The families were of mixed ancestry, predominantly
resulting from intermarriage between the original inhabitants of the
area, the Khoi-San, and early settlers of European origin. Carr et al.
(2007) noted that the phenotype was more severe and showed earlier onset
than typical familial adult myoclonic epilepsy (FAME1; 601068). The
phenotype was also progressive, falling within the spectrum of
progressive myoclonic epilepsies. Linkage analysis excluded FAME1 and
FAME2 (607876). Striano et al. (2008) commented that the phenotype
described by Carr et al. (2007) was more severe than typically seen for
FAME, and suggested that the disorder described by Carr et al. (2007) as
'FAME3,' should be placed within the group of progressive myoclonic
epilepsies. Striano et al. (2008) suggested that the designation FAME be
reserved for familial nonprogressive cortical tremor and epilepsy. In a
large French family with FAME, a locus designated FAME3 (613608) was
mapped to chromosome 5p15 by Depienne et al. (2010).
MOLECULAR GENETICS
Pennacchio et al. (1996) used a combination of genetic and physical
mapping information to search systematically for the causative gene for
EPM1. Several cDNAs identified with a bacterial artificial chromosome
(BAC) clone encoded a previously described protein, cystatin B (601145),
a cysteine protease inhibitor. Because of the wide expression of the
cystatin B gene in normal individuals and the finding of reduced
expression in lymphoblastoid cells from affected individuals, Pennacchio
et al. (1996) sequenced the cystatin B gene (also known as stefin B)
from affected individuals and identified 2 different mutations in the
gene. Cystatin C (CST3; 604312) is the site of heterozygous mutations
causing hereditary cerebral amyloid angiopathy. This dominantly
inherited disorder is characterized by the deposition of cystatin C-rich
amyloid fibrils in affected brain arteries. EPM1 is inherited as a
recessive and appears to be the result of decreased amounts of cystatin
B, suggesting different mechanisms for the 2 diseases. The genes
responsible for Lafora disease (254780) (EPM2A; 607566) and juvenile
myoclonic epilepsy (254770) mapped to 6q and 6p, respectively. The
identification of cystatin B defects in EPM1 suggested that other
members of the cystatin superfamily or their substrates may be defective
in these related epilepsies. See 601145 for point mutations identified
in the stefin B gene in patients with EPM1.
Lafreniere et al. (1997) and Virtaneva et al. (1997) reported a novel
type of disease-causing mutation, an unstable minisatellite repeat
expansion in the putative promoter region of the gene (601145.0003). The
mutation accounted for most EPM1 patients worldwide. Virtaneva et al.
(1997) noted that haplotype data from their study were compatible with a
single ancestral founder mutation. The length of the repeat array
differed between chromosomes and families, but changes in repeat number
seemed to be comparatively rare events.
Lalioti et al. (1997) identified 6 nucleotide changes in the CSTB gene
in non-Finnish EPM1 families from northern Africa and Europe. One of
these, a homozygous G-to-C transversion at nucleotide 426 in exon 1,
resulted in a gly4-to-arg substitution (G4R; 601145.0004) and was the
first missense mutation described in association with EPM1. Molecular
modeling predicted that this substitution would severely affect the
contact of cystatin B with papain. The 6 mutations were found in 7 of
the 29 unrelated EPM1 patients analyzed, in homozygosity in 1, and in
heterozygosity in the others. They also found a tandem repeat of a
dodecamer (CCCCGCCCCGCG) in the 5-prime untranslated region as a
polymorphism (601145.0003). They identified 2 allelic variants with 2 or
3 tandem copies. The frequency of the 3-copy allele was 66% in the
normal Caucasian population.
In an elaboration on their previous work, Lalioti et al. (1997) stated
that the common mutation mechanism in EPM1 is the expansion of the
dodecamer repeat (601145.0003), and considered this mutation to be the
most likely source of the disorder. An examination of 58 EPM1 alleles
revealed that 50 of these contained the dodecamer repeat expansion. In
addition to the expanded repeat mutation and the 2 or 3 repeats found in
alleles considered to be normal, Lalioti et al. (1997) identified
alleles with 12 to 17 repeats, which they termed 'premutational,' that
were transmitted unstably to offspring. These 'premutational' alleles
were not connected with a clinical phenotype of EPM1. Lalioti et al.
(1997) stated that no correlation between number of repeat expansions
and age of onset or severity had been found.
Antonarakis (1997) confirmed that the only EPM1-related point mutation
in the cystatin B gene found in homozygous state was the G4R amino acid
substitution. All other point mutations identified in EPM1 patients were
found as compound heterozygotes with the 12-bp repeat expansion allele.
The repeat expansion allele was also homozygous in some patients.
Antonarakis (1997) found no patients with null point mutations (e.g.,
nonsense, frameshift, or splice site) in homozygous state; all EPM1
patients had residual gene activity. He proposed that homozygosity for
null alleles was either nonviable or presented a different phenotype.
POPULATION GENETICS
Koskiniemi et al. (1980) estimated that over 100 cases in 70 sibships
had been identified in Finland. Fewer cases had been found in all the
rest of the world. The incidence in Finland is about 1 in 20,000.
Moulard et al. (2002) stated that Unverricht-Lundborg disease is also
common North Africa but less common in western Europe. They performed a
haplotype study of Unverricht-Lundborg disease chromosomes with a
dodecamer repeat expansion in the CSTB gene (601145.0003), the most
frequent cause of the disorder. They found that 29 (61.7%) of 47
patients from North Africa shared the same haplotype, thus establishing
a founder effect in this population. The haplotypes from 48 Caucasian
patients from western Europe were heterogeneous.
HISTORY
Stevenson pointed out, in a discussion of genetic aspects of the study
by Harriman and Millar (1955), that Lundborg's study is 'of considerable
historic interest in human genetics.' Lundborg's data were used to test
statistically the recessive hypothesis, the first such analysis in man.
The statistical analysis was done first by Weinberg (1912) and later by
Bernstein (1929).
Lundborg's report was one of the earliest of recessive inheritance. He
published the names of those affected. When Book (1978) later attempted
a follow-up, he found that marriage of relatives had been carefully
avoided in the group and no more cases had occurred. Book (1978)
suggested that this was one of the earliest and largest instances of
group genetic counseling.
ANIMAL MODEL
A possibly homologous disorder in Poll Hereford cattle was shown by
Gundlach et al. (1988) to have a defect in glycine/strychnine receptors.
The symptoms of the disorder suggested a failure of spinal interneuron
inhibition and are similar to those in subconvulsive strychnine
poisoning. Strychnine blocks the synaptic action of the inhibitory amino
acid transmitter glycine by interacting with the postsynaptic glycine
receptor. The mouse mutant 'spastic' may have a similar defect. The gene
for the 'spastic' mutant maps to mouse chromosome 3 (Eicher and Lane,
1980). Grenningloh et al. (1990) indicated that it is the alpha-1 form
of the glycine receptor (138491) that is coded by an autosome, whereas
the alpha-2 receptor (305990) is X-linked.
The features of EPM1 were reproduced by targeted disruption of the
cystatin B gene in mice (Pennacchio et al., 1998).
Lieuallen et al. (2001) identified 7 genes with consistently increased
transcript levels in neurologic tissues from Cstb-deficient knockout
mice: cathepsin S (116845), C1q B-chain of complement (120570),
beta-2-microglobulin (109700), glial fibrillary acidic protein (137780),
apolipoprotein D (107740), fibronectin-1 (135600), and metallothionein
II (156360). These proteins are expected to be involved in increased
proteolysis, apoptosis, and glial activation. The molecular changes in
Cstb-deficient mice were consistent with the pathology found in the
mouse model.
*FIELD* SA
Ford et al. (1951); Kraus-Ruppert et al. (1970); Lundborg (1912);
Lundborg (1913); Morse (1949); Vogel et al. (1965)
*FIELD* RF
1. Antonarakis, S.: Personal Communication. Geneva, Switzerland
4/8/1997.
2. Bernstein, F.: Variations-und Erblichkeitsstatistik. Berlin
(pub.) 1929.
3. Book, J. A.: Personal Communication. Uppsala, Sweden 1978.
4. Canafoglia, L.; Ciano, C.; Panzica, F.; Scaioli, V.; Zucca, C.;
Agazzi, P.; Visani, E.; Avanzini, G.; Franceschetti, S.: Sensorimotor
cortex excitability in Unverricht-Lundborg disease and Lafora body
disease. Neurology 63: 2309-2315, 2004.
5. Carr, J. A.; van der Walt, P. E.; Nakayama, J.; Fu, Y.-H.; Corfield,
V.; Brink, P.; Ptacek, L.: FAME3: a novel form of progressive myoclonus
and epilepsy. Neurology 68: 1382-1389, 2007.
6. Cochius, J.; Carpenter, S.; Andermann, E.; Rouleau, G.; Nousiainen,
U.; Kalviainen, R.; Farrell, K.; Andermann, F.: Sweat gland vacuoles
in Unverricht-Lundborg disease: a clue to diagnosis? Neurology 44:
2372-2375, 1994.
7. Depienne, C.; Magnin, E.; Bouteiller, D.; Stevanin, G.; Saint-Martin,
C.; Vidailhet, M.; Apartis, E.; Hirsch, E.; LeGuern, E.; Labauge,
P.; Rumbach, L.: Familial cortical myoclonic tremor with epilepsy:
the third locus (FCMTE3) maps to 5p. Neurology 74: 2000-2003, 2010.
8. Edwards, M. J. J.; Hargreaves, I. P.; Heales, S. J. R.; Jones,
S. J.; Ramachandran, V.; Bhatia, K. P.; Sisodiya, S.: N-acetylcysteine
and Unverricht-Lundborg disease. Neurology 59: 1447-1449, 2002.
9. Eicher, E. M.; Lane, P. W.: Assignment of LH XVI to chromosome
3 in the mouse. J. Hered. 71: 315-318, 1980.
10. Eldridge, R.; Iivanainen, M.; Stern, R.; Koerber, T.; Wilder,
B. J.: 'Baltic' myoclonus epilepsy: a treatable hereditary disorder
of childhood. (Abstract) Sixth Int. Cong. Hum. Genet., Jerusalem 256,
1981.
11. Eldridge, R.; Iivanainen, M.; Stern, R.; Koerber, T.; Wilder,
B. J.: 'Baltic' myoclonus epilepsy: hereditary disorder of childhood
made worse by phenytoin. Lancet 322: 838-842, 1983. Note: Originally
Volume II.
12. Ford, F. R.; Livingston, S.; Pryles, C. V.: Familial degeneration
of cerebral gray matter in childhood, with convulsions, myoclonus,
spasticity, cerebellar ataxia, choreoathetosis, dementia, and death
in status epilepticus: differentiation of infantile and juvenile types. J.
Pediat. 39: 33-43, 1951.
13. Grenningloh, G.; Schmieden, V.; Schofield, P. R.; Seeburg, P.
H.; Siddique, T.; Mohandas, T. K.; Becker, C.-M.; Betz, H.: Alpha
subunit variants of the human glycine receptor: primary structures,
functional expression and chromosomal localization of the corresponding
genes. EMBO J. 9: 771-776, 1990.
14. Gundlach, A. L.; Dodd, P. R.; Grabara, C. S. G.; Watson, W. E.
J.; Johnston, G. A. R.; Harper, P. A. W.; Dennis, J. A.; Healy, P.
J.: Deficit of spinal cord glycine/strychnine receptors in inherited
myoclonus of Poll Hereford calves. Science 241: 1807-1810, 1988.
15. Harriman, D. G. F.; Millar, J. H. D.: Progressive familial myoclonic
epilepsy in 3 families: its clinical features and pathological basis. Brain 78:
325-349, 1955.
16. Hurd, R. W.; Wilder, B. J.; Helveston, W. R.; Uthman, B. M.:
Treatment of four siblings with progressive myoclonus epilepsy of
the Unverricht-Lundborg type with N-acetylcysteine. Neurology 47:
1264-1268, 1996.
17. Kinrions, P.; Ibrahim, N.; Murphy, K.; Lehesjoki, A.-E.; Jarvela,
I.; Delanty, N.: Efficacy of levetiracetam in a patient with Unverricht-Lundborg
progressive myoclonic epilepsy. Neurology 60: 1394-1395, 2003.
18. Koskiniemi, M.; Donner, M.; Toivakka, E.; Norio, R.: Progressive
myoclonus epilepsy (PME).In: Eriksson, A. W.; Forsius, H. R.; Nevanlinna,
H. R.; Workman, P. L.; Norio, R. K.: Population Structure and Genetic
Disorders. New York: Academic Press (pub.) 1980. Pp. 669-672.
19. Kraus-Ruppert, R.; Ostertag, B.; Hafner, H.: A study of the late
form (type Lundborg) of progressive myoclonic epilepsy. J. Neurol.
Sci. 11: 1-15, 1970.
20. Kyllerman, M.; Sommerfelt, K.; Hedstrom, A.; Wennergren, G.; Holmgren,
D.: Clinical and neurophysiological development of Unverricht-Lundborg
disease in four Swedish siblings. Epilepsia 32: 900-909, 1991.
21. Lafreniere, R. G.; Rochefort, D. L.; Chretien, N.; Rommens, J.
M.; Cochius, J. I.; Kalviainen, R.; Nousiainen, U.; Patry, G.; Farrell,
K.; Soderfeldt, B.; Federico, A.; Hale, B. R.; Cossio, O. H.; Sorensen,
T.; Pouliot, M. A.; Kmiec, T.; Uldall, P.; Janszky, J.; Pranzatelli,
M. R.; Andermann, F.; Andermann, E.; Rouleau, G. A.: Unstable insertion
of the 5-prime flanking region of the cystatin B gene is the most
common mutation in progressive myoclonus epilepsy type 1, EPM1. Nature
Genet. 15: 298-302, 1997.
22. Lalioti, M. D.; Mirotsou, M.; Buresi, C.; Peitsch, M. C.; Rossier,
C.; Ouazzani, R.; Baldy-Moulinier, M.; Bottani, A.; Malafosse, A.;
Antonarakis, S. E.: Identification of mutations in cystatin B, the
gene responsible for the Unverricht-Lundborg type of progressive myoclonus
epilepsy (EPM1). Am. J. Hum. Genet. 60: 342-351, 1997.
23. Lalioti, M. D.; Scott, H. S.; Buresi, C.; Rossier, C.; Bottani,
A.; Morris, M. A.; Malafosse, A.; Antonarakis, S. E.: Dodecamer repeat
expansion in cystatin B gene in progressive myoclonus epilepsy. Nature 386:
847-851, 1997.
