Full text data of CNBP
CNBP
(RNF163, ZNF9)
[Confidence: low (only semi-automatic identification from reviews)]
Cellular nucleic acid-binding protein; CNBP (Zinc finger protein 9)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Cellular nucleic acid-binding protein; CNBP (Zinc finger protein 9)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P62633
ID CNBP_HUMAN Reviewed; 177 AA.
AC P62633; A8K7V4; B2RAV9; D3DNB9; D3DNC0; D3DNC1; E9PDR7; P20694;
read moreAC Q4JGY0; Q5QJR0; Q5U0E9; Q6PJI7; Q96NV3;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 19-JUL-2004, sequence version 1.
DT 22-JAN-2014, entry version 102.
DE RecName: Full=Cellular nucleic acid-binding protein;
DE Short=CNBP;
DE AltName: Full=Zinc finger protein 9;
GN Name=CNBP; Synonyms=RNF163, ZNF9;
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 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2562787; DOI=10.1126/science.2562787;
RA Rajavashisth T.B., Taylor A.K., Andalibi A., Svenson K.L., Lusis A.J.;
RT "Identification of a zinc finger protein that binds to the sterol
RT regulatory element.";
RL Science 245:640-643(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Placenta;
RX PubMed=7590281; DOI=10.1016/0378-1119(95)00421-2;
RA Flink I.L., Morkin E.;
RT "Organization of the gene encoding cellular nucleic acid-binding
RT protein.";
RL Gene 163:279-282(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND DISEASE.
RX PubMed=11486088; DOI=10.1126/science.1062125;
RA Liquori C.L., Ricker K., Moseley M.L., Jacobsen J.F., Kress W.,
RA Naylor S.L., Day J.W., Ranum L.P.;
RT "Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of
RT ZNF9.";
RL Science 293:864-867(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 4 AND 5).
RA Yang F., Yan H., Zhang S.;
RT "Cloning of novel transcript variants of human cellular nucleic acid
RT binding protein.";
RL Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 3 AND 6).
RC TISSUE=Placenta, and Synovium;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, Lung, and Uterus;
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 [10]
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 [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
CC -!- FUNCTION: Single-stranded DNA-binding protein, with specificity to
CC the sterol regulatory element (SRE). Involved in sterol-mediated
CC repression.
CC -!- SUBCELLULAR LOCATION: Cytoplasm (By similarity). Endoplasmic
CC reticulum (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1;
CC IsoId=P62633-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P62633-2; Sequence=VSP_010981;
CC Name=3;
CC IsoId=P62633-3; Sequence=VSP_010982;
CC Name=4;
CC IsoId=P62633-4; Sequence=VSP_043304;
CC Name=5;
CC IsoId=P62633-5; Sequence=VSP_010981, VSP_043424;
CC Note=No experimental confirmation available;
CC Name=6;
CC IsoId=P62633-6; Sequence=VSP_043424;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Present in all tissues examined.
CC -!- DISEASE: Dystrophia myotonica 2 (DM2) [MIM:602668]: A multisystem
CC disease characterized by the association of proximal muscle
CC weakness with myotonia, cardiac manifestations and cataract.
CC Additional features can include hyperhidrosis, testicular atrophy,
CC insulin resistance and diabetes and central nervous system
CC anomalies in rare cases. Note=The disease is caused by mutations
CC affecting the gene represented in this entry. The causative
CC mutation is a CCTG expansion (mean approximately 5000 repeats)
CC located in intron 1 of the CNBP gene.
CC -!- SIMILARITY: Contains 7 CCHC-type zinc fingers.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CNBP";
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; M28372; AAA61975.1; -; mRNA.
DR EMBL; U19765; AAA91782.1; -; Genomic_DNA.
DR EMBL; AY329622; AAR89462.1; -; Genomic_DNA.
DR EMBL; DQ092367; AAY96755.1; -; mRNA.
DR EMBL; DQ091187; AAY89856.1; -; mRNA.
DR EMBL; AK054592; BAB70769.1; -; mRNA.
DR EMBL; AK292119; BAF84808.1; -; mRNA.
DR EMBL; AK314380; BAG37006.1; -; mRNA.
DR EMBL; BT019613; AAV38419.1; -; mRNA.
DR EMBL; AC108673; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC135587; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471052; EAW79271.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW79272.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW79273.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW79274.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW79275.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW79277.1; -; Genomic_DNA.
DR EMBL; BC000288; AAH00288.1; -; mRNA.
DR EMBL; BC014911; AAH14911.1; -; mRNA.
DR EMBL; BC093058; AAH93058.1; -; mRNA.
DR PIR; A32760; A32760.
DR RefSeq; NP_001120664.1; NM_001127192.1.
DR RefSeq; NP_001120665.1; NM_001127193.1.
DR RefSeq; NP_001120666.1; NM_001127194.1.
DR RefSeq; NP_001120668.1; NM_001127196.1.
DR RefSeq; NP_003409.1; NM_003418.4.
DR RefSeq; XP_005247804.1; XM_005247747.1.
DR UniGene; Hs.518249; -.
DR ProteinModelPortal; P62633; -.
DR SMR; P62633; 4-70, 74-112, 135-174.
DR IntAct; P62633; 5.
DR MINT; MINT-4589059; -.
DR STRING; 9606.ENSP00000303844; -.
DR PhosphoSite; P62633; -.
DR DMDM; 50401852; -.
DR PaxDb; P62633; -.
DR PRIDE; P62633; -.
DR DNASU; 7555; -.
DR Ensembl; ENST00000422453; ENSP00000410619; ENSG00000169714.
DR Ensembl; ENST00000441626; ENSP00000410769; ENSG00000169714.
DR Ensembl; ENST00000446936; ENSP00000400444; ENSG00000169714.
DR Ensembl; ENST00000451728; ENSP00000399488; ENSG00000169714.
DR Ensembl; ENST00000502976; ENSP00000421323; ENSG00000169714.
DR Ensembl; ENST00000504813; ENSP00000422110; ENSG00000169714.
DR GeneID; 7555; -.
DR KEGG; hsa:7555; -.
DR UCSC; uc021xdu.1; human.
DR CTD; 7555; -.
DR GeneCards; GC03M128886; -.
DR HGNC; HGNC:13164; CNBP.
DR MIM; 116955; gene.
DR MIM; 602668; phenotype.
DR neXtProt; NX_P62633; -.
DR Orphanet; 606; Proximal myotonic myopathy.
DR PharmGKB; PA37737; -.
DR eggNOG; COG5082; -.
DR HOGENOM; HOG000186262; -.
DR HOVERGEN; HBG000397; -.
DR InParanoid; P62633; -.
DR KO; K09250; -.
DR OMA; CPNGQGG; -.
DR OrthoDB; EOG790G22; -.
DR PhylomeDB; P62633; -.
DR ChiTaRS; CNBP; human.
DR GeneWiki; CNBP; -.
DR GenomeRNAi; 7555; -.
DR NextBio; 29559; -.
DR PRO; PR:P62633; -.
DR ArrayExpress; P62633; -.
DR Bgee; P62633; -.
DR CleanEx; HS_CNBP; -.
DR Genevestigator; P62633; -.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0003700; F:sequence-specific DNA binding transcription factor activity; TAS:ProtInc.
DR GO; GO:0003697; F:single-stranded DNA binding; IEA:Ensembl.
DR GO; GO:0003727; F:single-stranded RNA binding; IEA:Ensembl.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006695; P:cholesterol biosynthetic process; TAS:ProtInc.
DR GO; GO:0008284; P:positive regulation of cell proliferation; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; ISS:UniProtKB.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR Gene3D; 4.10.60.10; -; 4.
DR InterPro; IPR001878; Znf_CCHC.
DR Pfam; PF00098; zf-CCHC; 7.
DR SMART; SM00343; ZnF_C2HC; 7.
DR SUPFAM; SSF57756; SSF57756; 4.
DR PROSITE; PS50158; ZF_CCHC; 7.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Complete proteome; Cytoplasm;
KW DNA-binding; Endoplasmic reticulum; Metal-binding; Reference proteome;
KW Repeat; Repressor; Transcription; Transcription regulation; Zinc;
KW Zinc-finger.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 177 Cellular nucleic acid-binding protein.
FT /FTId=PRO_0000089965.
FT ZN_FING 4 21 CCHC-type 1.
FT ZN_FING 52 69 CCHC-type 2.
FT ZN_FING 72 89 CCHC-type 3.
FT ZN_FING 96 113 CCHC-type 4.
FT ZN_FING 117 134 CCHC-type 5.