24. Lehesjoki, A.-E.; Eldridge, R.; Eldridge, J.; Wilder, B. J.; de
la Chapelle, A.: Progressive myoclonus epilepsy of Unverricht-Lundborg
type: a clinical and molecular genetic study of a family from the
United States with four affected sibs. Neurology 43: 2384-2386,
1993.
25. Lehesjoki, A.-E.; Koskiniemi, M.; Norio, R.; Tirrito, S.; Sistonen,
P.; Lander, E.; de la Chapelle, A.: Localization of the EPM1 gene
for progressive myoclonus epilepsy on chromosome 21: linkage disequilibrium
allows high resolution mapping. Hum. Molec. Genet. 2: 1229-1234,
1993.
26. Lehesjoki, A.-E.; Koskiniemi, M.; Pandolfo, M.; Antonelli, A.;
Kyllerman, M.; Wahlstrom, J.; Nergardh, A.; Burmeister, M.; Sistonen,
P.; Norio, R.; de la Chapelle, A.: Linkage studies in progressive
myoclonus epilepsy: Unverricht-Lundborg and Lafora's diseases. Neurology 42:
1545-1550, 1992.
27. Lehesjoki, A.-E.; Koskiniemi, M.; Sistonen, P.; Miao, J.; Hastbacka,
J.; Norio, R.; de la Chapelle, A.: Localization of a gene for progressive
myoclonus epilepsy to chromosome 21q22. Proc. Nat. Acad. Sci. 88:
3696-3699, 1991.
28. Lehesjoki, A.-E.; Tassinari, C. A.; Avanzini, G.; Michelucci,
R.; Franceschetti, S.; Antonelli, A.; Rubboli, G.; de la Chapelle,
A.: PME of Unverricht-Lundborg type in the Mediterranean region:
linkage and linkage disequilibrium confirm the assignment to the EPM1
locus. Hum. Genet. 93: 668-674, 1994.
29. Lieuallen, K.; Pennacchio, L. A.; Park, M.; Myers, R. M.; Lennon,
G. G.: Cystatin B-deficient mice have increased expression of apoptosis
and glial activation genes. Hum. Molec. Genet. 10: 1867-1871, 2001.
30. Lundborg, H. B.: Die progressive Myoklonusepilepsie (Unverricht's
Myoklonie). Uppsala: Almqvist and Wiksell (pub.) 8: 1903. Pp.
567-570.
31. Lundborg, H. B.: Der Erbgang der progressiven Myoklonusepilepsie.
(Myoklonie-Epilepsie, Unverricht's familiaere Myoklonie). Z. Ges.
Neurol. Psychiat. 9: 353-358, 1912.
32. Lundborg, H. B.: Medizinisch-biologische Familienforschungen
innerhalb eines 2232 koepfigen Bauerngeschlechtes in Schweden. Jena:
Fischer (pub.) 1913.
33. Marseille Consensus Group: Classification of progressive myoclonus
epilepsies and related disorders. Ann. Neurol. 28: 113-116, 1990.
34. Mascalchi, M.; Michelucci, R.; Cosottini, M.; Tessa, C.; Lolli,
F.; Riguzzi, P.; Lehesjoki, A. E.; Tosetti, M.; Villari, N.; Tassinari,
C. A.: Brainstem involvement in Unverricht-Lundborg disease (EPM1):
an MRI and 1-H MRS study. Neurology 58: 1686-1689, 2002.
35. Mazarib, A.; Xiong, L.; Neufeld, M. Y.; Birnbaum, M.; Korczyn,
A. D.; Pandolfo, M.; Berkovic, S. F.: Unverricht-Lundborg disease
in a five-generation Arab family: instability of dodecamer repeats. Neurology 57:
1050-1054, 2001.
36. Mendonca de Siqueira, L. F.: Progressive myoclonic epilepsies:
review of clinical, molecular and therapeutic aspects. J. Neurol. 257:
1612-1619, 2010.
37. Morse, W. I.: Hereditary myoclonus epilepsy: two cases with pathological
findings. Bull. Johns Hopkins Hosp. 84: 116-134, 1949.
38. Moulard, B.; Genton, P.; Grid, D.; Jeanpierre, M.; Ouazzani, R.;
Mrabet, A.; Morris, M.; LeGuern, E.; Dravet, C.; Mauguiere, F.; Utermann,
B.; Baldy-Moulinier, M.; and 13 others: Haplotype study of West
European and north African Unverricht-Lundborg chromosomes: evidence
for a few founder mutations. Hum. Genet. 111: 255-262, 2002.
39. Noad, K. B.; Lance, J. W.: Familial myoclonic epilepsy and its
association with cerebellar disturbance. Brain 83: 618-630, 1960.
40. Norio, R.; Koskiniemi, M.: Progressive myoclonus epilepsy: genetic
and nosological aspects with special reference to 107 Finnish patients. Clin.
Genet. 15: 382-398, 1979.
41. Pennacchio, L. A.; Bouley, D. M.; Higgins, K. M.; Scott, M. P.;
Noebels, J. L.; Myers, R. M.: Progressive ataxia, myoclonic epilepsy
and cerebellar apoptosis in cystatin B-deficient mice. Nature Genet. 20:
251-258, 1998.
42. Pennacchio, L. A.; Lehesjoki, A.-E.; Stone, N. E.; Willour, V.
L.; Virtaneva, K.; Miao, J.; D'Amato, E.; Ramirez, L.; Faham, M.;
Koskiniemi, M.; Warrington, J. A.; Norio, R.; de la Chapelle, A.;
Cox, D. R.; Myers, R. M.: Mutations in the gene encoding cystatin
B in progressive myoclonus epilepsy (EPM1). Science 271: 1731-1734,
1996.
43. Ramachandran, N.; Girard, J.-M.; Turnbull, J.; Minassian, B. A.
: The autosomal recessively inherited progressive myoclonus epilepsies
and their genes. Epilepsia 50 (suppl.): 29-36, 2009.
44. Selwa, L. M.: N-acetylcysteine therapy for Unverricht-Lundborg
disease. Neurology 52: 426-427, 1999.
45. Striano, P.; Striano, S.; Zara, F.: FAME3: a novel form of progressive
myoclonus and epilepsy. (Letter) Neurology 70: 85 only, 2008.
46. Unverricht, H.: Ueber familiaere Myoclonie. Dtsch. Z. Nervenheilk. 7:
32-67, 1895.
47. Unverricht, H.: Die Myoclonie. Berlin: Franz Deuticke (pub.)
1891.
48. Virtaneva, K.; D'Amato, E.; Miao, J.; Koskiniemi, M.; Norio, R.;
Avanzini, G.; Franceschetti, S.; Michelucci, R.; Tassinari, C. A.;
Omer, S.; Pennacchio, L. A.; Myers, R. M.; Dieguez-Lucena, J. L.;
Krahe, R.; de la Chapelle, A.; Lehesjoki, A.-E.: Unstable minisatellite
expansion causing recessively inherited myoclonus epilepsy, EPM1. Nature
Genet. 15: 393-396, 1997.
49. Vogel, F.; Hafner, H.; Diebold, K.: Zur Genetik der progressiven
Myoklonusepilepsien (Unverricht-Lundborg). Humangenetik 1: 437-475,
1965.
50. Weinberg, W.: Weitere Beitrage zur Theorie der Vererbung. 4.
Ueber Methode und Fehlerquellen der Untersuchung auf Mendelsche Zahlen
beim Menschen. Arch. Rass. Ges. Biol. 9: 165-174, 1912.
*FIELD* CS
INHERITANCE:
Autosomal recessive
NEUROLOGIC:
[Central nervous system];
Visual blackouts (stage 1);
EEG - polyspike on photic stimulation (stage 1);
Stimulation sensitive segmental myoclonus (stage 2);
Stimulation sensitive generalized myoclonus (stage 3);
Generalized tonic-clonic seizures (stage 2 and 3);
Absence seizures (stage 2 and 3);
Minor motor impairment (stage 2);
Intermittent wheelchair dependence (stage 3);
EEG - alpha slowing, 4-6 Hz spike waves, myoclonus on photic stimulation
(stage 2);
EEG - alpha abolished, continuous spike waves, intense myoclonus on
photic stimulation (stage 3);
Action myoclonus (triggered by voluntary movements);
Ataxia;
Mild mental deterioration;
Dysarthria
MISCELLANEOUS:
Onset 6-13 years;
Three stages of disease progression - Stage 1 (subclinical), Stage
2 (early myoclonic), Stage 3 (disabling myoclonic);
Incidence of 1 in 20,000 live births;
High frequency in Finnish population
MOLECULAR BASIS:
Caused by mutation in the cystatin B gene (CSTB, 601145.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 1/21/2011
Cassandra L. Kniffin - updated: 4/6/2005
Kelly A. Przylepa - revised: 10/15/2001
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 02/07/2012
ckniffin: 1/21/2011
ckniffin: 4/6/2005
joanna: 10/15/2001
*FIELD* CN
Cassandra L. Kniffin - updated: 1/21/2011
Cassandra L. Kniffin - updated: 2/4/2008
Cassandra L. Kniffin - updated: 4/6/2005
Cassandra L. Kniffin - updated: 6/11/2003
Victor A. McKusick - updated: 1/22/2003
Victor A. McKusick - updated: 10/10/2002
Cassandra L. Kniffin - updated: 9/3/2002
George E. Tiller - updated: 1/28/2002
Carol A. Bocchini - reorganized: 11/8/2001
Victor A. McKusick - updated: 11/2/2001
Orest Hurko - updated: 3/24/1999
Victor A. McKusick - updated: 10/23/1998
Stylianos E. Antonarakis - updated: 9/22/1997
Mark H. Paalman - updated: 4/9/1997
Victor A. McKusick - updated: 3/31/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
wwang: 06/10/2011
ckniffin: 5/31/2011
terry: 4/28/2011
wwang: 3/29/2011
ckniffin: 3/25/2011
alopez: 3/11/2011
wwang: 2/21/2011
ckniffin: 1/21/2011
wwang: 10/26/2010
ckniffin: 10/20/2010
carol: 5/4/2010
terry: 3/13/2009
wwang: 12/5/2008
ckniffin: 11/24/2008
wwang: 4/23/2008
ckniffin: 4/17/2008
wwang: 2/25/2008
wwang: 2/22/2008
wwang: 2/4/2008
ckniffin: 2/4/2008
carol: 4/20/2005
wwang: 4/15/2005
ckniffin: 4/6/2005
terry: 3/3/2005
tkritzer: 1/15/2004
carol: 6/16/2003
ckniffin: 6/11/2003
ckniffin: 2/27/2003
carol: 2/27/2003
cwells: 1/29/2003
tkritzer: 1/22/2003
carol: 10/17/2002
tkritzer: 10/16/2002
terry: 10/10/2002
carol: 9/10/2002
ckniffin: 9/3/2002
carol: 2/21/2002
cwells: 2/14/2002
cwells: 1/28/2002
carol: 11/8/2001
mcapotos: 11/2/2001
carol: 11/24/1999
terry: 4/29/1999
mgross: 4/8/1999
carol: 3/24/1999
dkim: 11/6/1998
carol: 10/23/1998
dkim: 9/10/1998
alopez: 5/20/1998
dholmes: 12/4/1997
alopez: 9/22/1997
terry: 8/27/1997
mark: 4/9/1997
mark: 3/31/1997
terry: 3/28/1997
mark: 3/21/1996
terry: 3/18/1996
mimman: 2/8/1996
mark: 6/13/1995
terry: 2/9/1995
carol: 2/1/1995
pfoster: 8/16/1994
warfield: 4/15/1994
mimadm: 4/12/1994
*RECORD*
*FIELD* NO
254800
*FIELD* TI
#254800 MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
;;ULD;;
EPILEPSY, PROGRESSIVE MYOCLONIC 1; EPM1;;
read morePROGRESSIVE MYOCLONIC EPILEPSY; PME;;
BALTIC MYOCLONIC EPILEPSY;;
EPILEPSY, PROGRESSIVE MYOCLONIC 1A; EPM1A
*FIELD* TX
A number sign (#) is used with this entry because myoclonic epilepsy of
Unverricht and Lundborg (ULD, or EPM1) is caused by mutation in the
cystatin B gene (CSTB; 601145) on chromosome 21q22.
DESCRIPTION
Myoclonic epilepsy of Unverricht and Lundborg is an autosomal recessive
disorder characterized by onset of neurodegeneration between 6 and 13
years of age. Although it is considered a progressive myoclonic
epilepsy, it differs from other forms in that is appears to be
progressive only in adolescence, with dramatic worsening of myoclonus
and ataxia in the first 6 years after onset. The disease stabilizes in
early adulthood, and myoclonus and ataxia may even improve, and there is
minimal to no cognitive decline (summary by Ramachandran et al., 2009).
- Genetic Heterogeneity of Progressive Myoclonic Epilepsy
Progressive myoclonic epilepsy refers to a clinically and genetically
heterogeneous group of neurodegenerative disorders, usually with
debilitating symptoms, although severity varies. See also EPM1B
(612437), caused by mutation in the PRICKLE1 gene (608500); Lafora
disease (EPM2A/B; 254780), caused by mutation in either the EPM2A
(607566) or the NHLRC1 (608072) gene; EPM3 (611726), caused by mutation
in the KCTD7 gene (611725); EPM4 (254900), caused by mutation in the
SCARB2 gene (602257); EPM5 (613832), caused by mutation in the PRICKLE2
gene (608501); and EPM6 (614018), caused by mutation in the GOSR2 gene
(604027).
Other disorders characterized by progressive myoclonic epilepsy include
the neuronal ceroid lipofuscinoses (see, e.g., CLN1; 256730); sialidosis
(256550); MERFF (545000); and DRPLA (125370), among others (reviews by
Ramachandran et al., 2009 and Mendonca de Siqueira, 2010).
CLINICAL FEATURES
Unverricht (1891, 1895) and Lundborg (1903) first reported a type of
progressive myoclonic epilepsy common in Finland. Onset of the disorder
occurred around age 10 years, and was characterized by progressive
myoclonus resulting in incapacitation, but only mild mental
deterioration. Histological studies of the brain showed 'degenerative'
changes without inclusion bodies. Severity and survival were variable
(Norio and Koskiniemi, 1979).
Eldridge et al. (1981, 1983) referred to this disorder as the 'Baltic
type' of myoclonic epilepsy because the descriptions first by Unverricht
and then by Lundborg were in families from Estonia and Eastern Sweden
and subsequent patients were found in Finland. Eldridge et al. (1983)
found 15 families in the United States. The 27 affected members had the
following features starting at about age 10 years: stimulus- and
photo-sensitive and occasionally violent myoclonus, usually worse upon
waking; generalized tonic-clonic seizures, sometimes associated with
absence attacks; and light-sensitive, generally synchronous,
spike-and-wave discharges on EEG that preceded clinical manifestations.
Necropsy showed marked loss of Purkinje cells of the cerebellum, but no
inclusion bodies. Phenytoin was associated with progressive motor and
intellectual deterioration, marked ataxia, and even death. Treatment
with valproic acid was associated with marked improvement. Contrary to
myoclonic epilepsy with Lafora bodies, intelligence in this form was
only slightly affected and psychotic symptoms were not found. In
addition, Lafora body disease is invariably fatal.
Kyllerman et al. (1991) described 4 sibs who demonstrated a subclinical
stage of this disorder at the age of 9 to 11 years, with visual
blackouts and polyspike electroencephalographic (EEG) activity on photic
stimulation; an early myoclonic stage at the age of 12 to 15 years, with
increasing segmental, stimulus-sensitive myoclonus, occasional nocturnal
buildup myoclonic 'cascade' seizures, slowing of EEG alpha-activity,
episodic 4-6 Hz bilateral sharp waves and polyspikes with myoclonus on
photic stimulation; and a disabling myoclonic stage at the age of 16 to
18 years, with periodic generalized myoclonus, nocturnal myoclonic
'cascade' seizures, ataxia, dysarthria, mental changes, intermittent
wheelchair dependency, and continuous EEG slow waves with polyspikes and
intense myoclonus on photic stimulation. One of the sibs died at the age
of 18 years with no apparent cause of death.
As pointed out by the Marseille Consensus Group (1990), patients with
Ramsay Hunt syndrome (159700) cannot be distinguished clinically from
patients with Unverricht-Lundborg disease. Linkage studies may help
determine whether that disorder is caused by mutation at the same locus.
Cochius et al. (1994) reported for the first time a pathologic
abnormality outside the central nervous system in patients with
Unverricht-Lundborg disease. They found membrane-bound vacuoles with
clear contents in eccrine clear cells and dark cells in 5 of 7 patients,
as well as in 1 clinically unaffected sib. Sweat gland vacuoles were not
seen in the biopsies of 8 patients with Lafora disease.
Photosensitivity, i.e., precipitation of myoclonic jerks by intermittent
photic stimulation, is a characteristic feature of progressive myoclonic
epilepsies. Mazarib et al. (2001) described an affected Arab family in
which photosensitivity was absent.
Mascalchi et al. (2002) performed MRI and proton MRS on 10 patients with
genetically confirmed EPM1 and found significant loss of bulk of the
basis pontis, medulla, and cerebellar hemispheres as well as mild
cerebral atrophy, compared to 20 healthy controls. The findings differed
in some critical features from those in olivopontocerebellar atrophy.
Mascalchi et al. (2002) concluded that their findings support the
hypothesis that the disease results from a decreased inhibitory control
of the cerebral cortex by the brainstem and cerebellum via the
thalamocortical loop.
Canafoglia et al. (2004) found different electrophysiologic profiles
representing sensorimotor cortex hyperexcitability in 8 patients with
Lafora disease (age range, 14 to 27 years) and 10 patients with
Unverricht-Lundborg disease (age range, 25 to 62 years). In general, the
ULD patients had a quasistationary disease course, rare seizures, and
little or no mental impairment, whereas the Lafora disease patients had
recurrent seizures and worsening mental status. Patients with ULD had
prominent action myoclonus clearly triggered by voluntary movements.
Lafora disease patients experienced spontaneous myoclonic jerks
associated with clear EEG paroxysms with only minor action myoclonus.
Although both groups had enlarged or giant somatosensory evoked
potentials, the pattern in the Lafora group was consistent with a
distortion of cortical circuitry. Patients with ULD had enhanced
long-loop reflexes with extremely brief cortical relay times. The
findings were consistent with an aberrant subcortical or cortical loop,
possibly short-cutting the somatosensory cortex, that may be involved in
generating the prominent action myoclonus that characterizes ULD.
Patients with Lafora disease had varied cortical relay times and delayed
and prolonged facilitation as evidenced by sustained hyperexcitability
of the sensorimotor cortex in response to afferent stimuli. The findings
were consistent with an impairment of inhibitory mechanisms in Lafora
disease.
INHERITANCE
Noad and Lance (1960) described myoclonic epilepsy with cerebellar
ataxia in several offspring of a mating of first cousins once removed,
indicating autosomal recessive inheritance.
CLINICAL MANAGEMENT
Pennacchio et al. (1996) stated that, even in chronic and severe cases,
patients with EPM1 show marked improvement when treated with the
antiepileptic drug sodium valproate; however, phenytoin, another drug
that is effective against some other forms of epilepsy, does not improve
the condition of EPM1 patients, often shows toxic effects, and, in some
cases, is fatal. They stated that the identification of mutant genes
encoding cystatin B in patients with EPM1 may help understanding of the
differential response to these 2 drugs. Furthermore, this knowledge
provides a biochemical pathway and molecular target for the treatment of
EPM1 and perhaps other forms of epilepsy. Selwa (1999) reported
significant improvement in seizures, tremors, speech and ambulation in a
40-year-old patient with Unverricht-Lundborg disease who was given
N-acetylcysteine as well as other vitamin preparations containing
antioxidants. The patient relapsed when medication was discontinued, but
improvement was sustained during a 10-month follow-up after resumption
of treatment. Improvement had previously been reported in 4 similarly
treated sibs (Hurd et al., 1996).
Edwards et al. (2002) found low glutathione levels in a patient with
Unverricht-Lundborg disease proven by DNA studies. Glutathione levels
increased during treatment with N-acetylcysteine (NAC). This increase
was mirrored by an improvement in seizures, but not in myoclonus or
ataxia. Three other patients with clinically determined
Unverricht-Lundborg disease showed a variable response and some notable
side effects during treatment with NAC, including sensorineural
deafness.
Kinrions et al. (2003) reported that levetiracetam, a piracetam analog,
markedly improved myoclonus and quality of life in a 38-year-old woman
with genetically confirmed Unverricht-Lundborg disease. Her illness
began at age 13 and had progressed to leave her wheelchair-bound,
dysarthric, and with multifocal myoclonus. Treatment with multiple
medications had been unsuccessful. The authors cited previous reports of
the effectiveness of levetiracetam in symptomatic myoclonus of various
etiologies.
MAPPING
Lehesjoki et al. (1991) demonstrated close linkage between the EPM1
locus and 3 markers on distal chromosome 21. The loci BCEI (113710) and
D21S154 gave the highest positive lod scores of 5.49 and 4.25,
respectively, at zero recombination. The third locus, D21S112, gave a
lod score of 6.91 at a recombination fraction of 0.034. No evidence of
heterogeneity was found in the 12 families studied. Multipoint lod
scores calculated against a fixed map of the 3 marker loci gave a
maximum 4-point lod score of 10.08 at a location of the disease gene at
6.0 cM distal to locus BCEI and 0.8 cM proximal to D21S154. Both of
these markers had previously been localized to 21q22.3. Lehesjoki et al.
(1992) refined the localization of EPM1 by linkage analysis between the
disease phenotype and 9 DNA markers in 13 Finnish families. A maximum
multipoint lod score of 11.04 was reached at loci D21S154/PFKL (171860),
which had previously been mapped to 21q22.3. Lehesjoki et al. (1993)
narrowed the assignment of EPM1 to an interval of approximately 7 cM,
between loci D21S212 and CD18, by analyzing crossover events in
multiplex families. They refined the localization further by applying
linkage disequilibrium mapping in 38 Finnish families, consisting of 12
with multiple affected children and 26 with a single affected child. In
this way, they were able to conclude that EPM1 resides within 0.3 cM of
PFKL, D21S25, and D21S154. This represents a likely physical distance of
300 kb or less. In a family reported by Eldridge et al. (1983), of mixed
Italian and Irish ancestry, living in the United States, Lehesjoki et
al. (1993) again found linkage to markers in the distal part of
chromosome 21. Crossover events in the family helped refine the gene
localization by placing EPM1 between CBS (613381) and D21S112.
Uncertainty has existed about the relationship between
Unverricht-Lundborg disease, also referred to as Baltic myoclonus, and
Mediterranean myoclonus, formerly considered to be a subgroup of the
Ramsay Hunt syndrome. Lehesjoki et al. (1994) studied 7 phenotypically
homogeneous Mediterranean myoclonus families, using DNA markers from the
genetically defined EPM1 region on chromosome 21. No recombination
between the disease phenotype and the markers studied was detected.
Within the EPM1 region, the highest lod score was 5.07 (at theta = 0.00)
for PFKL. Significant allelic association between the disease mutation
and PFKL was detected, suggesting a founder effect in Mediterranean
myoclonus. However, haplotype data from 4 marker loci residing within
300 kb of each other and of EPM1 suggested the occurrence of more than 1
mutation.
Using linkage disequilibrium and recombination breakpoint mapping with
Finnish EPM1 patients, Pennacchio et al. (1996) refined the location of
the EPM1 gene to a region between markers D21S2040 and D21S1259. This
region was entirely encompassed in a 750-kb bacterial clone contig
generated by sequence tagged site content mapping and walking. A
detailed restriction map of the contig determined that the distance
between the DNA markers defining the boundaries of EPM1 was about 175
kb.
HETEROGENEITY
Carr et al. (2007) reported 2 large families from the Western Cape
province of South Africa with generalized tonic-clonic seizures and
myoclonus. The mean age at onset was 20 years (range 13 to 31).
Myoclonus predominantly affected the trunk and upper limbs but was also
observed in the lower limbs. Hand tremor became apparent on posture
holding. Additional features included nystagmus, abnormal pursuit,
dysarthria, hyperreflexia, cerebellar ataxia, and cerebellar atrophy. A
number of patients also had progressive cognitive impairment, resulting
in dementia in some. EEG studies were abnormal in the majority of
patients, with polyspike and wave activity and/or clear epileptogenic
activity. Postmortem examination of 1 patient showed cerebellar atrophy
and cerebellar neuronal loss. Several patients died in their thirties
and forties. The families were of mixed ancestry, predominantly
resulting from intermarriage between the original inhabitants of the
area, the Khoi-San, and early settlers of European origin. Carr et al.
(2007) noted that the phenotype was more severe and showed earlier onset
than typical familial adult myoclonic epilepsy (FAME1; 601068). The
phenotype was also progressive, falling within the spectrum of
progressive myoclonic epilepsies. Linkage analysis excluded FAME1 and
FAME2 (607876). Striano et al. (2008) commented that the phenotype
described by Carr et al. (2007) was more severe than typically seen for
FAME, and suggested that the disorder described by Carr et al. (2007) as
'FAME3,' should be placed within the group of progressive myoclonic
epilepsies. Striano et al. (2008) suggested that the designation FAME be
reserved for familial nonprogressive cortical tremor and epilepsy. In a
large French family with FAME, a locus designated FAME3 (613608) was
mapped to chromosome 5p15 by Depienne et al. (2010).
MOLECULAR GENETICS
Pennacchio et al. (1996) used a combination of genetic and physical
mapping information to search systematically for the causative gene for
EPM1. Several cDNAs identified with a bacterial artificial chromosome
(BAC) clone encoded a previously described protein, cystatin B (601145),
a cysteine protease inhibitor. Because of the wide expression of the
cystatin B gene in normal individuals and the finding of reduced
expression in lymphoblastoid cells from affected individuals, Pennacchio
et al. (1996) sequenced the cystatin B gene (also known as stefin B)
from affected individuals and identified 2 different mutations in the
gene. Cystatin C (CST3; 604312) is the site of heterozygous mutations
causing hereditary cerebral amyloid angiopathy. This dominantly
inherited disorder is characterized by the deposition of cystatin C-rich
amyloid fibrils in affected brain arteries. EPM1 is inherited as a
recessive and appears to be the result of decreased amounts of cystatin
B, suggesting different mechanisms for the 2 diseases. The genes
responsible for Lafora disease (254780) (EPM2A; 607566) and juvenile
myoclonic epilepsy (254770) mapped to 6q and 6p, respectively. The
identification of cystatin B defects in EPM1 suggested that other
members of the cystatin superfamily or their substrates may be defective
in these related epilepsies. See 601145 for point mutations identified
in the stefin B gene in patients with EPM1.
Lafreniere et al. (1997) and Virtaneva et al. (1997) reported a novel
type of disease-causing mutation, an unstable minisatellite repeat
expansion in the putative promoter region of the gene (601145.0003). The
mutation accounted for most EPM1 patients worldwide. Virtaneva et al.
(1997) noted that haplotype data from their study were compatible with a
single ancestral founder mutation. The length of the repeat array
differed between chromosomes and families, but changes in repeat number
seemed to be comparatively rare events.
Lalioti et al. (1997) identified 6 nucleotide changes in the CSTB gene
in non-Finnish EPM1 families from northern Africa and Europe. One of
these, a homozygous G-to-C transversion at nucleotide 426 in exon 1,
resulted in a gly4-to-arg substitution (G4R; 601145.0004) and was the
first missense mutation described in association with EPM1. Molecular
modeling predicted that this substitution would severely affect the
contact of cystatin B with papain. The 6 mutations were found in 7 of
the 29 unrelated EPM1 patients analyzed, in homozygosity in 1, and in
heterozygosity in the others. They also found a tandem repeat of a
dodecamer (CCCCGCCCCGCG) in the 5-prime untranslated region as a
polymorphism (601145.0003). They identified 2 allelic variants with 2 or
3 tandem copies. The frequency of the 3-copy allele was 66% in the
normal Caucasian population.
In an elaboration on their previous work, Lalioti et al. (1997) stated
that the common mutation mechanism in EPM1 is the expansion of the
dodecamer repeat (601145.0003), and considered this mutation to be the
most likely source of the disorder. An examination of 58 EPM1 alleles
revealed that 50 of these contained the dodecamer repeat expansion. In
addition to the expanded repeat mutation and the 2 or 3 repeats found in
alleles considered to be normal, Lalioti et al. (1997) identified
alleles with 12 to 17 repeats, which they termed 'premutational,' that
were transmitted unstably to offspring. These 'premutational' alleles
were not connected with a clinical phenotype of EPM1. Lalioti et al.