FT ZN_FING 135 152 CCHC-type 6.
FT ZN_FING 156 173 CCHC-type 7.
FT MOD_RES 2 2 N-acetylserine.
FT VAR_SEQ 36 42 Missing (in isoform 2 and isoform 5).
FT /FTId=VSP_010981.
FT VAR_SEQ 42 51 Missing (in isoform 3).
FT /FTId=VSP_010982.
FT VAR_SEQ 72 72 D -> DE (in isoform 4).
FT /FTId=VSP_043304.
FT VAR_SEQ 72 72 D -> DVE (in isoform 5 and isoform 6).
FT /FTId=VSP_043424.
FT CONFLICT 6 6 C -> R (in Ref. 5; BAF84808).
SQ SEQUENCE 177 AA; 19463 MW; 996F398285F52618 CRC64;
MSSNECFKCG RSGHWARECP TGGGRGRGMR SRGRGGFTSD RGFQFVSSSL PDICYRCGES
GHLAKDCDLQ EDACYNCGRG GHIAKDCKEP KREREQCCYN CGKPGHLARD CDHADEQKCY
SCGEFGHIQK DCTKVKCYRC GETGHVAINC SKTSEVNCYR CGESGHLARE CTIEATA
//
ID CNBP_HUMAN Reviewed; 177 AA.
AC P62633; A8K7V4; B2RAV9; D3DNB9; D3DNC0; D3DNC1; E9PDR7; P20694;
read moreAC Q4JGY0; Q5QJR0; Q5U0E9; Q6PJI7; Q96NV3;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 19-JUL-2004, sequence version 1.
DT 22-JAN-2014, entry version 102.
DE RecName: Full=Cellular nucleic acid-binding protein;
DE Short=CNBP;
DE AltName: Full=Zinc finger protein 9;
GN Name=CNBP; Synonyms=RNF163, ZNF9;
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 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2562787; DOI=10.1126/science.2562787;
RA Rajavashisth T.B., Taylor A.K., Andalibi A., Svenson K.L., Lusis A.J.;
RT "Identification of a zinc finger protein that binds to the sterol
RT regulatory element.";
RL Science 245:640-643(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Placenta;
RX PubMed=7590281; DOI=10.1016/0378-1119(95)00421-2;
RA Flink I.L., Morkin E.;
RT "Organization of the gene encoding cellular nucleic acid-binding
RT protein.";
RL Gene 163:279-282(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND DISEASE.
RX PubMed=11486088; DOI=10.1126/science.1062125;
RA Liquori C.L., Ricker K., Moseley M.L., Jacobsen J.F., Kress W.,
RA Naylor S.L., Day J.W., Ranum L.P.;
RT "Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of
RT ZNF9.";
RL Science 293:864-867(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 4 AND 5).
RA Yang F., Yan H., Zhang S.;
RT "Cloning of novel transcript variants of human cellular nucleic acid
RT binding protein.";
RL Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 3 AND 6).
RC TISSUE=Placenta, and Synovium;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, Lung, and Uterus;
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 [10]
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 [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
CC -!- FUNCTION: Single-stranded DNA-binding protein, with specificity to
CC the sterol regulatory element (SRE). Involved in sterol-mediated
CC repression.
CC -!- SUBCELLULAR LOCATION: Cytoplasm (By similarity). Endoplasmic
CC reticulum (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1;
CC IsoId=P62633-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P62633-2; Sequence=VSP_010981;
CC Name=3;
CC IsoId=P62633-3; Sequence=VSP_010982;
CC Name=4;
CC IsoId=P62633-4; Sequence=VSP_043304;
CC Name=5;
CC IsoId=P62633-5; Sequence=VSP_010981, VSP_043424;
CC Note=No experimental confirmation available;
CC Name=6;
CC IsoId=P62633-6; Sequence=VSP_043424;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Present in all tissues examined.
CC -!- DISEASE: Dystrophia myotonica 2 (DM2) [MIM:602668]: A multisystem
CC disease characterized by the association of proximal muscle
CC weakness with myotonia, cardiac manifestations and cataract.
CC Additional features can include hyperhidrosis, testicular atrophy,
CC insulin resistance and diabetes and central nervous system
CC anomalies in rare cases. Note=The disease is caused by mutations
CC affecting the gene represented in this entry. The causative
CC mutation is a CCTG expansion (mean approximately 5000 repeats)
CC located in intron 1 of the CNBP gene.
CC -!- SIMILARITY: Contains 7 CCHC-type zinc fingers.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CNBP";
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; M28372; AAA61975.1; -; mRNA.
DR EMBL; U19765; AAA91782.1; -; Genomic_DNA.
DR EMBL; AY329622; AAR89462.1; -; Genomic_DNA.
DR EMBL; DQ092367; AAY96755.1; -; mRNA.
DR EMBL; DQ091187; AAY89856.1; -; mRNA.
DR EMBL; AK054592; BAB70769.1; -; mRNA.
DR EMBL; AK292119; BAF84808.1; -; mRNA.
DR EMBL; AK314380; BAG37006.1; -; mRNA.
DR EMBL; BT019613; AAV38419.1; -; mRNA.
DR EMBL; AC108673; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC135587; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471052; EAW79271.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW79272.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW79273.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW79274.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW79275.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW79277.1; -; Genomic_DNA.
DR EMBL; BC000288; AAH00288.1; -; mRNA.
DR EMBL; BC014911; AAH14911.1; -; mRNA.
DR EMBL; BC093058; AAH93058.1; -; mRNA.
DR PIR; A32760; A32760.
DR RefSeq; NP_001120664.1; NM_001127192.1.
DR RefSeq; NP_001120665.1; NM_001127193.1.
DR RefSeq; NP_001120666.1; NM_001127194.1.
DR RefSeq; NP_001120668.1; NM_001127196.1.
DR RefSeq; NP_003409.1; NM_003418.4.
DR RefSeq; XP_005247804.1; XM_005247747.1.
DR UniGene; Hs.518249; -.
DR ProteinModelPortal; P62633; -.
DR SMR; P62633; 4-70, 74-112, 135-174.
DR IntAct; P62633; 5.
DR MINT; MINT-4589059; -.
DR STRING; 9606.ENSP00000303844; -.
DR PhosphoSite; P62633; -.
DR DMDM; 50401852; -.
DR PaxDb; P62633; -.
DR PRIDE; P62633; -.
DR DNASU; 7555; -.
DR Ensembl; ENST00000422453; ENSP00000410619; ENSG00000169714.
DR Ensembl; ENST00000441626; ENSP00000410769; ENSG00000169714.
DR Ensembl; ENST00000446936; ENSP00000400444; ENSG00000169714.
DR Ensembl; ENST00000451728; ENSP00000399488; ENSG00000169714.
DR Ensembl; ENST00000502976; ENSP00000421323; ENSG00000169714.
DR Ensembl; ENST00000504813; ENSP00000422110; ENSG00000169714.
DR GeneID; 7555; -.
DR KEGG; hsa:7555; -.
DR UCSC; uc021xdu.1; human.
DR CTD; 7555; -.
DR GeneCards; GC03M128886; -.
DR HGNC; HGNC:13164; CNBP.
DR MIM; 116955; gene.
DR MIM; 602668; phenotype.
DR neXtProt; NX_P62633; -.
DR Orphanet; 606; Proximal myotonic myopathy.
DR PharmGKB; PA37737; -.
DR eggNOG; COG5082; -.
DR HOGENOM; HOG000186262; -.
DR HOVERGEN; HBG000397; -.
DR InParanoid; P62633; -.
DR KO; K09250; -.
DR OMA; CPNGQGG; -.
DR OrthoDB; EOG790G22; -.
DR PhylomeDB; P62633; -.
DR ChiTaRS; CNBP; human.
DR GeneWiki; CNBP; -.
DR GenomeRNAi; 7555; -.
DR NextBio; 29559; -.
DR PRO; PR:P62633; -.
DR ArrayExpress; P62633; -.
DR Bgee; P62633; -.
DR CleanEx; HS_CNBP; -.
DR Genevestigator; P62633; -.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0003700; F:sequence-specific DNA binding transcription factor activity; TAS:ProtInc.
DR GO; GO:0003697; F:single-stranded DNA binding; IEA:Ensembl.
DR GO; GO:0003727; F:single-stranded RNA binding; IEA:Ensembl.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006695; P:cholesterol biosynthetic process; TAS:ProtInc.
DR GO; GO:0008284; P:positive regulation of cell proliferation; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; ISS:UniProtKB.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR Gene3D; 4.10.60.10; -; 4.