(1997) stated that no correlation between number of repeat expansions
and age of onset or severity had been found.
Antonarakis (1997) confirmed that the only EPM1-related point mutation
in the cystatin B gene found in homozygous state was the G4R amino acid
substitution. All other point mutations identified in EPM1 patients were
found as compound heterozygotes with the 12-bp repeat expansion allele.
The repeat expansion allele was also homozygous in some patients.
Antonarakis (1997) found no patients with null point mutations (e.g.,
nonsense, frameshift, or splice site) in homozygous state; all EPM1
patients had residual gene activity. He proposed that homozygosity for
null alleles was either nonviable or presented a different phenotype.
POPULATION GENETICS
Koskiniemi et al. (1980) estimated that over 100 cases in 70 sibships
had been identified in Finland. Fewer cases had been found in all the
rest of the world. The incidence in Finland is about 1 in 20,000.
Moulard et al. (2002) stated that Unverricht-Lundborg disease is also
common North Africa but less common in western Europe. They performed a
haplotype study of Unverricht-Lundborg disease chromosomes with a
dodecamer repeat expansion in the CSTB gene (601145.0003), the most
frequent cause of the disorder. They found that 29 (61.7%) of 47
patients from North Africa shared the same haplotype, thus establishing
a founder effect in this population. The haplotypes from 48 Caucasian
patients from western Europe were heterogeneous.
HISTORY
Stevenson pointed out, in a discussion of genetic aspects of the study
by Harriman and Millar (1955), that Lundborg's study is 'of considerable
historic interest in human genetics.' Lundborg's data were used to test
statistically the recessive hypothesis, the first such analysis in man.
The statistical analysis was done first by Weinberg (1912) and later by
Bernstein (1929).
Lundborg's report was one of the earliest of recessive inheritance. He
published the names of those affected. When Book (1978) later attempted
a follow-up, he found that marriage of relatives had been carefully
avoided in the group and no more cases had occurred. Book (1978)
suggested that this was one of the earliest and largest instances of
group genetic counseling.
ANIMAL MODEL
A possibly homologous disorder in Poll Hereford cattle was shown by
Gundlach et al. (1988) to have a defect in glycine/strychnine receptors.
The symptoms of the disorder suggested a failure of spinal interneuron
inhibition and are similar to those in subconvulsive strychnine
poisoning. Strychnine blocks the synaptic action of the inhibitory amino
acid transmitter glycine by interacting with the postsynaptic glycine
receptor. The mouse mutant 'spastic' may have a similar defect. The gene
for the 'spastic' mutant maps to mouse chromosome 3 (Eicher and Lane,
1980). Grenningloh et al. (1990) indicated that it is the alpha-1 form
of the glycine receptor (138491) that is coded by an autosome, whereas
the alpha-2 receptor (305990) is X-linked.
The features of EPM1 were reproduced by targeted disruption of the
cystatin B gene in mice (Pennacchio et al., 1998).
Lieuallen et al. (2001) identified 7 genes with consistently increased
transcript levels in neurologic tissues from Cstb-deficient knockout
mice: cathepsin S (116845), C1q B-chain of complement (120570),
beta-2-microglobulin (109700), glial fibrillary acidic protein (137780),
apolipoprotein D (107740), fibronectin-1 (135600), and metallothionein
II (156360). These proteins are expected to be involved in increased
proteolysis, apoptosis, and glial activation. The molecular changes in
Cstb-deficient mice were consistent with the pathology found in the
mouse model.
*FIELD* SA
Ford et al. (1951); Kraus-Ruppert et al. (1970); Lundborg (1912);
Lundborg (1913); Morse (1949); Vogel et al. (1965)
*FIELD* RF
1. Antonarakis, S.: Personal Communication. Geneva, Switzerland
4/8/1997.
2. Bernstein, F.: Variations-und Erblichkeitsstatistik. Berlin
(pub.) 1929.
3. Book, J. A.: Personal Communication. Uppsala, Sweden 1978.
4. Canafoglia, L.; Ciano, C.; Panzica, F.; Scaioli, V.; Zucca, C.;
Agazzi, P.; Visani, E.; Avanzini, G.; Franceschetti, S.: Sensorimotor
cortex excitability in Unverricht-Lundborg disease and Lafora body
disease. Neurology 63: 2309-2315, 2004.
5. Carr, J. A.; van der Walt, P. E.; Nakayama, J.; Fu, Y.-H.; Corfield,
V.; Brink, P.; Ptacek, L.: FAME3: a novel form of progressive myoclonus
and epilepsy. Neurology 68: 1382-1389, 2007.
6. Cochius, J.; Carpenter, S.; Andermann, E.; Rouleau, G.; Nousiainen,
U.; Kalviainen, R.; Farrell, K.; Andermann, F.: Sweat gland vacuoles
in Unverricht-Lundborg disease: a clue to diagnosis? Neurology 44:
2372-2375, 1994.
7. Depienne, C.; Magnin, E.; Bouteiller, D.; Stevanin, G.; Saint-Martin,
C.; Vidailhet, M.; Apartis, E.; Hirsch, E.; LeGuern, E.; Labauge,
P.; Rumbach, L.: Familial cortical myoclonic tremor with epilepsy:
the third locus (FCMTE3) maps to 5p. Neurology 74: 2000-2003, 2010.
8. Edwards, M. J. J.; Hargreaves, I. P.; Heales, S. J. R.; Jones,
S. J.; Ramachandran, V.; Bhatia, K. P.; Sisodiya, S.: N-acetylcysteine
and Unverricht-Lundborg disease. Neurology 59: 1447-1449, 2002.
9. Eicher, E. M.; Lane, P. W.: Assignment of LH XVI to chromosome
3 in the mouse. J. Hered. 71: 315-318, 1980.
10. Eldridge, R.; Iivanainen, M.; Stern, R.; Koerber, T.; Wilder,
B. J.: 'Baltic' myoclonus epilepsy: a treatable hereditary disorder
of childhood. (Abstract) Sixth Int. Cong. Hum. Genet., Jerusalem 256,
1981.
11. Eldridge, R.; Iivanainen, M.; Stern, R.; Koerber, T.; Wilder,
B. J.: 'Baltic' myoclonus epilepsy: hereditary disorder of childhood
made worse by phenytoin. Lancet 322: 838-842, 1983. Note: Originally
Volume II.
12. Ford, F. R.; Livingston, S.; Pryles, C. V.: Familial degeneration
of cerebral gray matter in childhood, with convulsions, myoclonus,
spasticity, cerebellar ataxia, choreoathetosis, dementia, and death
in status epilepticus: differentiation of infantile and juvenile types. J.
Pediat. 39: 33-43, 1951.
13. Grenningloh, G.; Schmieden, V.; Schofield, P. R.; Seeburg, P.
H.; Siddique, T.; Mohandas, T. K.; Becker, C.-M.; Betz, H.: Alpha
subunit variants of the human glycine receptor: primary structures,
functional expression and chromosomal localization of the corresponding
genes. EMBO J. 9: 771-776, 1990.
14. Gundlach, A. L.; Dodd, P. R.; Grabara, C. S. G.; Watson, W. E.
J.; Johnston, G. A. R.; Harper, P. A. W.; Dennis, J. A.; Healy, P.
J.: Deficit of spinal cord glycine/strychnine receptors in inherited
myoclonus of Poll Hereford calves. Science 241: 1807-1810, 1988.
15. Harriman, D. G. F.; Millar, J. H. D.: Progressive familial myoclonic
epilepsy in 3 families: its clinical features and pathological basis. Brain 78:
325-349, 1955.
16. Hurd, R. W.; Wilder, B. J.; Helveston, W. R.; Uthman, B. M.:
Treatment of four siblings with progressive myoclonus epilepsy of
the Unverricht-Lundborg type with N-acetylcysteine. Neurology 47:
1264-1268, 1996.
17. Kinrions, P.; Ibrahim, N.; Murphy, K.; Lehesjoki, A.-E.; Jarvela,
I.; Delanty, N.: Efficacy of levetiracetam in a patient with Unverricht-Lundborg
progressive myoclonic epilepsy. Neurology 60: 1394-1395, 2003.
18. Koskiniemi, M.; Donner, M.; Toivakka, E.; Norio, R.: Progressive
myoclonus epilepsy (PME).In: Eriksson, A. W.; Forsius, H. R.; Nevanlinna,
H. R.; Workman, P. L.; Norio, R. K.: Population Structure and Genetic
Disorders. New York: Academic Press (pub.) 1980. Pp. 669-672.
19. Kraus-Ruppert, R.; Ostertag, B.; Hafner, H.: A study of the late
form (type Lundborg) of progressive myoclonic epilepsy. J. Neurol.
Sci. 11: 1-15, 1970.
20. Kyllerman, M.; Sommerfelt, K.; Hedstrom, A.; Wennergren, G.; Holmgren,
D.: Clinical and neurophysiological development of Unverricht-Lundborg
disease in four Swedish siblings. Epilepsia 32: 900-909, 1991.
21. Lafreniere, R. G.; Rochefort, D. L.; Chretien, N.; Rommens, J.
M.; Cochius, J. I.; Kalviainen, R.; Nousiainen, U.; Patry, G.; Farrell,
K.; Soderfeldt, B.; Federico, A.; Hale, B. R.; Cossio, O. H.; Sorensen,
T.; Pouliot, M. A.; Kmiec, T.; Uldall, P.; Janszky, J.; Pranzatelli,
M. R.; Andermann, F.; Andermann, E.; Rouleau, G. A.: Unstable insertion
of the 5-prime flanking region of the cystatin B gene is the most
common mutation in progressive myoclonus epilepsy type 1, EPM1. Nature
Genet. 15: 298-302, 1997.
22. Lalioti, M. D.; Mirotsou, M.; Buresi, C.; Peitsch, M. C.; Rossier,
C.; Ouazzani, R.; Baldy-Moulinier, M.; Bottani, A.; Malafosse, A.;
Antonarakis, S. E.: Identification of mutations in cystatin B, the
gene responsible for the Unverricht-Lundborg type of progressive myoclonus
epilepsy (EPM1). Am. J. Hum. Genet. 60: 342-351, 1997.
23. Lalioti, M. D.; Scott, H. S.; Buresi, C.; Rossier, C.; Bottani,
A.; Morris, M. A.; Malafosse, A.; Antonarakis, S. E.: Dodecamer repeat
expansion in cystatin B gene in progressive myoclonus epilepsy. Nature 386:
847-851, 1997.
24. Lehesjoki, A.-E.; Eldridge, R.; Eldridge, J.; Wilder, B. J.; de
la Chapelle, A.: Progressive myoclonus epilepsy of Unverricht-Lundborg
type: a clinical and molecular genetic study of a family from the
United States with four affected sibs. Neurology 43: 2384-2386,
1993.
25. Lehesjoki, A.-E.; Koskiniemi, M.; Norio, R.; Tirrito, S.; Sistonen,
P.; Lander, E.; de la Chapelle, A.: Localization of the EPM1 gene
for progressive myoclonus epilepsy on chromosome 21: linkage disequilibrium
allows high resolution mapping. Hum. Molec. Genet. 2: 1229-1234,
1993.
26. Lehesjoki, A.-E.; Koskiniemi, M.; Pandolfo, M.; Antonelli, A.;
Kyllerman, M.; Wahlstrom, J.; Nergardh, A.; Burmeister, M.; Sistonen,
P.; Norio, R.; de la Chapelle, A.: Linkage studies in progressive
myoclonus epilepsy: Unverricht-Lundborg and Lafora's diseases. Neurology 42:
1545-1550, 1992.
27. Lehesjoki, A.-E.; Koskiniemi, M.; Sistonen, P.; Miao, J.; Hastbacka,
J.; Norio, R.; de la Chapelle, A.: Localization of a gene for progressive
myoclonus epilepsy to chromosome 21q22. Proc. Nat. Acad. Sci. 88:
3696-3699, 1991.
28. Lehesjoki, A.-E.; Tassinari, C. A.; Avanzini, G.; Michelucci,
R.; Franceschetti, S.; Antonelli, A.; Rubboli, G.; de la Chapelle,
A.: PME of Unverricht-Lundborg type in the Mediterranean region:
linkage and linkage disequilibrium confirm the assignment to the EPM1
locus. Hum. Genet. 93: 668-674, 1994.
29. Lieuallen, K.; Pennacchio, L. A.; Park, M.; Myers, R. M.; Lennon,
G. G.: Cystatin B-deficient mice have increased expression of apoptosis
and glial activation genes. Hum. Molec. Genet. 10: 1867-1871, 2001.
30. Lundborg, H. B.: Die progressive Myoklonusepilepsie (Unverricht's
Myoklonie). Uppsala: Almqvist and Wiksell (pub.) 8: 1903. Pp.
567-570.
31. Lundborg, H. B.: Der Erbgang der progressiven Myoklonusepilepsie.
(Myoklonie-Epilepsie, Unverricht's familiaere Myoklonie). Z. Ges.
Neurol. Psychiat. 9: 353-358, 1912.
32. Lundborg, H. B.: Medizinisch-biologische Familienforschungen
innerhalb eines 2232 koepfigen Bauerngeschlechtes in Schweden. Jena:
Fischer (pub.) 1913.
33. Marseille Consensus Group: Classification of progressive myoclonus
epilepsies and related disorders. Ann. Neurol. 28: 113-116, 1990.
34. Mascalchi, M.; Michelucci, R.; Cosottini, M.; Tessa, C.; Lolli,
F.; Riguzzi, P.; Lehesjoki, A. E.; Tosetti, M.; Villari, N.; Tassinari,
C. A.: Brainstem involvement in Unverricht-Lundborg disease (EPM1):
an MRI and 1-H MRS study. Neurology 58: 1686-1689, 2002.
35. Mazarib, A.; Xiong, L.; Neufeld, M. Y.; Birnbaum, M.; Korczyn,
A. D.; Pandolfo, M.; Berkovic, S. F.: Unverricht-Lundborg disease
in a five-generation Arab family: instability of dodecamer repeats. Neurology 57:
1050-1054, 2001.
36. Mendonca de Siqueira, L. F.: Progressive myoclonic epilepsies:
review of clinical, molecular and therapeutic aspects. J. Neurol. 257:
1612-1619, 2010.
37. Morse, W. I.: Hereditary myoclonus epilepsy: two cases with pathological
findings. Bull. Johns Hopkins Hosp. 84: 116-134, 1949.
38. Moulard, B.; Genton, P.; Grid, D.; Jeanpierre, M.; Ouazzani, R.;
Mrabet, A.; Morris, M.; LeGuern, E.; Dravet, C.; Mauguiere, F.; Utermann,
B.; Baldy-Moulinier, M.; and 13 others: Haplotype study of West
European and north African Unverricht-Lundborg chromosomes: evidence
for a few founder mutations. Hum. Genet. 111: 255-262, 2002.
39. Noad, K. B.; Lance, J. W.: Familial myoclonic epilepsy and its
association with cerebellar disturbance. Brain 83: 618-630, 1960.
40. Norio, R.; Koskiniemi, M.: Progressive myoclonus epilepsy: genetic
and nosological aspects with special reference to 107 Finnish patients. Clin.
Genet. 15: 382-398, 1979.
41. Pennacchio, L. A.; Bouley, D. M.; Higgins, K. M.; Scott, M. P.;
Noebels, J. L.; Myers, R. M.: Progressive ataxia, myoclonic epilepsy
and cerebellar apoptosis in cystatin B-deficient mice. Nature Genet. 20:
251-258, 1998.
42. Pennacchio, L. A.; Lehesjoki, A.-E.; Stone, N. E.; Willour, V.
L.; Virtaneva, K.; Miao, J.; D'Amato, E.; Ramirez, L.; Faham, M.;
Koskiniemi, M.; Warrington, J. A.; Norio, R.; de la Chapelle, A.;
Cox, D. R.; Myers, R. M.: Mutations in the gene encoding cystatin
B in progressive myoclonus epilepsy (EPM1). Science 271: 1731-1734,
1996.
43. Ramachandran, N.; Girard, J.-M.; Turnbull, J.; Minassian, B. A.
: The autosomal recessively inherited progressive myoclonus epilepsies
and their genes. Epilepsia 50 (suppl.): 29-36, 2009.
44. Selwa, L. M.: N-acetylcysteine therapy for Unverricht-Lundborg
disease. Neurology 52: 426-427, 1999.
45. Striano, P.; Striano, S.; Zara, F.: FAME3: a novel form of progressive
myoclonus and epilepsy. (Letter) Neurology 70: 85 only, 2008.
46. Unverricht, H.: Ueber familiaere Myoclonie. Dtsch. Z. Nervenheilk. 7:
32-67, 1895.
47. Unverricht, H.: Die Myoclonie. Berlin: Franz Deuticke (pub.)
1891.
48. Virtaneva, K.; D'Amato, E.; Miao, J.; Koskiniemi, M.; Norio, R.;
Avanzini, G.; Franceschetti, S.; Michelucci, R.; Tassinari, C. A.;
Omer, S.; Pennacchio, L. A.; Myers, R. M.; Dieguez-Lucena, J. L.;
Krahe, R.; de la Chapelle, A.; Lehesjoki, A.-E.: Unstable minisatellite
expansion causing recessively inherited myoclonus epilepsy, EPM1. Nature
Genet. 15: 393-396, 1997.
49. Vogel, F.; Hafner, H.; Diebold, K.: Zur Genetik der progressiven
Myoklonusepilepsien (Unverricht-Lundborg). Humangenetik 1: 437-475,
1965.
50. Weinberg, W.: Weitere Beitrage zur Theorie der Vererbung. 4.
Ueber Methode und Fehlerquellen der Untersuchung auf Mendelsche Zahlen
beim Menschen. Arch. Rass. Ges. Biol. 9: 165-174, 1912.
*FIELD* CS
INHERITANCE:
Autosomal recessive
NEUROLOGIC:
[Central nervous system];
Visual blackouts (stage 1);
EEG - polyspike on photic stimulation (stage 1);
Stimulation sensitive segmental myoclonus (stage 2);
Stimulation sensitive generalized myoclonus (stage 3);
Generalized tonic-clonic seizures (stage 2 and 3);
Absence seizures (stage 2 and 3);
Minor motor impairment (stage 2);
Intermittent wheelchair dependence (stage 3);
EEG - alpha slowing, 4-6 Hz spike waves, myoclonus on photic stimulation
(stage 2);
EEG - alpha abolished, continuous spike waves, intense myoclonus on
photic stimulation (stage 3);
Action myoclonus (triggered by voluntary movements);
Ataxia;
Mild mental deterioration;
Dysarthria
MISCELLANEOUS:
Onset 6-13 years;
Three stages of disease progression - Stage 1 (subclinical), Stage
2 (early myoclonic), Stage 3 (disabling myoclonic);
Incidence of 1 in 20,000 live births;
High frequency in Finnish population
MOLECULAR BASIS:
Caused by mutation in the cystatin B gene (CSTB, 601145.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 1/21/2011
Cassandra L. Kniffin - updated: 4/6/2005
Kelly A. Przylepa - revised: 10/15/2001
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 02/07/2012
ckniffin: 1/21/2011
ckniffin: 4/6/2005
joanna: 10/15/2001
*FIELD* CN
Cassandra L. Kniffin - updated: 1/21/2011
Cassandra L. Kniffin - updated: 2/4/2008
Cassandra L. Kniffin - updated: 4/6/2005
Cassandra L. Kniffin - updated: 6/11/2003
Victor A. McKusick - updated: 1/22/2003
Victor A. McKusick - updated: 10/10/2002
Cassandra L. Kniffin - updated: 9/3/2002
George E. Tiller - updated: 1/28/2002
Carol A. Bocchini - reorganized: 11/8/2001
Victor A. McKusick - updated: 11/2/2001
Orest Hurko - updated: 3/24/1999
Victor A. McKusick - updated: 10/23/1998
Stylianos E. Antonarakis - updated: 9/22/1997
Mark H. Paalman - updated: 4/9/1997
Victor A. McKusick - updated: 3/31/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
wwang: 06/10/2011
ckniffin: 5/31/2011
terry: 4/28/2011
wwang: 3/29/2011
ckniffin: 3/25/2011
alopez: 3/11/2011
wwang: 2/21/2011
ckniffin: 1/21/2011
wwang: 10/26/2010
ckniffin: 10/20/2010
carol: 5/4/2010
terry: 3/13/2009
wwang: 12/5/2008
ckniffin: 11/24/2008
wwang: 4/23/2008
ckniffin: 4/17/2008
wwang: 2/25/2008
wwang: 2/22/2008
wwang: 2/4/2008
ckniffin: 2/4/2008
carol: 4/20/2005
wwang: 4/15/2005
ckniffin: 4/6/2005
terry: 3/3/2005
tkritzer: 1/15/2004
carol: 6/16/2003
ckniffin: 6/11/2003
ckniffin: 2/27/2003
carol: 2/27/2003
cwells: 1/29/2003
tkritzer: 1/22/2003
carol: 10/17/2002
tkritzer: 10/16/2002
terry: 10/10/2002
carol: 9/10/2002
ckniffin: 9/3/2002
carol: 2/21/2002
cwells: 2/14/2002
cwells: 1/28/2002
carol: 11/8/2001
mcapotos: 11/2/2001
carol: 11/24/1999
terry: 4/29/1999
mgross: 4/8/1999
carol: 3/24/1999
dkim: 11/6/1998
carol: 10/23/1998
dkim: 9/10/1998
alopez: 5/20/1998
dholmes: 12/4/1997
alopez: 9/22/1997
terry: 8/27/1997
mark: 4/9/1997
mark: 3/31/1997
terry: 3/28/1997
mark: 3/21/1996
terry: 3/18/1996
mimman: 2/8/1996
mark: 6/13/1995
terry: 2/9/1995
carol: 2/1/1995
pfoster: 8/16/1994
warfield: 4/15/1994
mimadm: 4/12/1994
MIM
601145
*RECORD*
*FIELD* NO
601145
*FIELD* TI
*601145 CYSTATIN B; CSTB
;;STEFIN B; STFB
*FIELD* TX
DESCRIPTION
Stefin B (also called cystatin B) is a small protein that is a member of
read morethe superfamily of cysteine protease inhibitors (Jarvinen and Rinne,
1982; Turk and Bode, 1991). It has been isolated from human spleen and
liver and its amino acid sequence has been fully determined. It is
widely distributed and is localized mostly intracellularly, but has been
found extracellularly. Its role is thought to be as a protector against
the proteinases leaking from lysosomes.
CLONING
In the course of positional cloning of the gene responsible for
progressive myoclonus epilepsy (EPM1; 254800) which had been mapped to
chromosome 21 in a segment of about 175 kb between D21S2040 and
D21S1259, Pennacchio et al. (1996) found a cDNA that encoded cystatin B
which was previously known but had not been mapped to a specific
chromosomal site. They confirmed previous reports that the gene encoding
cystatin B is widely expressed by demonstrating that a probe made from
the cDNA clone detected an mRNA approximately 0.8 kb in length in all
tissues examined. On Northern blots, lymphoblastoid cells from affected
individuals from 4 unrelated families showed reduced levels of cystatin
B mRNA compared to those from unaffected, noncarrier individuals and the
carrier parents of EPM1 patients.
Jerala et al. (1988) synthesized a gene coding for human stefin B by the
solid-phase phosphite method and cloned it in the pUC8 cloning vector.
Protein prepared in expression vectors was inhibitory to papain and
reacted with antibodies against human stefin B. Pennacchio et al. (1996)
stated that cystatin B is a tightly binding reversible inhibitor of
cathepsins L (116880), H (116820), and B (116810).
GENE STRUCTURE
Pennacchio et al. (1996) sequenced the STFB gene from affected and
unaffected individuals whose families had EPM1. Sequencing revealed that
the STFB gene is 2,500 bp in length and contains 3 small exons encoding
the 98-amino acid protein, whose mature mRNA and amino acid sequence
were previously known.
Pennacchio and Myers (1996) isolated and characterized the mouse homolog
of cystatin B. The gene spans 3 kb of genomic DNA and contains 3 exons
as in human and rat. The gene encodes a predicted 98-amino acid
polypeptide identical in length to the rat, bovine, and human genes and
bearing 86%, 71%, and 79% similarity, respectively, to the genes of the
other species. By Northern analysis, they showed that mouse cystatin B
is expressed in many tissues.
GENE FUNCTION
Using a yeast 2-hybrid system, Di Giaimo et al. (2002) identified 5
recombinant proteins interacting with cystatin B, none of which was a
protease. Three of these proteins, RACK1 (176981), beta-spectrin (see
182790), and NFL (162280), coimmunoprecipitated with cystatin B in rat
cerebellum. Confocal immunofluorescence analysis showed that the same
proteins were present in the granule cells of developing cerebellum, as
well as in Purkinje cells of adult rat cerebellum. The authors proposed
that a cystatin B multiprotein complex might have a specific cerebellar
function, and that the loss of this function might contribute to the
etiopathogenesis of EPM1.
Using a monoclonal CSTB antibody and organelle-specific markers in human
primary myoblasts, Alakurtti et al. (2005) showed that endogenous CSTB
localizes not only to the nucleus and cytoplasm but also associates with
lysosomes. Upon differentiation to myotubes, CSTB becomes excluded from
the nucleus and lysosomes, suggesting that the subcellular distribution
of CSTB is dependent on the differentiation status of the cell.
MAPPING
Pennacchio and Myers (1996) mapped the mouse cystatin B gene by
interspecific backcross analysis to mouse chromosome 10, extending
knowledge of the homology of synteny between this region of mouse
chromosome 10 and human chromosome 21q22.3.
MOLECULAR GENETICS
Lalioti et al. (1997) identified 6 nucleotide changes in the CSTB gene
in non-Finnish EPM1 families from northern Africa and Europe. One of
these, a homozygous G-to-C transversion at nucleotide 426 in exon 1,
resulted in a gly4-to-arg substitution (601145.0004) and was the first
missense mutation described in association with EPM1. Molecular modeling
predicted that this substitution would severely affect the contact of
cystatin B with papain. The 6 mutations were found in 7 of the 29
unrelated EPM1 patients analyzed, in homozygosity in 1, and in
heterozygosity in the others. They also found a tandem repeat of a
dodecamer (CCCCGCCCCGCG) in the 5-prime untranslated region as a
polymorphism (601145.0003). They identified 2 allelic variants with 2 or
3 tandem copies. The frequency of the 3-copy allele was 66% in the
normal Caucasian population.
Lafreniere et al. (1997) presented haplotype and mutation analyses of 20
unrelated EPM1 patients and families from different ethnic groups. They
identified 4 different mutations, the most common of which consisted of
an unstable insertion of approximately 600 to 900 bp that was resistant
to PCR amplification. This insertion mapped to a 12-bp polymorphic
tandem repeat located in the 5-prime flanking region of the STFB gene in
the region of the promoter (601145.0003). The size of the insertion
varied between different EPM1 chromosomes sharing a common haplotype and
a common origin, suggesting some level of meiotic instability over the
course of many generations. Lafreniere et al. (1997) speculated that
this dynamic mutation, which appeared distinct from conventional
trinucleotide repeat expansions, may arise via a novel mechanism related
to the instability of tandemly repeated sequences. Independently,
Virtaneva et al. (1997) identified unstable minisatellite expansions in
the promoter region of the cystatin B gene (symbolized CST6 by them).
They stated that the mutation accounts for the majority of EFM1 patients
worldwide. Haplotype data were compatible with a single ancestral
founder mutation. The length of the repeat array differed between
chromosomes and families, but changes in repeat numbers seemed to be
comparatively rare events. Virtaneva et al. (1997) noted that unstable
trinucleotide microsatellite repeat expansions are associated with at
least 10 inherited neurologic disorders and are associated in all cases,
except for Friedreich ataxia (229300), with strong anticipation. Unlike
unstable trinucleotide repeats, which show a high degree of
intergenerational instability, the EPM1-associated minisatellite
mutation did not appear to be as unstable and anticipation has not been
recognized in EPM1.
Antonarakis (1997) confirmed that the only EPM1-related point mutation
in the cystatin B gene found in homozygous state was the gly-to-arg
amino acid substitution (601145.0004). All other point mutations
identified in EPM1 patients were found as compound heterozygotes with
the 12-bp repeat expansion allele. The repeat expansion allele was also
homozygous in some patients. Antonarakis (1997) found no patients with
null point mutations (e.g., nonsense, frameshift, or splice site) in
homozygous state; all EPM1 patients had residual gene activity. He
proposed that homozygosity for null alleles was either nonviable or
presented a different phenotype.