DR InterPro; IPR001878; Znf_CCHC.
DR Pfam; PF00098; zf-CCHC; 7.
DR SMART; SM00343; ZnF_C2HC; 7.
DR SUPFAM; SSF57756; SSF57756; 4.
DR PROSITE; PS50158; ZF_CCHC; 7.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Complete proteome; Cytoplasm;
KW DNA-binding; Endoplasmic reticulum; Metal-binding; Reference proteome;
KW Repeat; Repressor; Transcription; Transcription regulation; Zinc;
KW Zinc-finger.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 177 Cellular nucleic acid-binding protein.
FT /FTId=PRO_0000089965.
FT ZN_FING 4 21 CCHC-type 1.
FT ZN_FING 52 69 CCHC-type 2.
FT ZN_FING 72 89 CCHC-type 3.
FT ZN_FING 96 113 CCHC-type 4.
FT ZN_FING 117 134 CCHC-type 5.
FT ZN_FING 135 152 CCHC-type 6.
FT ZN_FING 156 173 CCHC-type 7.
FT MOD_RES 2 2 N-acetylserine.
FT VAR_SEQ 36 42 Missing (in isoform 2 and isoform 5).
FT /FTId=VSP_010981.
FT VAR_SEQ 42 51 Missing (in isoform 3).
FT /FTId=VSP_010982.
FT VAR_SEQ 72 72 D -> DE (in isoform 4).
FT /FTId=VSP_043304.
FT VAR_SEQ 72 72 D -> DVE (in isoform 5 and isoform 6).
FT /FTId=VSP_043424.
FT CONFLICT 6 6 C -> R (in Ref. 5; BAF84808).
SQ SEQUENCE 177 AA; 19463 MW; 996F398285F52618 CRC64;
MSSNECFKCG RSGHWARECP TGGGRGRGMR SRGRGGFTSD RGFQFVSSSL PDICYRCGES
GHLAKDCDLQ EDACYNCGRG GHIAKDCKEP KREREQCCYN CGKPGHLARD CDHADEQKCY
SCGEFGHIQK DCTKVKCYRC GETGHVAINC SKTSEVNCYR CGESGHLARE CTIEATA
//
MIM
116955
*RECORD*
*FIELD* NO
116955
*FIELD* TI
*116955 ZINC FINGER PROTEIN 9; ZNF9
;;CELLULAR RETROVIRAL NUCLEIC ACID-BINDING PROTEIN 1; CNBP1
read more*FIELD* TX
DESCRIPTION
The ZNF9 protein contains 7 zinc finger domains and is believed to
function as an RNA-binding protein. A CCTG expansion in intron 1 of the
ZNF9 gene results in myotonic dystrophy-2 (602668).
CLONING
Cholesterol homeostasis is maintained in part by negative feedback
regulation of the genes for proteins involved in cholesterol synthesis
and the cellular uptake of cholesterol. The apparent coordinate
regulation of several such genes, including HMG-CoA reductase (142910),
HMG-CoA synthase (142940), farnesylpyrophosphate synthetase (134629),
and the LDL receptor (606945) suggest that these genes may be regulated
by a common trans-acting factor that is able to 'sense' the levels of
cellular sterols. In a search for such a trans-acting factor,
Rajavashisth et al. (1989) identified a cDNA that encodes a 19-kD
protein containing 7 highly conserved zinc finger repeats with
remarkable sequence similarity to the finger domains of the family of
retroviral nucleic acid-binding proteins (NBPs). They designated the
protein cellular NBP (CNBP). In common with the viral NBPs, CNBP
appeared to have a strong preference for single-stranded DNA.
MAPPING
Lusis et al. (1990) assigned the CNBP gene to chromosome 3 by Southern
analysis of DNAs from mouse/human somatic cell hybrids and regionalized
the gene to 3q13.3-q24 by in situ hybridization.
MOLECULAR GENETICS
Liquori et al. (2001) demonstrated that a CCTG repeat expansion in
intron 1 of the ZNF9 gene is responsible for DM2 (602668). The range of
expanded allele sizes is extremely broad, from 75 to approximately
11,000 CCTG repeats. The mean repeat length is about 5,000. The expanded
ZNF9 RNA accumulates in discrete foci within the nucleus. ZNF9 contains
7 zinc finger domains and is thought to be an RNA-binding protein. It is
broadly expressed, with the most abundant expression in heart and
skeletal muscle, 2 tissues prominently affected in DM2. The similarity
of mechanism of mutation between DM2 and DM1 (160900) is striking: a
trinucleotide repeat expansion in the 3-prime untranslated region of the
DMPK gene (605377) is responsible for DM1. Clinical and molecular
parallels between DM1 and DM2 indicate that microsatellite expansions in
RNA can themselves be pathogenic.
To investigate the ancestral origins of the DM2 CCTG expansion, Liquori
et al. (2003) used 19 short tandem repeat markers flanking the repeat
tract to compare haplotypes of 71 families with genetically confirmed
DM2. All the families were white, and most were of northern
European/German descent; a single family was from Afghanistan. A common
interval that was shared by all families with DM2 immediately flanked
the repeat, extending up to 216 kb telomeric and 119 kb centromeric of
the CCTG expansion. Liquori et al. (2003) examined haplotypes of 228
control chromosomes and identified a potential premutation allele with
20 uninterrupted CCTG repeats on a haplotype that was identical to the
most common affected haplotype. The data suggested that the predominant
northern European ancestry of families with DM2 resulted from a common
founder and that the loss of interruptions within the CCTG portion of
the repeat tract may predispose alleles to further expansion. To gain
insight into possible function of the repeat tract, the authors looked
for evolutionary conservation. The complex repeat motif and flanking
sequences within intron 1 were found to be conserved among human,
chimpanzee, gorilla, mouse, and rat, suggesting a conserved biologic
function.
Bachinski et al. (2003) noted that multiple families, predominantly of
German descent, with clinically variable presentations of myotonic
dystrophy that included proximal myotonic myopathy (PROMM; 602668) and
DM2, but without the DM1 CCTG expansion, had been reported. They
presented evidence of linkage to 3q21 and confirmation of the CCTG
expansion mutation in intron 1 of ZNF9 in 17 kindreds of European origin
with PROMM and proximal myotonic dystrophy from geographically distinct
populations. They found a single shared haplotype of at least 132 kb
among patients from the different populations. With the exception of the
CCTG expansion, the available markers indicated that the DM2 haplotype
is identical to the most common haplotype in normal individuals, a
situation reminiscent of that seen in DM1. Taken together, these data
suggested a single founding mutation in DM2 patients of European origin.
Bachinski et al. (2003) estimated the age of the founding haplotype and
of the DM2 CCTG expansion mutation to be 200 to 540 generations.
Bachinski et al. (2009) identified 3 classes of large non-DM2 repeat
alleles: short interrupted alleles of up to CCTG(24) with 2
interruptions, long interrupted alleles of up to CCTG(32) with up to 4
interruptions, and uninterrupted alleles of CCTG(22-33) with lengths of
92 to 132 bp. Large non-DM2 alleles above 40 repeats were more common
among African Americans (8.5%) than European Caucasians (less than 2%).
Uninterrupted alleles were significantly more unstable than interrupted
alleles (p = 10(-4) to 10(-7)). SNP analysis was consistent with the
hypothesis that all large alleles occurred on the same haplotype as the
DM2 expansion. Bachinski et al. (2009) concluded that unstable
uninterrupted CCTG(22-33) alleles may represent a premutation allele
pool for DM2 full mutations.
*FIELD* AV
.0001
MYOTONIC DYSTROPHY 2
ZNF9, CCTG(n) EXPANSION
Liquori et al. (2001) found that myotonic dystrophy-2 (602668) is caused
by a CCTG expansion in intron 1 of the ZNF9 gene. Expanded alleles
ranged from 75 to approximately 11,000 CCTG repeats, with a mean of
about 5,000 repeats. Repeat length expands with age. Expansion sizes in
the blood of affected children are usually shorter than in their parents
(reverse anticipation): the time-dependent somatic variation of repeat
size complicates interpretation of this difference. No significant
correlation between age of onset and expansion size was observed.
Liquori et al. (2003) and Bachinski et al. (2003) provided evidence for
a founder effect of the CCTG(n) expansion in European populations.
Saito et al. (2008) reported a Japanese woman with DM2 who had a
heterozygous expanded ZNF9 CCTG allele of 3,400 repeats. Haplotype
analysis showed a background distinct from that observed in European
patients, indicating a different ancestral origin of the mutation in
this patient.