In an elaboration on their previous work, Lalioti et al. (1997) stated
that the common mutation mechanism in EPM1 is the expansion of the
dodecamer repeat (601145.0003), and considered this mutation to be the
most likely source of the Finnish disorder described in 254800. An
examination of 58 EPM1 alleles revealed that 50 of these contained the
dodecamer repeat expansion. In addition to the expanded repeat mutation
and the 2 or 3 repeats found in alleles considered to be normal, Lalioti
et al. (1997) identified alleles with 12 to 17 repeats, which they
termed 'premutational,' that were transmitted unstably to offspring.
These 'premutational' alleles were not connected with a clinical
phenotype of EPM1. Lalioti et al. (1997) stated that no correlation
between number of repeat expansions and age of onset or severity had
been found.
Most EPM1 alleles contain large expansions of the dodecamer repeat
located upstream of the 5-prime transcription start site of the CSTB
gene; normal alleles contain 2 or 3 copies of this repeat. All EPM1
alleles with an expansion were resistant to standard PCR amplification.
To determine the size of the repeat in affected individuals, Lalioti et
al. (1998) developed a detection protocol involving PCR amplification
and subsequent hybridization with an oligonucleotide containing the
repeat. In EPM1 patients, the largest detected expansion was
approximately 75 copies; the smallest was approximately 30 copies. They
identified affected sibs with repeat expansions of different sizes on
the same haplotype, which confirmed the repeats' instability during
transmissions. Expansions were observed directly; contractions were
deduced by comparison of allele sizes within a family. In a sample of 28
patients, they found no correlation between age at onset of EPM1 and the
size of the expanded dodecamer. This suggested that once the dodecamer
repeat expands beyond a critical threshold, CSTB expression is reduced
in certain cells, with pathologic consequences.
Haplotype analysis in a previous study suggested that 3 of 4 independent
EPM1 mutations were present in 4 families. By sequence comparison,
Pennacchio et al. (1996) identified 2 different mutations in the
cystatin B gene. One was a G-to-C transversion at the last nucleotide of
intron 1 (601145.0001), altering the sequence of the 3-prime splice site
AG dinucleotide that is in this position in almost all introns. The
second mutation, which was found in alleles of the cystatin B gene from
2 of the 4 families, changed CGA to TGA, generating a translation stop
codon at amino acid position 68 (601145.0002). Despite identifying these
2 mutations in affected chromosomes from 3 of the 4 families, Pennacchio
et al. (1996) were unable to detect any sequence difference in the gene
encoding cystatin B from the remaining 1 or 2 alleles they had available
for study. Specifically, the Finnish ancestral mutation was not
identified. However, studies indicated that the expression of the
Finnish gene, as well as that of all the other mutant alleles, was
defective. Pennacchio et al. (1996) stated that, despite ubiquitous
expression of this protein, it is not understood why mutation of the
gene encoding cystatin B causes the symptoms of EPM1, an apparent
tissue-specific phenotype.
Alakurtti et al. (2005) transiently expressed 4 mutations altering the
CSTB polypeptide in BHK-21 cells. The 2400_2402delTC
(601145.0005)-truncated mutant protein showed diffuse cytoplasmic and
nuclear distribution, whereas R68X (601145.0002) was rapidly degraded.
Two missense mutations, G4R (601145.0004), affecting the highly
conserved glycine that is critical for cathepsin binding, and Q71P
(601145.0006), failed to associate with lysosomes. Alakurtti et al.
(2005) concluded that CSTB has an important lysosome-associated
physiologic function and suggested that loss of this association
contributes to the molecular pathogenesis of EPM1.
ANIMAL MODEL
Pennacchio et al. (1998) found that mice lacking cystatin B as a result
of targeted disruption of the gene develop myoclonic seizures and ataxia
similar to the symptoms shown in EPM1. The principal cytopathology
appeared to be loss of cerebellar granule cells, which frequently
display condensed nuclei, fragmented DNA, and other cellular changes
characteristic of apoptosis. This mouse model of EPM1 was thought to
provide evidence that cystatin B, as a noncaspase cysteine protease
inhibitor, has a role in preventing cerebellar apoptosis.
Lieuallen et al. (2001) identified 7 genes with consistently increased
transcript levels in neurologic tissues from Cstb-deficient knockout
mice: cathepsin S (116845), C1q B-chain of complement (120570),
beta-2-microglobulin (109700), glial fibrillary acidic protein (137780),
apolipoprotein D (107740), fibronectin-1 (135600), and metallothionein
II (156360). These proteins are expected to be involved in increased
proteolysis, apoptosis, and glial activation. The molecular changes in
Cstb-deficient mice were consistent with the pathology found in the
mouse model.
*FIELD* AV
.0001
MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
CSTB, IVS1, G-C, -1
By complete sequencing of the cystatin B gene in affected members of 4
families with myoclonic epilepsy of Unverricht and Lundborg (254800),
Pennacchio et al. (1996) identified 2 different mutations in the
cystatin B gene. One of these found in an American family was a G-to-C
transversion at the last nucleotide of intron 1, altering the 3-prime
splice site AG to AC.
.0002
MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
CSTB, ARG68TER
In 2 of 4 families studied with progressive myoclonus epilepsy (254800),
Pennacchio et al. (1996) found that affected individuals carried a CGA-
(arg) to-TGA (stop) mutation in the cystatin B gene.
Alakurtti et al. (2005) transiently expressed the R68X mutation in
BHK-21 cells. The altered CSTB polypeptide was rapidly degraded.
.0003
MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
CSTB, (CCCCGCCCCGCG)n EXPANSION, 12-MER EXPANSION, PROMOTER REGION
In non-Finnish EPM1 (254800) families from northern Africa and Europe,
Lalioti et al. (1997) identified a tandem repeat of a dodecamer
(CCCCGCCCCGCG) in the 5-prime untranslated region of the cystatin B
gene. They identified 2 allelic variants with 2 or 3 tandem copies. The
frequency of the 3-copy allele was 66% in the normal Caucasian
population.
In cases of EPM1, Lafreniere et al. (1997) identified homozygosity for
an unstable insertion of approximately 600 to 900 bp that was resistant
to PCR amplification. This insertion mapped to a 12-bp polymorphic
tandem repeat located in the 5-prime flanking region of the STFB gene.
The insertion mutation was identified in 38 unrelated EPM1 chromosomes
of various ethnic origins. The size of the insertion varied between
different EPM1 chromosomes sharing a common haplotype and a common
origin, suggesting some level of meiotic instability. The most striking
attributes of the mutation in the 5-prime flanking region were its
unstable nature (size variation) and its resistance to PCR
amplification. Both of these attributes have been documented in fragile
X syndrome (300624), which represents an expansion of up to 4 kb of a
polymorphic CGG trinucleotide repeat in the 5-prime untranslated region
of the FMR1 gene (309550).
Independently, Virtaneva et al. (1997) reported unstable 15- to 18-mer
minisatellite repeat expansions within the cystatin B promoter region in
EPM1 patients. The repeat units were flanked by the 12-mer tandem repeat
and were similar to the 12-mer in sequence. Haplotype data were
compatible with a single ancestral founder mutation. The length of the
repeat array differed between chromosomes and families, but changes in
repeat numbers seemed to be comparatively rare events. They stated that
the mutation accounts for a majority of EPM1 cases worldwide. Lalioti et
al. (1997) presented further evidence that the common mutation mechanism
in EPM1 is expansion of the dodecamer repeat, not the expansion of de
novo 15- or 18-mer minisatellites, as had been suggested by Virtaneva et
al. (1997).
Mazarib et al. (2001) studied a 5-generation Arab EPM1 family lacking
photosensitivity, i.e., myoclonic jerks were not precipitated by photic
stimulation. Three living affected individuals were homozygous for
repeat expansions and 11 of the 16 unaffected family members were
heterozygous. Instability was demonstrated by the presence of expansions
of different sizes occurring on the same haplotype background in this
inbred family. The lack of photosensitivity in this family was
unexplained.
.0004
MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
CSTB, GLY4ARG
Lalioti et al. (1997) identified a homozygous G-to-C transversion at
nucleotide 426 in exon 1 of the cystatin B gene in non-Finnish EPM1
(254800) families from northern Africa and Europe. The mutation resulted
in a gly4-to-arg substitution and was the first missense mutation
described in association with EPM1. Molecular modeling predicted that
this substitution severely affected the contact of cystatin B with
papain.
Alakurtti et al. (2005) transiently expressed the G4R mutation in BHK-21
cells. The mutant protein failed to associate with lysosomes.
.0005
MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
CSTB, 2-BP DEL, 2404TC
Bespalova et al. (1997) described the complete sequence of the CSTB
coding region and splice junctions of a patient with progressive
myoclonus epilepsy (254800) who had decreased cystatin B mRNA levels but
lacked previously characterized mutations. The patient was found to be
heterozygous for a 2-bp deletion (2404delTC) in the third exon of the
CSTB gene. The mutation caused a translational frameshift and protein
truncation after 74 amino acids. The patient (EP6) had been described in
detail by Pranzatelli et al. (1995). This mutation was also found by
Lalioti et al. (1997) and Lafreniere et al. (1997). Alakurtti et al.
(2005) transiently expressed the 2400delTC mutation in BHK-21 cells. The
truncated mutant protein showed diffuse cytoplasmic and nuclear
distribution.
.0006
MYCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
CSTB, GLN71PRO
In a Dutch patient with progressive myclonus epilepsy (254800), de Haan
et al. (2004) identified a 2398A-C transversion in the CSTB gene,
resulting in a gln71-to-pro substitution (Q71P).
Alakurtti et al. (2005) transiently expressed the Q71P mutation in
BHK-21 cells. The mutant protein failed to associate with lysosomes.
*FIELD* RF
1. Alakurtti, K.; Weber, E.; Rinne, R.; Theil, G.; de Haan, G.-J.;
Lindhout, D.; Salmikangas, P.; Saukko, P.; Lahtinen, U.; Lehesjoki,
A.-E.: Loss of lysosomal association of cystatin B proteins representing
progressive myoclonus epilepsy, EPM1, mutations. Europ. J. Hum. Genet. 13:
208-215, 2005. Note: Erratum: Europ. J. Hum. Genet. 13: 264 only,
2005.
2. Antonarakis, S.: Personal Communication. Geneva, Switzerland
4/8/1997.
3. Bespalova, I. N.; Adkins, S.; Pranzatelli, M.; Burmeister, M.:
Novel cystatin B mutation and diagnostic PCR assay in an Unverricht-Lundborg
progressive myoclonus epilepsy patient. Am. J. Med. Genet. 74: 467-471,
1997.
4. de Haan, G.-J.; Halley, D. J. J.; Doelman, J. C.; Geesink, H. H.;
Augustijn, P. B.; Jager-Jongkind, A. D.; Majoie, M.; Bader, A. J.;
Leliefeld-ten Doeschate, L. A. W. M.; Deelen, W. H.; Bertram, E.;
Lehesjoki, A. E.; Lindhout, D.: Univerricht-Lundborg (sic) disease:
underdiagnosed in the Netherlands. Epilepsia 45: 1061-1063, 2004.
5. Di Giaimo, R.; Riccio, M.; Santi, S.; Galeotti, C.; Ambrosetti,
D. C.; Melli, M.: New insights into the molecular basis of progressive
myoclonus epilepsy: a multiprotein complex with cystatin B. Hum.
Molec. Genet. 11: 2941-2950, 2002.
6. Jarvinen, M.; Rinne, A.: Human spleen cysteine proteinase inhibitor:
purification, fractionation into isoelectric variants and some properties
of the variants. Biochim. Biophys. Acta 708: 210-217, 1982.
7. Jerala, R.; Trstenjak, M.; Lenarcic, B.; Turk, V.: Cloning a synthetic
gene for human stefin B and its expression in E. coli. FEBS Lett. 239:
41-44, 1988.
8. Lafreniere, R. G.; Rochefort, D. L.; Chretien, N.; Rommens, J.
M.; Cochius, J. I.; Kalviainen, R.; Nousiainen, U.; Patry, G.; Farrell,
K.; Soderfeldt, B.; Federico, A.; Hale, B. R.; Cossio, O. H.; Sorensen,
T.; Pouliot, M. A.; Kmiec, T.; Uldall, P.; Janszky, J.; Pranzatelli,
M. R.; Andermann, F.; Andermann, E.; Rouleau, G. A.: Unstable insertion
of the 5-prime flanking region of the cystatin B gene is the most
common mutation in progressive myoclonus epilepsy type 1, EPM1. Nature
Genet. 15: 298-302, 1997.
9. Lalioti, M. D.; Mirotsou, M.; Buresi, C.; Peitsch, M. C.; Rossier,
C.; Ouazzani, R.; Baldy-Moulinier, M.; Bottani, A.; Malafosse, A.;
Antonarakis, S. E.: Identification of mutations in cystatin B, the
gene responsible for the Unverricht-Lundborg type of progressive myoclonus
epilepsy (EPM1). Am. J. Hum. Genet. 60: 342-351, 1997.
10. Lalioti, M. D.; Scott, H. S.; Antonarakis, S. E.: What is expanded
in progressive myoclonus epilepsy? (Letter) Nature Genet. 17: 17
only, 1997.
11. Lalioti, M. D.; Scott, H. S.; Buresi, C.; Rossier, C.; Bottani,
A.; Morris, M. A.; Malafosse, A.; Antonarakis, S. E.: Dodecamer repeat
expansion in cystatin B gene in progressive myoclonus epilepsy. Nature 386:
847-851, 1997.
12. Lalioti, M. D.; Scott, H. S.; Genton, P.; Grid, D.; Ouazzani,
R.; M'Rabet, A.; Ibrahim, S.; Gouider, R.; Dravet, C.; Chkili, T.;
Bottani, A.; Buresi, C.; Malafosse, A.; Antonarakis, S. E.: A PCR
amplification method reveals instability of the dodecamer repeat in
progressive myoclonus epilepsy (EPM1) and no correlation between the
size of the repeat and age at onset. Am. J. Hum. Genet. 62: 842-847,
1998.
13. Lieuallen, K.; Pennacchio, L. A.; Park, M.; Myers, R. M.; Lennon,
G. G.: Cystatin B-deficient mice have increased expression of apoptosis
and glial activation genes. Hum. Molec. Genet. 10: 1867-1871, 2001.
14. Mazarib, A.; Xiong, L.; Neufeld, M. Y.; Birnbaum, M.; Korczyn,
A. D.; Pandolfo, M.; Berkovic, S. F.: Unverricht-Lundborg disease
in a five-generation Arab family: instability of dodecamer repeats. Neurology 57:
1050-1054, 2001.