*FIELD* RF
1. Bachinski, L. L.; Czernuszewicz, T.; Ramagli, L. S.; Suominen,
T.; Shriver, M. D.; Udd, B.; Siciliano, M. J.; Krahe, R.: Premutation
allele pool in myotonic dystrophy type 2. Neurology 72: 490-497,
2009.
2. Bachinski, L. L.; Udd, B.; Meola, G.; Sansone, V.; Bassez, G.;
Eymard, B.; Thornton, C. A.; Moxley, R. T.; Harper, P. S.; Rogers,
M. T.; Jurkat-Rott, K.; Lehmann-Horn, F.; and 11 others: Confirmation
of the type 2 myotonic dystrophy (CCTG)n expansion mutation in patients
with proximal myotonic myopathy/proximal myotonic dystrophy of different
European origins: a single shared haplotype indicates an ancestral
founder effect. Am. J. Hum. Genet. 73: 835-848, 2003.
3. Liquori, C. L.; Ikeda, Y.; Weatherspoon, M.; Ricker, K.; Schoser,
B. G. H.; Dalton, J. C.; Day, J. W.; Ranum, L. P. W.: Myotonic dystrophy
type 2: human founder haplotype and evolutionary conservation of the
repeat tract. Am. J. Hum. Genet. 73: 849-862, 2003.
4. Liquori, C. L.; Ricker, K.; Moseley, M. L.; Jacobsen, J. F.; Kress,
W.; Naylor, S. L.; Day, J. W.; Ranum, L. P. W.: Myotonic dystrophy
type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293:
864-867, 2001.
5. Lusis, A. J.; Rajavashisth, T. B.; Klisak, I.; Heinzmann, C.; Mohandas,
T.; Sparkes, R. S.: Mapping of the gene for CNBP, a finger protein,
to human chromosome 3q13.3-q24. Genomics 8: 411-414, 1990. Note:
Erratum: Genomics 9: 564 only, 1991.
6. Rajavashisth, T. B.; Taylor, A. K.; Andalibi, A.; Svenson, K. L.;
Lusis, A. J.: Identification of a zinc finger protein that binds
to the sterol regulatory element. Science 245: 640-643, 1989.
7. Saito, T.; Amakusa, Y.; Kimura, T.; Yahara, O.; Aizawa, H.; Ikeda,
Y.; Day, J. W.; Ranum, L. P. W.; Ohno, K.; Matsuura, T.: Myotonic
dystrophy type 2 in Japan: ancestral origin distinct from Caucasian
families. Neurogenetics 9: 61-63, 2008.
*FIELD* CN
Cassandra L. Kniffin - updated: 4/6/2009
Cassandra L. Kniffin - updated: 3/18/2008
Victor A. McKusick - updated: 10/7/2003
Ada Hamosh - updated: 8/27/2001
*FIELD* CD
Victor A. McKusick: 10/11/1990
*FIELD* ED
carol: 03/21/2011
terry: 5/28/2010
wwang: 4/13/2009
ckniffin: 4/6/2009
wwang: 4/16/2008
ckniffin: 3/18/2008
joanna: 5/23/2005
carol: 6/21/2004
alopez: 5/27/2004
terry: 5/21/2004
tkritzer: 10/10/2003
terry: 10/7/2003
ckniffin: 6/5/2002
alopez: 8/28/2001
terry: 8/27/2001
terry: 8/19/1998
pfoster: 3/25/1994
mimadm: 2/11/1994
supermim: 3/16/1992
carol: 3/2/1992
carol: 3/7/1991
carol: 10/11/1990
*RECORD*
*FIELD* NO
116955
*FIELD* TI
*116955 ZINC FINGER PROTEIN 9; ZNF9
;;CELLULAR RETROVIRAL NUCLEIC ACID-BINDING PROTEIN 1; CNBP1
read more*FIELD* TX
DESCRIPTION
The ZNF9 protein contains 7 zinc finger domains and is believed to
function as an RNA-binding protein. A CCTG expansion in intron 1 of the
ZNF9 gene results in myotonic dystrophy-2 (602668).
CLONING
Cholesterol homeostasis is maintained in part by negative feedback
regulation of the genes for proteins involved in cholesterol synthesis
and the cellular uptake of cholesterol. The apparent coordinate
regulation of several such genes, including HMG-CoA reductase (142910),
HMG-CoA synthase (142940), farnesylpyrophosphate synthetase (134629),
and the LDL receptor (606945) suggest that these genes may be regulated
by a common trans-acting factor that is able to 'sense' the levels of
cellular sterols. In a search for such a trans-acting factor,
Rajavashisth et al. (1989) identified a cDNA that encodes a 19-kD
protein containing 7 highly conserved zinc finger repeats with
remarkable sequence similarity to the finger domains of the family of
retroviral nucleic acid-binding proteins (NBPs). They designated the
protein cellular NBP (CNBP). In common with the viral NBPs, CNBP
appeared to have a strong preference for single-stranded DNA.
MAPPING
Lusis et al. (1990) assigned the CNBP gene to chromosome 3 by Southern
analysis of DNAs from mouse/human somatic cell hybrids and regionalized
the gene to 3q13.3-q24 by in situ hybridization.
MOLECULAR GENETICS
Liquori et al. (2001) demonstrated that a CCTG repeat expansion in
intron 1 of the ZNF9 gene is responsible for DM2 (602668). The range of
expanded allele sizes is extremely broad, from 75 to approximately
11,000 CCTG repeats. The mean repeat length is about 5,000. The expanded
ZNF9 RNA accumulates in discrete foci within the nucleus. ZNF9 contains
7 zinc finger domains and is thought to be an RNA-binding protein. It is
broadly expressed, with the most abundant expression in heart and
skeletal muscle, 2 tissues prominently affected in DM2. The similarity
of mechanism of mutation between DM2 and DM1 (160900) is striking: a
trinucleotide repeat expansion in the 3-prime untranslated region of the
DMPK gene (605377) is responsible for DM1. Clinical and molecular
parallels between DM1 and DM2 indicate that microsatellite expansions in
RNA can themselves be pathogenic.
To investigate the ancestral origins of the DM2 CCTG expansion, Liquori
et al. (2003) used 19 short tandem repeat markers flanking the repeat
tract to compare haplotypes of 71 families with genetically confirmed
DM2. All the families were white, and most were of northern
European/German descent; a single family was from Afghanistan. A common
interval that was shared by all families with DM2 immediately flanked
the repeat, extending up to 216 kb telomeric and 119 kb centromeric of
the CCTG expansion. Liquori et al. (2003) examined haplotypes of 228
control chromosomes and identified a potential premutation allele with
20 uninterrupted CCTG repeats on a haplotype that was identical to the
most common affected haplotype. The data suggested that the predominant
northern European ancestry of families with DM2 resulted from a common
founder and that the loss of interruptions within the CCTG portion of
the repeat tract may predispose alleles to further expansion. To gain
insight into possible function of the repeat tract, the authors looked
for evolutionary conservation. The complex repeat motif and flanking
sequences within intron 1 were found to be conserved among human,
chimpanzee, gorilla, mouse, and rat, suggesting a conserved biologic
function.
Bachinski et al. (2003) noted that multiple families, predominantly of
German descent, with clinically variable presentations of myotonic
dystrophy that included proximal myotonic myopathy (PROMM; 602668) and
DM2, but without the DM1 CCTG expansion, had been reported. They
presented evidence of linkage to 3q21 and confirmation of the CCTG
expansion mutation in intron 1 of ZNF9 in 17 kindreds of European origin
with PROMM and proximal myotonic dystrophy from geographically distinct
populations. They found a single shared haplotype of at least 132 kb
among patients from the different populations. With the exception of the
CCTG expansion, the available markers indicated that the DM2 haplotype
is identical to the most common haplotype in normal individuals, a
situation reminiscent of that seen in DM1. Taken together, these data
suggested a single founding mutation in DM2 patients of European origin.
Bachinski et al. (2003) estimated the age of the founding haplotype and
of the DM2 CCTG expansion mutation to be 200 to 540 generations.
Bachinski et al. (2009) identified 3 classes of large non-DM2 repeat
alleles: short interrupted alleles of up to CCTG(24) with 2
interruptions, long interrupted alleles of up to CCTG(32) with up to 4
interruptions, and uninterrupted alleles of CCTG(22-33) with lengths of
92 to 132 bp. Large non-DM2 alleles above 40 repeats were more common
among African Americans (8.5%) than European Caucasians (less than 2%).
Uninterrupted alleles were significantly more unstable than interrupted
alleles (p = 10(-4) to 10(-7)). SNP analysis was consistent with the
hypothesis that all large alleles occurred on the same haplotype as the
DM2 expansion. Bachinski et al. (2009) concluded that unstable
uninterrupted CCTG(22-33) alleles may represent a premutation allele
pool for DM2 full mutations.
*FIELD* AV
.0001
MYOTONIC DYSTROPHY 2
ZNF9, CCTG(n) EXPANSION
Liquori et al. (2001) found that myotonic dystrophy-2 (602668) is caused
by a CCTG expansion in intron 1 of the ZNF9 gene. Expanded alleles
ranged from 75 to approximately 11,000 CCTG repeats, with a mean of
about 5,000 repeats. Repeat length expands with age. Expansion sizes in
the blood of affected children are usually shorter than in their parents
(reverse anticipation): the time-dependent somatic variation of repeat
size complicates interpretation of this difference. No significant
correlation between age of onset and expansion size was observed.
Liquori et al. (2003) and Bachinski et al. (2003) provided evidence for
a founder effect of the CCTG(n) expansion in European populations.
Saito et al. (2008) reported a Japanese woman with DM2 who had a
heterozygous expanded ZNF9 CCTG allele of 3,400 repeats. Haplotype
analysis showed a background distinct from that observed in European
patients, indicating a different ancestral origin of the mutation in
this patient.
*FIELD* RF
1. Bachinski, L. L.; Czernuszewicz, T.; Ramagli, L. S.; Suominen,
T.; Shriver, M. D.; Udd, B.; Siciliano, M. J.; Krahe, R.: Premutation
allele pool in myotonic dystrophy type 2. Neurology 72: 490-497,
2009.
2. Bachinski, L. L.; Udd, B.; Meola, G.; Sansone, V.; Bassez, G.;
Eymard, B.; Thornton, C. A.; Moxley, R. T.; Harper, P. S.; Rogers,
M. T.; Jurkat-Rott, K.; Lehmann-Horn, F.; and 11 others: Confirmation
of the type 2 myotonic dystrophy (CCTG)n expansion mutation in patients
with proximal myotonic myopathy/proximal myotonic dystrophy of different
European origins: a single shared haplotype indicates an ancestral
founder effect. Am. J. Hum. Genet. 73: 835-848, 2003.
3. Liquori, C. L.; Ikeda, Y.; Weatherspoon, M.; Ricker, K.; Schoser,
B. G. H.; Dalton, J. C.; Day, J. W.; Ranum, L. P. W.: Myotonic dystrophy
type 2: human founder haplotype and evolutionary conservation of the
repeat tract. Am. J. Hum. Genet. 73: 849-862, 2003.
4. Liquori, C. L.; Ricker, K.; Moseley, M. L.; Jacobsen, J. F.; Kress,
W.; Naylor, S. L.; Day, J. W.; Ranum, L. P. W.: Myotonic dystrophy
type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293:
864-867, 2001.
5. Lusis, A. J.; Rajavashisth, T. B.; Klisak, I.; Heinzmann, C.; Mohandas,
T.; Sparkes, R. S.: Mapping of the gene for CNBP, a finger protein,
to human chromosome 3q13.3-q24. Genomics 8: 411-414, 1990. Note:
Erratum: Genomics 9: 564 only, 1991.
6. Rajavashisth, T. B.; Taylor, A. K.; Andalibi, A.; Svenson, K. L.;
Lusis, A. J.: Identification of a zinc finger protein that binds
to the sterol regulatory element. Science 245: 640-643, 1989.
7. Saito, T.; Amakusa, Y.; Kimura, T.; Yahara, O.; Aizawa, H.; Ikeda,
Y.; Day, J. W.; Ranum, L. P. W.; Ohno, K.; Matsuura, T.: Myotonic
dystrophy type 2 in Japan: ancestral origin distinct from Caucasian
families. Neurogenetics 9: 61-63, 2008.
*FIELD* CN
Cassandra L. Kniffin - updated: 4/6/2009
Cassandra L. Kniffin - updated: 3/18/2008
Victor A. McKusick - updated: 10/7/2003
Ada Hamosh - updated: 8/27/2001
*FIELD* CD
Victor A. McKusick: 10/11/1990
*FIELD* ED
carol: 03/21/2011
terry: 5/28/2010
wwang: 4/13/2009
ckniffin: 4/6/2009
wwang: 4/16/2008
ckniffin: 3/18/2008
joanna: 5/23/2005
carol: 6/21/2004
alopez: 5/27/2004
terry: 5/21/2004
tkritzer: 10/10/2003
terry: 10/7/2003
ckniffin: 6/5/2002
alopez: 8/28/2001
terry: 8/27/2001
terry: 8/19/1998
pfoster: 3/25/1994
mimadm: 2/11/1994
supermim: 3/16/1992
carol: 3/2/1992
carol: 3/7/1991
carol: 10/11/1990
MIM
602668
*RECORD*
*FIELD* NO
602668
*FIELD* TI
#602668 MYOTONIC DYSTROPHY 2; DM2
;;DYSTROPHIA MYOTONICA 2;;
PROXIMAL MYOTONIC MYOPATHY; PROMM;;
read moreMYOTONIC MYOPATHY, PROXIMAL;;
RICKER SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because myotonic dystrophy-2
(DM2/PROMM) is caused by heterozygous expansion of a CCTG repeat in
intron 1 of the zinc finger protein-9 gene (ZNF9; 116955).
Normal ZNF9 alleles have up to 30 repeats; pathogenic alleles contain
from 75 to 11,000 repeats (Todd and Paulson, 2010).
DESCRIPTION
Myotonic dystrophy (DM) is a multisystem disorder and the most common
form of muscular dystrophy in adults. Individuals with DM2 have muscle
pain and stiffness, progressive muscle weakness, myotonia, male
hypogonadism, cardiac arrhythmias, diabetes, and early cataracts. Other
features may include cognitive dysfunction, hypersomnia, tremor, and
hearing loss (summary by Heatwole et al., 2011).
See also myotonic dystrophy-1 (DM1; 160900), caused by an expanded CTG
repeat in the dystrophia myotonica protein kinase gene (DMPK; 605377) on
19q13.
Although originally reported as 2 disorders, myotonic dystrophy-2 and
proximal myotonic myopathy are now referred to collectively as DM2 (Udd
et al., 2003).
CLINICAL FEATURES
Thornton et al. (1994) reported patients with clinical characteristics
consistent with classic myotonic dystrophy, but without the CTG repeat
in the DMPK gene (see also Rowland, 1994).
Ricker et al. (1994) described 15 affected individuals in 3 pedigrees
showing segregation of a novel autosomal dominant disorder, termed
proximal myotonic myopathy (PROMM). Affected individuals showed features
of myotonia, typically appearing between the third and fourth decade of
life, and mild proximal weakness, which did not appear until the fifth
to seventh decade. The severity of this disease was quite variable. None
of the patients had hypersomnia, gonadal atrophy, hearing deficits,
gastrointestinal hypermotility, ptosis, cardiac arrhythmia, or
respiratory weakness, features often present in cases of classic
myotonic dystrophy-1. Muscle biopsy demonstrated a nonspecific mild
myopathy with hypertrophy of type 2 fibers with variation in diameter,
but no ringbinden or subsarcolemmal masses. Physiologic studies of
muscle fiber bundles taken from 2 patients demonstrated long-lasting
runs of repetitive action potentials which were abolished by
tetrodotoxin and/or consistently diminished by increasing the potassium
concentration, a finding distinct from that present in myotonic
dystrophy. Chloride conductance was normal. The number of CTG repeats in
the DMPK gene was normal in the proband from each of the families.
Linkage analysis performed on each of the 3 kindreds gave a significant
negative lod score for DM1, chloride channel-1 (CLCN1; 118425) on
chromosome 7q, and muscle sodium channel (SCN4A; 603967) on 17q,
excluding allelism with DM1, myotonia congenita, and paramyotonia.
Ricker et al. (1995) reported 27 patients with proximal myotonic
myopathy from 14 families. Of the 27, 21 had proximal without distal
weakness of the legs. Although only 17 of them had clinical myotonia, 23
had myotonia demonstrated electromyographically. Twenty-four had
cataracts, several of which were similar to those seen in DM1. Fourteen
patients complained of a burning, tearing muscle pain. Muscle atrophy
was not a major feature. Ricker et al. (1995) concluded that PROMM is a
multisystem disorder similar to DM1 with involvement of skeletal muscle,
lens, and heart. However, it appeared to have a more favorable long-term
prognosis inasmuch as none of these patients demonstrated late
deterioration in mental status, hypersomnia, dysphagia, or other
respiratory complications. Clinically, PROMM could be distinguished from
myotonic dystrophy by the proximal, rather than distal, weakness and
sparing of the facial muscles. Ricker (1999) concluded that PROMM is a
more benign disorder than DM1, and suggested that, in Germany, the
frequency of PROMM may be almost equal to that of DM. Abbruzzese et al.