15. Pennacchio, L. A.; Bouley, D. M.; Higgins, K. M.; Scott, M. P.;
Noebels, J. L.; Myers, R. M.: Progressive ataxia, myoclonic epilepsy
and cerebellar apoptosis in cystatin B-deficient mice. Nature Genet. 20:
251-258, 1998.
16. Pennacchio, L. A.; Lehesjoki, A.-E.; Stone, N. E.; Willour, V.
L.; Virtaneva, K.; Miao, J.; D'Amato, E.; Ramirez, L.; Faham, M.;
Koskiniemi, M.; Warrington, J. A.; Norio, R.; de la Chapelle, A.;
Cox, D. R.; Myers, R. M.: Mutations in the gene encoding cystatin
B in progressive myoclonus epilepsy (EPM1). Science 271: 1731-1733,
1996.
17. Pennacchio, L. A.; Myers, R. M.: Isolation and characterization
of the mouse cystatin B gene. Genome Res. 6: 1103-1109, 1996.
18. Pranzatelli, M. R.; Tate, E.; Huang, Y.; Haas, R. H.; Bodensteiner,
J.; Ashwal, S.; Franz, D.: Neuropharmacology of progressive myoclonus
epilepsy: response to 5-hydroxy-L-tryptophan. Epilepsia 36: 783-791,
1995.
19. Turk, V.; Bode, W.: The cystatins: protein inhibitors of cysteine
proteinases. FEBS Lett. 285: 213-219, 1991.
20. Virtaneva, K.; D'Amato, E.; Miao, J.; Koskiniemi, M.; Norio, R.;
Avanzini, G.; Franceschetti, S.; Michelucci, R.; Tassinari, C. A.;
Omer, S.; Pennacchio, L. A.; Myers, R. M.; Dieguez-Lucena, J. L.;
Krahe, R.; de la Chapelle, A.; Lehesjoki, A.-E.: Unstable minisatellite
expansion causing recessively inherited myoclonus epilepsy, EPM1. Nature
Genet. 15: 393-396, 1997.
*FIELD* CN
Victor A. McKusick - updated: 4/11/2005
George E. Tiller - updated: 3/31/2004
George E. Tiller - updated: 1/28/2002
Victor A. McKusick - updated: 10/22/1998
Victor A. McKusick - updated: 5/14/1998
Victor A. McKusick - updated: 11/11/1997
Stylianos E. Antonarakis - updated: 9/22/1997
Victor A. McKusick - updated: 8/28/1997
Victor A. McKusick - updated: 4/8/1997
Victor A. McKusick - updated: 3/31/1997
Victor A. McKusick - updated: 3/2/1997
Mark H. Paalman - updated: 11/5/1996
*FIELD* CD
Victor A. McKusick: 3/21/1996
*FIELD* ED
carol: 11/27/2006
alopez: 5/10/2006
wwang: 4/29/2005
wwang: 4/20/2005
terry: 4/11/2005
tkritzer: 3/31/2004
carol: 2/27/2003
cwells: 2/14/2002
cwells: 1/28/2002
carol: 11/8/2001
mcapotos: 11/2/2001
terry: 11/24/1999
alopez: 10/26/1998
carol: 10/22/1998
dkim: 9/10/1998
alopez: 5/19/1998
terry: 5/14/1998
dholmes: 11/21/1997
terry: 11/14/1997
terry: 11/11/1997
alopez: 9/22/1997
alopez: 9/17/1997
jenny: 9/1/1997
terry: 8/28/1997
terry: 7/9/1997
mark: 6/4/1997
terry: 5/20/1997
mark: 4/9/1997
mark: 4/8/1997
terry: 4/4/1997
mark: 3/31/1997
terry: 3/28/1997
mark: 3/2/1997
terry: 2/28/1997
mark: 12/17/1996
terry: 11/6/1996
mark: 11/5/1996
terry: 5/24/1996
mark: 3/21/1996
*RECORD*
*FIELD* NO
601145
*FIELD* TI
*601145 CYSTATIN B; CSTB
;;STEFIN B; STFB
*FIELD* TX
DESCRIPTION
Stefin B (also called cystatin B) is a small protein that is a member of
read morethe superfamily of cysteine protease inhibitors (Jarvinen and Rinne,
1982; Turk and Bode, 1991). It has been isolated from human spleen and
liver and its amino acid sequence has been fully determined. It is
widely distributed and is localized mostly intracellularly, but has been
found extracellularly. Its role is thought to be as a protector against
the proteinases leaking from lysosomes.
CLONING
In the course of positional cloning of the gene responsible for
progressive myoclonus epilepsy (EPM1; 254800) which had been mapped to
chromosome 21 in a segment of about 175 kb between D21S2040 and
D21S1259, Pennacchio et al. (1996) found a cDNA that encoded cystatin B
which was previously known but had not been mapped to a specific
chromosomal site. They confirmed previous reports that the gene encoding
cystatin B is widely expressed by demonstrating that a probe made from
the cDNA clone detected an mRNA approximately 0.8 kb in length in all
tissues examined. On Northern blots, lymphoblastoid cells from affected
individuals from 4 unrelated families showed reduced levels of cystatin
B mRNA compared to those from unaffected, noncarrier individuals and the
carrier parents of EPM1 patients.
Jerala et al. (1988) synthesized a gene coding for human stefin B by the
solid-phase phosphite method and cloned it in the pUC8 cloning vector.
Protein prepared in expression vectors was inhibitory to papain and
reacted with antibodies against human stefin B. Pennacchio et al. (1996)
stated that cystatin B is a tightly binding reversible inhibitor of
cathepsins L (116880), H (116820), and B (116810).
GENE STRUCTURE
Pennacchio et al. (1996) sequenced the STFB gene from affected and
unaffected individuals whose families had EPM1. Sequencing revealed that
the STFB gene is 2,500 bp in length and contains 3 small exons encoding
the 98-amino acid protein, whose mature mRNA and amino acid sequence
were previously known.
Pennacchio and Myers (1996) isolated and characterized the mouse homolog
of cystatin B. The gene spans 3 kb of genomic DNA and contains 3 exons
as in human and rat. The gene encodes a predicted 98-amino acid
polypeptide identical in length to the rat, bovine, and human genes and
bearing 86%, 71%, and 79% similarity, respectively, to the genes of the
other species. By Northern analysis, they showed that mouse cystatin B
is expressed in many tissues.
GENE FUNCTION
Using a yeast 2-hybrid system, Di Giaimo et al. (2002) identified 5
recombinant proteins interacting with cystatin B, none of which was a
protease. Three of these proteins, RACK1 (176981), beta-spectrin (see
182790), and NFL (162280), coimmunoprecipitated with cystatin B in rat
cerebellum. Confocal immunofluorescence analysis showed that the same
proteins were present in the granule cells of developing cerebellum, as
well as in Purkinje cells of adult rat cerebellum. The authors proposed
that a cystatin B multiprotein complex might have a specific cerebellar
function, and that the loss of this function might contribute to the
etiopathogenesis of EPM1.
Using a monoclonal CSTB antibody and organelle-specific markers in human
primary myoblasts, Alakurtti et al. (2005) showed that endogenous CSTB
localizes not only to the nucleus and cytoplasm but also associates with
lysosomes. Upon differentiation to myotubes, CSTB becomes excluded from
the nucleus and lysosomes, suggesting that the subcellular distribution
of CSTB is dependent on the differentiation status of the cell.
MAPPING
Pennacchio and Myers (1996) mapped the mouse cystatin B gene by
interspecific backcross analysis to mouse chromosome 10, extending
knowledge of the homology of synteny between this region of mouse
chromosome 10 and human chromosome 21q22.3.
MOLECULAR GENETICS
Lalioti et al. (1997) identified 6 nucleotide changes in the CSTB gene
in non-Finnish EPM1 families from northern Africa and Europe. One of
these, a homozygous G-to-C transversion at nucleotide 426 in exon 1,
resulted in a gly4-to-arg substitution (601145.0004) and was the first
missense mutation described in association with EPM1. Molecular modeling
predicted that this substitution would severely affect the contact of
cystatin B with papain. The 6 mutations were found in 7 of the 29
unrelated EPM1 patients analyzed, in homozygosity in 1, and in
heterozygosity in the others. They also found a tandem repeat of a
dodecamer (CCCCGCCCCGCG) in the 5-prime untranslated region as a
polymorphism (601145.0003). They identified 2 allelic variants with 2 or
3 tandem copies. The frequency of the 3-copy allele was 66% in the
normal Caucasian population.
Lafreniere et al. (1997) presented haplotype and mutation analyses of 20
unrelated EPM1 patients and families from different ethnic groups. They
identified 4 different mutations, the most common of which consisted of
an unstable insertion of approximately 600 to 900 bp that was resistant
to PCR amplification. This insertion mapped to a 12-bp polymorphic
tandem repeat located in the 5-prime flanking region of the STFB gene in
the region of the promoter (601145.0003). The size of the insertion
varied between different EPM1 chromosomes sharing a common haplotype and
a common origin, suggesting some level of meiotic instability over the
course of many generations. Lafreniere et al. (1997) speculated that
this dynamic mutation, which appeared distinct from conventional
trinucleotide repeat expansions, may arise via a novel mechanism related
to the instability of tandemly repeated sequences. Independently,
Virtaneva et al. (1997) identified unstable minisatellite expansions in
the promoter region of the cystatin B gene (symbolized CST6 by them).
They stated that the mutation accounts for the majority of EFM1 patients
worldwide. Haplotype data were compatible with a single ancestral
founder mutation. The length of the repeat array differed between
chromosomes and families, but changes in repeat numbers seemed to be
comparatively rare events. Virtaneva et al. (1997) noted that unstable
trinucleotide microsatellite repeat expansions are associated with at
least 10 inherited neurologic disorders and are associated in all cases,
except for Friedreich ataxia (229300), with strong anticipation. Unlike
unstable trinucleotide repeats, which show a high degree of
intergenerational instability, the EPM1-associated minisatellite
mutation did not appear to be as unstable and anticipation has not been
recognized in EPM1.
Antonarakis (1997) confirmed that the only EPM1-related point mutation
in the cystatin B gene found in homozygous state was the gly-to-arg
amino acid substitution (601145.0004). All other point mutations
identified in EPM1 patients were found as compound heterozygotes with
the 12-bp repeat expansion allele. The repeat expansion allele was also
homozygous in some patients. Antonarakis (1997) found no patients with
null point mutations (e.g., nonsense, frameshift, or splice site) in
homozygous state; all EPM1 patients had residual gene activity. He
proposed that homozygosity for null alleles was either nonviable or
presented a different phenotype.
In an elaboration on their previous work, Lalioti et al. (1997) stated
that the common mutation mechanism in EPM1 is the expansion of the
dodecamer repeat (601145.0003), and considered this mutation to be the
most likely source of the Finnish disorder described in 254800. An
examination of 58 EPM1 alleles revealed that 50 of these contained the
dodecamer repeat expansion. In addition to the expanded repeat mutation
and the 2 or 3 repeats found in alleles considered to be normal, Lalioti
et al. (1997) identified alleles with 12 to 17 repeats, which they
termed 'premutational,' that were transmitted unstably to offspring.
These 'premutational' alleles were not connected with a clinical
phenotype of EPM1. Lalioti et al. (1997) stated that no correlation
between number of repeat expansions and age of onset or severity had
been found.
Most EPM1 alleles contain large expansions of the dodecamer repeat
located upstream of the 5-prime transcription start site of the CSTB
gene; normal alleles contain 2 or 3 copies of this repeat. All EPM1
alleles with an expansion were resistant to standard PCR amplification.
To determine the size of the repeat in affected individuals, Lalioti et
al. (1998) developed a detection protocol involving PCR amplification
and subsequent hybridization with an oligonucleotide containing the
repeat. In EPM1 patients, the largest detected expansion was
approximately 75 copies; the smallest was approximately 30 copies. They
identified affected sibs with repeat expansions of different sizes on
the same haplotype, which confirmed the repeats' instability during
transmissions. Expansions were observed directly; contractions were
deduced by comparison of allele sizes within a family. In a sample of 28
patients, they found no correlation between age at onset of EPM1 and the
size of the expanded dodecamer. This suggested that once the dodecamer
repeat expands beyond a critical threshold, CSTB expression is reduced
in certain cells, with pathologic consequences.
Haplotype analysis in a previous study suggested that 3 of 4 independent
EPM1 mutations were present in 4 families. By sequence comparison,
Pennacchio et al. (1996) identified 2 different mutations in the
cystatin B gene. One was a G-to-C transversion at the last nucleotide of
intron 1 (601145.0001), altering the sequence of the 3-prime splice site
AG dinucleotide that is in this position in almost all introns. The
second mutation, which was found in alleles of the cystatin B gene from
2 of the 4 families, changed CGA to TGA, generating a translation stop
codon at amino acid position 68 (601145.0002). Despite identifying these
2 mutations in affected chromosomes from 3 of the 4 families, Pennacchio
et al. (1996) were unable to detect any sequence difference in the gene
encoding cystatin B from the remaining 1 or 2 alleles they had available
for study. Specifically, the Finnish ancestral mutation was not
identified. However, studies indicated that the expression of the
Finnish gene, as well as that of all the other mutant alleles, was
defective. Pennacchio et al. (1996) stated that, despite ubiquitous
expression of this protein, it is not understood why mutation of the
gene encoding cystatin B causes the symptoms of EPM1, an apparent
tissue-specific phenotype.
Alakurtti et al. (2005) transiently expressed 4 mutations altering the
CSTB polypeptide in BHK-21 cells. The 2400_2402delTC
(601145.0005)-truncated mutant protein showed diffuse cytoplasmic and
nuclear distribution, whereas R68X (601145.0002) was rapidly degraded.
Two missense mutations, G4R (601145.0004), affecting the highly
conserved glycine that is critical for cathepsin binding, and Q71P
(601145.0006), failed to associate with lysosomes. Alakurtti et al.
(2005) concluded that CSTB has an important lysosome-associated
physiologic function and suggested that loss of this association
contributes to the molecular pathogenesis of EPM1.
ANIMAL MODEL
Pennacchio et al. (1998) found that mice lacking cystatin B as a result
of targeted disruption of the gene develop myoclonic seizures and ataxia
similar to the symptoms shown in EPM1. The principal cytopathology
appeared to be loss of cerebellar granule cells, which frequently
display condensed nuclei, fragmented DNA, and other cellular changes
characteristic of apoptosis. This mouse model of EPM1 was thought to
provide evidence that cystatin B, as a noncaspase cysteine protease
inhibitor, has a role in preventing cerebellar apoptosis.