(1996) reported 6 patients from 2 families with myotonic dystrophy
characterized by multisystem manifestations that were indistinguishable
from those seen in DM1 and PROMM, but who did not have expansions of the
chromosome 19 repeat.
Among 50 patients with PROMM from 10 unrelated families in Italy, Meola
et al. (1998) found that 38 showed autosomal dominant inheritance and
the remainder were sporadic cases. Symptoms at onset included myotonia
in 30 to 60% of patients, muscle pain in 30 to 50% of patients, and
lower leg weakness. Cataracts identical to those found in myotonic
dystrophy-1 were identified in 15 to 30% of patients. Cardiac symptoms
were present in only 5 to 10% of patients and consisted mainly of
cardiac arrhythmias. Linkage analysis in the families of Meola et al.
(1998) excluded linkage to chromosomes 19, 17, 7, and 3.
Ranum et al. (1998) identified a 5-generation family with a form of
myotonic dystrophy with clinical features remarkably similar to those
found in classic DM1, without the chromosome 19 CTG expansion. The
authors named the locus for the disorder myotonic dystrophy-2 (DM2).
Clinical features included myotonia, proximal and distal limb weakness,
frontal balding, polychromatic cataracts, infertility, and cardiac
arrhythmias. Day et al. (1999) noted that the genetically distinct form
of myotonic dystrophy in this 5-generation kindred shared some of the
clinical features of previously reported families with proximal myotonic
myopathy.
Newman et al. (1999) reported a family in which proximal myopathy,
cataracts, intermittent myotonia, and myalgia occurred in several
members in an autosomal dominant pattern. The presentation was unusual
in the proband and her 2 sisters, all of whom presented with myotonia
during pregnancy which resolved after each delivery. Two of the sisters
experienced myalgia between each pregnancy.
Vihola et al. (2003) reported the pathologic findings in DM2. Muscle
biopsies from affected patients showed myopathic changes, including
increased fiber size variation and internalized nuclei. There were
scattered thin, angular, atrophic fibers, with preferential type 2 fiber
atrophy.
Bonsch et al. (2003) discussed PROMM and DM2 as one entity characterized
by myotonia, muscular dystrophy with proximal weakness, cardiac
conduction defects, endocrine disorders, and cataracts. They noted that
hearing loss had been described as one feature of PROMM. Day et al.
(2003) provided a detailed review of DM2.
Schoser et al. (2004) reported 4 DM2 patients from 3 families who died
of sudden cardiac death between ages 31 and 44 years. None of the 4 had
high blood pressure, diabetes, or arteriosclerosis, and all had only
mild symptoms of DM2. Only 1 patient had increasing cardiac
insufficiency 6 months before death. Cardiopathologic findings in 3
patients showed dilated cardiomyopathy, with conduction system fibrosis
in 2 patients. Two patients had accumulation of CCUG ribonuclear
inclusions in cardiomyocytes.
Maurage et al. (2005) identified tau (MAPT; 157140)-positive
neurofibrillary tangles (NFTs) in multiple brain regions of a patient
with DM2 originally reported by Udd et al. (2003). The findings were
similar to the NFTs identified in patients with DM1 who also had
cognitive impairment or mental retardation. However, the patient with
DM2 studied by Maurage et al. (2005) was mentally normal, demonstrated
no cognitive decline, and died at age 71 years from a bilateral renal
thrombosis. Maurage et al. (2005) suggested that the findings may be
related to abnormal processing of tau protein isoforms similar to the
mechanism observed in DM1.
Rudnik-Schoneborn et al. (2006) reported the clinical details of
pregnancy in 42 women with DM2 from 37 families. Nine women (21%) had
the first symptoms of DM2 during pregnancy and worsening of symptoms in
subsequent pregnancies. There was often a marked improvement in symptoms
after delivery. Of 96 pregnancies, 13% ended as early miscarriage and 4%
as late miscarriage. Women with overt DM2 symptoms in pregnancy had a
high risk of preterm labor (50%) and preterm births (27%). There was no
evidence of congenital DM2 in the offspring and the overall neonatal
outcome was favorable.
Heatwole et al. (2011) analyzed the laboratory abnormalities of 83
patients with genetically confirmed or clinically probable DM2. Among
1,442 laboratory studies performed, 10 tests showed abnormal values in
more than 40% of patients. These included increased serum creatine
kinase, decreased IgG, increased total cholesterol, decreased lymphocyte
count, increased lactate dehydrogenase, increased ALT, decreased
creatinine, increased basophils, variable glucose levels, and decreased
total protein. Only 33% of patients had increased GGT. Although
endocrine laboratory studies were limited, the trend suggested low
testosterone and increased FSH. The findings reinforced the idea that
DM2 is a multisystem disorder and provided a means for disease screening
and monitoring.
DIAGNOSIS
Moxley et al. (1998) reviewed the diagnostic criteria of PROMM that had
been delineated at the 54th European Neuromuscular Center International
Workshop in 1997, before the causative ZNF9 mutation had been
identified. Mandatory inclusion criteria included autosomal dominant
inheritance, proximal weakness, primarily in the thighs, myotonia
demonstrable by EMG, cataracts identical to those seen in DM1, and a
normal size of the CTG repeat in the DM1 gene.
Noting that the extremely large size and somatic instability of the DM2
expansion make molecular testing and interpretation difficult, Day et
al. (2003) developed a repeat assay that increased the molecular
detection rate of DM2 to 99%.
MAPPING
In a 5-generation family with myotonic dystrophy, Ranum et al. (1998)
found that the disease locus, DM2, mapped to a 10-cM region of 3q. In
addition to excluding the DM1 locus on chromosome 19 in the large family
reported by Ranum et al. (1998), Day et al. (1999) excluded the
chromosomal regions containing the genes for muscle sodium and chloride
channels that are involved in other myotonic disorders.
Ricker et al. (1999) performed linkage analysis in 9 German families
with PROMM using DNA markers D3S1541 and D3S1589 from the region of the
locus for DM2. Two-point analysis yielded a lod score of 5.9. Ricker et
al. (1999) concluded that a gene causing PROMM is located on 3q and that
PROMM and DM2 are either allelic disorders or caused by closely linked
genes.
Sun et al. (1999) reported a Norwegian PROMM family in which the proband
was clinically diagnosed with myotonic dystrophy but lacked the
pathognomonic (CTG)n expansion. Haplotype analysis suggested exclusion
of the DM2 locus as well, perhaps indicating further genetic
heterogeneity. Interestingly, all family members, affected and
unaffected, were heterozygous for the arg894-to-ter (R894X) mutation in
the CLCN1 gene (118425.0010). The authors noted that Mastaglia et al.
(1998) had reported the R894X mutation in only 1 of 2 children with
PROMM, indicating that it was not the disease-causing mutation in that
family: they had termed it an incidental finding. Sun et al. (1999)
suggested that their findings, combined with those of Mastaglia et al.
(1998), likely reflected a fairly high carrier frequency in the
population, and they presented preliminary data indicating an R894X
allele frequency of 0.87% (4/460) in northern Scandinavia.
MOLECULAR GENETICS
Liquori et al. (2001) reported that DM2 is caused by a CCTG expansion
located in intron 1 of the ZNF9 gene (116955.0001). Expanded allele
sizes ranged from 75 to approximately 11,000 CCTG repeats, with a mean
of approximately 5,000 repeats. Expansion sizes in the blood of affected
children were usually shorter than in their parents (reverse
anticipation), but the authors noted that the time-dependent somatic
variation of repeat size may complicate interpretation of this
difference. No significant correlation between the age of onset and
expansion size was observed.
Liquori et al. (2003) and Bachinski et al. (2003) provided evidence for
a founder effect of the CCTG(n) expansion in European populations.
Saito et al. (2008) reported a Japanese woman with DM2 who had a
heterozygous expanded ZNF2 CCTG allele of 3,400 repeats. Haplotype
analysis showed a background distinct from that observed in European
patients, indicating a different ancestral origin of the mutation in
this patient.
Bachinski et al. (2009) identified 3 classes of large non-DM2 repeat
alleles: short interrupted alleles of up to CCTG(24) with 2
interruptions, long interrupted alleles of up to CCTG(32) with up to 4
interruptions, and uninterrupted alleles of CCTG(22-33) with lengths of
92 to 132 bp. Large non-DM2 alleles above 40 repeats were more common
among African Americans (8.5%) than European Caucasians (less than 2%).
Uninterrupted alleles were significantly more unstable than interrupted
alleles (p = 10(-4) to 10(-7)). SNP analysis was consistent with the
hypothesis that all large alleles occurred on the same haplotype as the
DM2 expansion. Bachinski et al. (2009) concluded that unstable
uninterrupted CCTG(22-33) alleles may represent a premutation allele
pool for DM2 full mutations.
GENOTYPE/PHENOTYPE CORRELATIONS
Sun et al. (2011) reported a large 3-generation Norwegian family in
which 13 individuals had DM2 confirmed by genetic analysis. Six of the
13 patients also carried a heterozygous F413C substitution in the CLCN1
gene (118425.0001); the F413C mutation is usually associated with
autosomal recessive myotonia congenita (255700) when present in the
homozygous or compound heterozygous state. All family members,
regardless of genotype, had myotonic discharges on EMG, but the
discharges were more prominent in those with both mutations. Similarly,
most patients reported muscle stiffness and myalgia, and but those with
both mutations tended to report more stiffness than those with only the
ZNF9 expansion. These findings suggested that the CLCN1 mutation may
have exaggerated the myotonia phenotype in those with the ZNF9
expansion. A 64-year-old man with only the ZNF9 expansion had
generalized myalgia during his entire adult life, bilateral cataracts,
and cardiomyopathy with evidence of abnormal relaxation of the
myocardium. He had mild action myotonia. EMG showed myopathic changes
and myotonia runs consistent with DM2. His brother, who had both
mutations, had myalgia and complained of stiffness and mild muscle
weakness, but strength was normal. EMG and physical examination showed
myotonia. All of his 5 daughters, 3 of whom carried both mutations,
developed myotonia during pregnancy that persisted after delivery. The
most severely affected daughter also had cold-induced stiffness in the
perioral muscles. All patients had normal cognitive function. The
genetic findings helped to explain the clinical variability in this
family.
PATHOGENESIS
Mankodi et al. (2001) investigated the possibility that DM2 is caused by
expansion of a CTG repeat or related sequence. Analysis of DNA by repeat
expansion detection methods and RNA by ribonuclease protection did not
show an expanded CTG or CUG repeat in DM2. However, hybridization of
muscle sections with fluorescence-labeled CAG-repeat oligonucleotides
showed nuclear foci in DM2 similar to those seen in DM1. Nuclear foci
were present in 9 patients with symptomatic DM1 and 9 patients with DM2,
but not in 23 disease controls or healthy subjects. The foci were not
seen with CUG- or GUC-repeat probes. Foci in DM2 were distinguished from
DM1 by lower stability of the probe-target duplex, suggesting that a
sequence related to the DM1 CUG expansion may accumulate in the DM2
nucleus. Muscleblind proteins (see MBNL1; 606516), which interact with
expanded CUG repeats in vitro, localized to the nuclear foci in both DM1
and DM2. The authors proposed that nuclear accumulation of mutant RNA is
pathogenic in DM1, a similar disease process may occur in DM2, and
muscleblind may play a role in the pathogenesis of both disorders.
In DM, expression of RNAs that contain expanded CUG or CCUG repeats is
associated with degeneration and repetitive action potentials (myotonia)
in skeletal muscle. Using skeletal muscle from a transgenic mouse model
of DM, Mankodi et al. (2002) showed that expression of expanded CUG
repeats reduces the transmembrane chloride conductance to levels well
below those expected to cause myotonia. The expanded CUG repeats trigger
aberrant splicing of pre-mRNA for CLC1 (118425), the main chloride
channel in muscle, resulting in loss of CLC1 protein from the surface
membrane. Mankodi et al. (2002) identified a similar defect in CLC1
splicing and expression in human DM1 and DM2. They proposed that a
transdominant effect of mutant RNA on RNA processing leads to chloride
channelopathy and membrane hyperexcitability in DM.
Fugier et al. (2011) demonstrated that alternative splicing of the BIN1
gene (601248) was disrupted in muscle cells derived from patients with
DM1 and DM2. Exon 11 of BIN1 mRNA was skipped, and the amount of skipped
mRNA correlated with disease severity. This splicing misregulation was
associated with sequestration of the splicing regulator MBNL1 due to
pathogenic expanded CUG or CCUG repeats. Expression of BIN1 without exon
11 resulted in little or no T tubule formation in cultured muscle cells,
since this splice variant lacks a phosphatidylinositol
5-phosphate-binding site necessary for membrane-tubulating activities.
Skeletal muscle biopsies from patients with DM1 showed disorganized BIN1
localization and irregular T tubule networks. Promotion of the skipping
of Bin1 exon 11 in mouse skeletal muscle resulted in abnormal T tubules
and decreased muscle strength, although muscle integrity was maintained.
There was also decreased expression of Cacna1s (114208), which plays a
role in the excitation-contraction coupling process. The findings
suggested a link between abnormal BIN1 expression and muscle weakness in
myotonic dystrophy.
Tang et al. (2012) observed altered splicing of the calcium channel
subunit CAV1.1 (CACNA1S) in muscle of patients with DM1 and DM2 compared
with normal adult muscle and muscle of patients with facioscapulohumeral
muscular dystrophy (FSHD; see 158900). A significant fraction of CAV1.1
transcripts in DM1 and DM2 muscle showed skipping of exon 29, which
represents a fetal splicing pattern. Forced exclusion of exon 29 in
normal mouse skeletal muscle altered channel gating properties and
increased current density and peak electrically evoked calcium transient
magnitude. Downregulation of Mbnl1 in mouse cardiac muscle or
overexpression of Cugbp1 (601074) in mouse tibialis anterior muscle
enhanced skipping of exon 29, suggesting that these splicing factors may
be involved in the CAV1.1 splicing defect in myotonic dystrophy.
POPULATION GENETICS
Suominen et al. (2011) found 2 DM2 mutations among 4,508 Finnish control
individuals. One of 988 Finnish patients with a neuromuscular disorder
also carried a DM2 mutation, but this patient also had genetically
verified tibial muscular dystrophy (TMD; 600334), but no myotonia. The
exact sizes of the expanded repeats could not be determined. Overall,
the DM2 mutation frequency was estimated to be 1 in 1,830 in the general
population. In addition, 1 of 93 Italian patients with proximal myopathy
or increased serum creatine kinase also carried a DM2 mutation. This
49-year-old patient had waddling gait, proximal weakness, and Gowers
sign, but normal serum creatine kinase. EMG showed a myopathic pattern
without myotonic discharges, possibly expanding the phenotypic spectrum
of DM2 or suggesting that patients with variant symptoms may not be
properly diagnosed. In the same study, the frequency of DM1 mutations
was estimated to be 1 in 2,760. Suominen et al. (2011) stated that the
estimates of DM1 and DM2 in their study were significantly higher than
previously reported estimates, which they cited as 1 in 8,000 for both
DM1 and DM2. They concluded that DM1 and DM2 are more frequent than
previously thought.
NOMENCLATURE
According to the Report of the 115th ENMC Workshop, the term myotonic
dystrophy type 2 refers to both DM2 and PROMM, which are essentially the
same disorder (Udd et al., 2003).
*FIELD* RF
1. Abbruzzese, C.; Krahe, R.; Liguori, M.; Tessarolo, D.; Siciliano,
M. J.; Ashizawa, T.; Giacanelli, M.: Myotonic dystrophy phenotype
without expansion of (CTG)n repeat: an entity distinct from proximal
myotonic myopathy (PROMM)? J. Neurol. 243: 715-721, 1996.
2. Bachinski, L. L.; Czernuszewicz, T.; Ramagli, L. S.; Suominen,
T.; Shriver, M. D.; Udd, B.; Siciliano, M. J.; Krahe, R.: Premutation
allele pool in myotonic dystrophy type 2. Neurology 72: 490-497,
2009.
3. Bachinski, L. L.; Udd, B.; Meola, G.; Sansone, V.; Bassez, G.;
Eymard, B.; Thornton, C. A.; Moxley, R. T.; Harper, P. S.; Rogers,
M. T.; Jurkat-Rott, K.; Lehmann-Horn, F.; and 11 others: Confirmation
of the type 2 myotonic dystrophy (CCTG)n expansion mutation in patients
with proximal myotonic myopathy/proximal myotonic dystrophy of different
European origins: a single shared haplotype indicates an ancestral
founder effect. Am. J. Hum. Genet. 73: 835-848, 2003.