Lieuallen et al. (2001) identified 7 genes with consistently increased
transcript levels in neurologic tissues from Cstb-deficient knockout
mice: cathepsin S (116845), C1q B-chain of complement (120570),
beta-2-microglobulin (109700), glial fibrillary acidic protein (137780),
apolipoprotein D (107740), fibronectin-1 (135600), and metallothionein
II (156360). These proteins are expected to be involved in increased
proteolysis, apoptosis, and glial activation. The molecular changes in
Cstb-deficient mice were consistent with the pathology found in the
mouse model.
*FIELD* AV
.0001
MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
CSTB, IVS1, G-C, -1
By complete sequencing of the cystatin B gene in affected members of 4
families with myoclonic epilepsy of Unverricht and Lundborg (254800),
Pennacchio et al. (1996) identified 2 different mutations in the
cystatin B gene. One of these found in an American family was a G-to-C
transversion at the last nucleotide of intron 1, altering the 3-prime
splice site AG to AC.
.0002
MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
CSTB, ARG68TER
In 2 of 4 families studied with progressive myoclonus epilepsy (254800),
Pennacchio et al. (1996) found that affected individuals carried a CGA-
(arg) to-TGA (stop) mutation in the cystatin B gene.
Alakurtti et al. (2005) transiently expressed the R68X mutation in
BHK-21 cells. The altered CSTB polypeptide was rapidly degraded.
.0003
MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
CSTB, (CCCCGCCCCGCG)n EXPANSION, 12-MER EXPANSION, PROMOTER REGION
In non-Finnish EPM1 (254800) families from northern Africa and Europe,
Lalioti et al. (1997) identified a tandem repeat of a dodecamer
(CCCCGCCCCGCG) in the 5-prime untranslated region of the cystatin B
gene. They identified 2 allelic variants with 2 or 3 tandem copies. The
frequency of the 3-copy allele was 66% in the normal Caucasian
population.
In cases of EPM1, Lafreniere et al. (1997) identified homozygosity for
an unstable insertion of approximately 600 to 900 bp that was resistant
to PCR amplification. This insertion mapped to a 12-bp polymorphic
tandem repeat located in the 5-prime flanking region of the STFB gene.
The insertion mutation was identified in 38 unrelated EPM1 chromosomes
of various ethnic origins. The size of the insertion varied between
different EPM1 chromosomes sharing a common haplotype and a common
origin, suggesting some level of meiotic instability. The most striking
attributes of the mutation in the 5-prime flanking region were its
unstable nature (size variation) and its resistance to PCR
amplification. Both of these attributes have been documented in fragile
X syndrome (300624), which represents an expansion of up to 4 kb of a
polymorphic CGG trinucleotide repeat in the 5-prime untranslated region
of the FMR1 gene (309550).
Independently, Virtaneva et al. (1997) reported unstable 15- to 18-mer
minisatellite repeat expansions within the cystatin B promoter region in
EPM1 patients. The repeat units were flanked by the 12-mer tandem repeat
and were similar to the 12-mer in sequence. Haplotype data were
compatible with a single ancestral founder mutation. The length of the
repeat array differed between chromosomes and families, but changes in
repeat numbers seemed to be comparatively rare events. They stated that
the mutation accounts for a majority of EPM1 cases worldwide. Lalioti et
al. (1997) presented further evidence that the common mutation mechanism
in EPM1 is expansion of the dodecamer repeat, not the expansion of de
novo 15- or 18-mer minisatellites, as had been suggested by Virtaneva et
al. (1997).
Mazarib et al. (2001) studied a 5-generation Arab EPM1 family lacking
photosensitivity, i.e., myoclonic jerks were not precipitated by photic
stimulation. Three living affected individuals were homozygous for
repeat expansions and 11 of the 16 unaffected family members were
heterozygous. Instability was demonstrated by the presence of expansions
of different sizes occurring on the same haplotype background in this
inbred family. The lack of photosensitivity in this family was
unexplained.
.0004
MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
CSTB, GLY4ARG
Lalioti et al. (1997) identified a homozygous G-to-C transversion at
nucleotide 426 in exon 1 of the cystatin B gene in non-Finnish EPM1
(254800) families from northern Africa and Europe. The mutation resulted
in a gly4-to-arg substitution and was the first missense mutation
described in association with EPM1. Molecular modeling predicted that
this substitution severely affected the contact of cystatin B with
papain.
Alakurtti et al. (2005) transiently expressed the G4R mutation in BHK-21
cells. The mutant protein failed to associate with lysosomes.
.0005
MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
CSTB, 2-BP DEL, 2404TC
Bespalova et al. (1997) described the complete sequence of the CSTB
coding region and splice junctions of a patient with progressive
myoclonus epilepsy (254800) who had decreased cystatin B mRNA levels but
lacked previously characterized mutations. The patient was found to be
heterozygous for a 2-bp deletion (2404delTC) in the third exon of the
CSTB gene. The mutation caused a translational frameshift and protein
truncation after 74 amino acids. The patient (EP6) had been described in
detail by Pranzatelli et al. (1995). This mutation was also found by
Lalioti et al. (1997) and Lafreniere et al. (1997). Alakurtti et al.
(2005) transiently expressed the 2400delTC mutation in BHK-21 cells. The
truncated mutant protein showed diffuse cytoplasmic and nuclear
distribution.
.0006
MYCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
CSTB, GLN71PRO
In a Dutch patient with progressive myclonus epilepsy (254800), de Haan
et al. (2004) identified a 2398A-C transversion in the CSTB gene,
resulting in a gln71-to-pro substitution (Q71P).
Alakurtti et al. (2005) transiently expressed the Q71P mutation in
BHK-21 cells. The mutant protein failed to associate with lysosomes.
*FIELD* RF
1. Alakurtti, K.; Weber, E.; Rinne, R.; Theil, G.; de Haan, G.-J.;
Lindhout, D.; Salmikangas, P.; Saukko, P.; Lahtinen, U.; Lehesjoki,
A.-E.: Loss of lysosomal association of cystatin B proteins representing
progressive myoclonus epilepsy, EPM1, mutations. Europ. J. Hum. Genet. 13:
208-215, 2005. Note: Erratum: Europ. J. Hum. Genet. 13: 264 only,
2005.
2. Antonarakis, S.: Personal Communication. Geneva, Switzerland
4/8/1997.
3. Bespalova, I. N.; Adkins, S.; Pranzatelli, M.; Burmeister, M.:
Novel cystatin B mutation and diagnostic PCR assay in an Unverricht-Lundborg
progressive myoclonus epilepsy patient. Am. J. Med. Genet. 74: 467-471,
1997.
4. de Haan, G.-J.; Halley, D. J. J.; Doelman, J. C.; Geesink, H. H.;
Augustijn, P. B.; Jager-Jongkind, A. D.; Majoie, M.; Bader, A. J.;
Leliefeld-ten Doeschate, L. A. W. M.; Deelen, W. H.; Bertram, E.;
Lehesjoki, A. E.; Lindhout, D.: Univerricht-Lundborg (sic) disease:
underdiagnosed in the Netherlands. Epilepsia 45: 1061-1063, 2004.
5. Di Giaimo, R.; Riccio, M.; Santi, S.; Galeotti, C.; Ambrosetti,
D. C.; Melli, M.: New insights into the molecular basis of progressive
myoclonus epilepsy: a multiprotein complex with cystatin B. Hum.
Molec. Genet. 11: 2941-2950, 2002.
6. Jarvinen, M.; Rinne, A.: Human spleen cysteine proteinase inhibitor:
purification, fractionation into isoelectric variants and some properties
of the variants. Biochim. Biophys. Acta 708: 210-217, 1982.
7. Jerala, R.; Trstenjak, M.; Lenarcic, B.; Turk, V.: Cloning a synthetic
gene for human stefin B and its expression in E. coli. FEBS Lett. 239:
41-44, 1988.
8. Lafreniere, R. G.; Rochefort, D. L.; Chretien, N.; Rommens, J.
M.; Cochius, J. I.; Kalviainen, R.; Nousiainen, U.; Patry, G.; Farrell,
K.; Soderfeldt, B.; Federico, A.; Hale, B. R.; Cossio, O. H.; Sorensen,
T.; Pouliot, M. A.; Kmiec, T.; Uldall, P.; Janszky, J.; Pranzatelli,
M. R.; Andermann, F.; Andermann, E.; Rouleau, G. A.: Unstable insertion
of the 5-prime flanking region of the cystatin B gene is the most
common mutation in progressive myoclonus epilepsy type 1, EPM1. Nature
Genet. 15: 298-302, 1997.
9. Lalioti, M. D.; Mirotsou, M.; Buresi, C.; Peitsch, M. C.; Rossier,
C.; Ouazzani, R.; Baldy-Moulinier, M.; Bottani, A.; Malafosse, A.;
Antonarakis, S. E.: Identification of mutations in cystatin B, the
gene responsible for the Unverricht-Lundborg type of progressive myoclonus
epilepsy (EPM1). Am. J. Hum. Genet. 60: 342-351, 1997.
10. Lalioti, M. D.; Scott, H. S.; Antonarakis, S. E.: What is expanded
in progressive myoclonus epilepsy? (Letter) Nature Genet. 17: 17
only, 1997.
11. Lalioti, M. D.; Scott, H. S.; Buresi, C.; Rossier, C.; Bottani,
A.; Morris, M. A.; Malafosse, A.; Antonarakis, S. E.: Dodecamer repeat
expansion in cystatin B gene in progressive myoclonus epilepsy. Nature 386:
847-851, 1997.
12. Lalioti, M. D.; Scott, H. S.; Genton, P.; Grid, D.; Ouazzani,
R.; M'Rabet, A.; Ibrahim, S.; Gouider, R.; Dravet, C.; Chkili, T.;
Bottani, A.; Buresi, C.; Malafosse, A.; Antonarakis, S. E.: A PCR
amplification method reveals instability of the dodecamer repeat in
progressive myoclonus epilepsy (EPM1) and no correlation between the
size of the repeat and age at onset. Am. J. Hum. Genet. 62: 842-847,
1998.
13. Lieuallen, K.; Pennacchio, L. A.; Park, M.; Myers, R. M.; Lennon,
G. G.: Cystatin B-deficient mice have increased expression of apoptosis
and glial activation genes. Hum. Molec. Genet. 10: 1867-1871, 2001.
14. Mazarib, A.; Xiong, L.; Neufeld, M. Y.; Birnbaum, M.; Korczyn,
A. D.; Pandolfo, M.; Berkovic, S. F.: Unverricht-Lundborg disease
in a five-generation Arab family: instability of dodecamer repeats. Neurology 57:
1050-1054, 2001.
15. Pennacchio, L. A.; Bouley, D. M.; Higgins, K. M.; Scott, M. P.;
Noebels, J. L.; Myers, R. M.: Progressive ataxia, myoclonic epilepsy
and cerebellar apoptosis in cystatin B-deficient mice. Nature Genet. 20:
251-258, 1998.
16. Pennacchio, L. A.; Lehesjoki, A.-E.; Stone, N. E.; Willour, V.
L.; Virtaneva, K.; Miao, J.; D'Amato, E.; Ramirez, L.; Faham, M.;
Koskiniemi, M.; Warrington, J. A.; Norio, R.; de la Chapelle, A.;
Cox, D. R.; Myers, R. M.: Mutations in the gene encoding cystatin
B in progressive myoclonus epilepsy (EPM1). Science 271: 1731-1733,
1996.
17. Pennacchio, L. A.; Myers, R. M.: Isolation and characterization
of the mouse cystatin B gene. Genome Res. 6: 1103-1109, 1996.
18. Pranzatelli, M. R.; Tate, E.; Huang, Y.; Haas, R. H.; Bodensteiner,
J.; Ashwal, S.; Franz, D.: Neuropharmacology of progressive myoclonus
epilepsy: response to 5-hydroxy-L-tryptophan. Epilepsia 36: 783-791,
1995.
19. Turk, V.; Bode, W.: The cystatins: protein inhibitors of cysteine
proteinases. FEBS Lett. 285: 213-219, 1991.
20. Virtaneva, K.; D'Amato, E.; Miao, J.; Koskiniemi, M.; Norio, R.;
Avanzini, G.; Franceschetti, S.; Michelucci, R.; Tassinari, C. A.;
Omer, S.; Pennacchio, L. A.; Myers, R. M.; Dieguez-Lucena, J. L.;
Krahe, R.; de la Chapelle, A.; Lehesjoki, A.-E.: Unstable minisatellite
expansion causing recessively inherited myoclonus epilepsy, EPM1. Nature
Genet. 15: 393-396, 1997.
*FIELD* CN
Victor A. McKusick - updated: 4/11/2005
George E. Tiller - updated: 3/31/2004
George E. Tiller - updated: 1/28/2002
Victor A. McKusick - updated: 10/22/1998
Victor A. McKusick - updated: 5/14/1998
Victor A. McKusick - updated: 11/11/1997
Stylianos E. Antonarakis - updated: 9/22/1997
Victor A. McKusick - updated: 8/28/1997
Victor A. McKusick - updated: 4/8/1997
Victor A. McKusick - updated: 3/31/1997
Victor A. McKusick - updated: 3/2/1997
Mark H. Paalman - updated: 11/5/1996
*FIELD* CD
Victor A. McKusick: 3/21/1996
*FIELD* ED
carol: 11/27/2006
alopez: 5/10/2006
wwang: 4/29/2005
wwang: 4/20/2005
terry: 4/11/2005
tkritzer: 3/31/2004
carol: 2/27/2003
cwells: 2/14/2002
cwells: 1/28/2002
carol: 11/8/2001
mcapotos: 11/2/2001
terry: 11/24/1999
alopez: 10/26/1998
carol: 10/22/1998
dkim: 9/10/1998
alopez: 5/19/1998
terry: 5/14/1998
dholmes: 11/21/1997
terry: 11/14/1997
terry: 11/11/1997
alopez: 9/22/1997
alopez: 9/17/1997
jenny: 9/1/1997
terry: 8/28/1997
terry: 7/9/1997
mark: 6/4/1997
terry: 5/20/1997
mark: 4/9/1997
mark: 4/8/1997
terry: 4/4/1997
mark: 3/31/1997
terry: 3/28/1997
mark: 3/2/1997
terry: 2/28/1997
mark: 12/17/1996
terry: 11/6/1996
mark: 11/5/1996
terry: 5/24/1996
mark: 3/21/1996