4. Bonsch, D.; Neumann, C.; Lang-Roth, R.; Witte, O.; Lamprecht-Dinnesen,
A.; Deufel, T.: PROMM and deafness: exclusion of ZNF9 as the disease
gene in DFNA18 suggests a polygenic origin of the PROMM/DM2 phenotype.
(Letter) Clin. Genet. 63: 73-75, 2003.
5. Day, J. W.; Ricker, K.; Jacobsen, J. F.; Rasmussen, L. J.; Dick,
K. A.; Kress, W.; Schneider, C.; Koch, M. C.; Beilman, G. J.; Harrison,
A. R.; Dalton, J. C.; Ranum, L. P. W.: Myotonic dystrophy type 2:
molecular, diagnostic and clinical spectrum. Neurology 60: 657-664,
2003.
6. Day, J. W.; Roelofs, R.; Leroy, B.; Pech, I.; Benzow, K.; Ranum,
L. P. W.: Clinical and genetic characteristics of a five-generation
family with a novel form of myotonic dystrophy (DM2). Neuromusc.
Disord. 9: 19-27, 1999.
7. Fugier, C.; Klein, A. F.; Hammer, C.; Vassilopoulos, S.; Ivarsson,
Y.; Toussaint, A.; Tosch, V.; Vignaud, A.; Ferry, A.; Messaddeq, N.;
Kokunai, Y.; Tsuburaya, R.; and 22 others: Misregulated alternative
splicing of BIN1 is associated with T tubule alterations and muscle
weakness in myotonic dystrophy. (Letter) Nature Med. 17: 720-725,
2011.
8. Heatwole, C.; Johnson, N.; Goldberg, B.; Martens, W.; Moxley, R.,
III: Laboratory abnormalities in patients with myotonic dystrophy
type 2. Arch. Neurol. 68: 1180-1184, 2011.
9. Liquori, C. L.; Ikeda, Y.; Weatherspoon, M.; Ricker, K.; Schoser,
B. G. H.; Dalton, J. C.; Day, J. W.; Ranum, L. P. W.: Myotonic dystrophy
type 2: human founder haplotype and evolutionary conservation of the
repeat tract. Am. J. Hum. Genet. 73: 849-862, 2003.
10. Liquori, C. L.; Ricker, K.; Moseley, M. L.; Jacobsen, J. F.; Kress,
W.; Naylor, S. L.; Day, J. W.; Ranum, L. P. W.: Myotonic dystrophy
type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293:
864-867, 2001.
11. Mankodi, A.; Takahashi, M. P.; Jiang, H.; Beck, C. L.; Bowers,
W. J.; Moxley, R. T.; Cannon, S. C.; Thornton, C. A.: Expanded CUG
repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA
and hyperexcitability of skeletal muscle in myotonic dystrophy. Molec.
Cell 10: 35-44, 2002.
12. Mankodi, A.; Urbinati, C. R.; Yuan, Q.-P.; Moxley, R. T.; Sansone,
V.; Krym, M.; Henderson, D.; Schalling, M.; Swanson, M. S.; Thornton,
C. A.: Muscleblind localizes to nuclear foci of aberrant RNA in myotonic
dystrophy types 1 and 2. Hum. Molec. Genet. 10: 2165-2170, 2001.
13. Mastaglia, F. L.; Harker, N.; Phillips, B. A.; Day, T. J.; Hankey,
G. J.; Laing, N. G.; Fabian, V.; Kakulas, B. A.: Dominantly inherited
proximal myotonic myopathy and leukoencephalopathy in a family with
an incidental CLCN1 mutation. J. Neurol. Neurosurg. Psychiat. 64:
543-547, 1998.
14. Maurage, C. A.; Udd, B.; Ruchoux, M. M.; Vermersch, P.; Kalimo,
H.; Krahe, R.; Delacourte, A.; Sergeant, N.: Similar brain tau pathology
in DM2/PROMM and DM1/Steinert disease. Neurology 65: 1636-1638,
2005.
15. Meola, G.; Sansone, V.; Rotondo, G.; Nobile-Orazio, E.; Mongini,
T.; Angelini, C.; Toscano, A.; Mancuso, M.; Siciliano, G.: PROMM
in Italy: clinical and biomolecular findings. Acta Myol. 2: 21-26,
1998.
16. Moxley, R. T., III; Udd, B.; Ricker, K.: Proximal myotonic myopathy
(PROMM) and other proximal myotonic syndromes. Neuromusc. Disord. 8:
519-520, 1998.
17. Newman, B.; Meola, G.; O'Donovan, D. G.; Schapira, A. H. V.; Kingston,
H.: Proximal myotonic myopathy (PROMM) presenting as myotonia during
pregnancy. Neuromusc. Disord. 9: 144-149, 1999.
18. Ranum, L. P. W.; Rasmussen, P. F.; Benzow, K. A.; Koob, M. D.;
Day, J. W.: Genetic mapping of a second myotonic dystrophy locus. Nature
Genet. 19: 196-198, 1998.
19. Ricker, K.: Myotonic dystrophy and proximal myotonic myopathy. J.
Neurol. 246: 334-338, 1999.
20. Ricker, K.; Grimm, T.; Koch, M. C.; Schneider, C.; Kress, W.;
Reimers, C. D.; Schulte-Mattler, W.; Mueller-Myhsok, B.; Toyka, K.
V.; Mueller, C. R.: Linkage of proximal myotonic myopathy to chromosome
3q. Neurology 52: 170-171, 1999.
21. Ricker, K.; Koch, M. C.; Lehmann-Horn, F.; Pongratz, D.; Otto,
M.; Heine, R.; Moxley, R. T., III: Proximal myotonic myopathy: a
new dominant disorder with myotonia, muscle weakness, and cataracts. Neurology 44:
1448-1452, 1994.
22. Ricker, K.; Koch, M. C.; Lehmann-Horn, F.; Pongratz, D.; Speich,
N.; Reiners, K.; Schneider, C.; Moxley, R. T., III: Proximal myotonic
myopathy: clinical features of a multisystem disorder similar to myotonic
dystrophy. Arch. Neurol. 52: 25-31, 1995.
23. Rowland, L. P.: Thornton-Griggs-Moxley disease: myotonic dystrophy
type 2. Ann. Neurol. 36: 803-804, 1994.
24. Rudnik-Schoneborn, S.; Schneider-Gold, C.; Raabe, U.; Kress, W.;
Zerres, K.; Schoser, B. G. H.: Outcome and effect of pregnancy in
myotonic dystrophy type 2. Neurology 66: 579-580, 2006.
25. Saito, T.; Amakusa, Y.; Kimura, T.; Yahara, O.; Aizawa, H.; Ikeda,
Y.; Day, J. W.; Ranum, L. P. W.; Ohno, K.; Matsuura, T.: Myotonic
dystrophy type 2 in Japan: ancestral origin distinct from Caucasian
families. Neurogenetics 9: 61-63, 2008.
26. Schoser, B. G. H.; Ricker, K.; Schneider-Gold, C.; Hengstenberg,
C.; Durre, J.; Bultmann, B.; Kress, W.; Day, J. W.; Ranum, L. P. W.
: Sudden cardiac death in myotonic dystrophy type 2. Neurology 63:
2402-2404, 2004.
27. Sun, C.; Henriksen, O. A.; Tranebjaerg, L.: Proximal myotonic
myopathy: clinical and molecular investigation of a Norwegian family
with PROMM. Clin. Genet. 56: 457-461, 1999.
28. Sun, C.; Van Ghelue, M.; Tranebjaerg, L.; Thyssen, F.; Nilssen,
O.; Torbergsen, T.: Myotonia congenita and myotonic dystrophy in
the same family: coexistence of a CLCN1 mutation and expansion in
the CNBP (ZNF9) gene. Clin. Genet. 80: 574-580, 2011.
29. Suominen, T.; Bachinski, L. L.; Auvinen, S.; Hackman, P.; Baggerly,
K. A.; Angelini, C.; Peltonen, L.; Krahe, R.; Udd, B.: Population
frequency of myotonic dystrophy: higher than expected frequency of
myotonic dystrophy type 2 (DM2) mutation in Finland. Europ. J. Hum.
Genet. 19: 776-782, 2011.
30. Tang, Z. Z.; Yarotskyy, V.; Wei, L.; Sobczak, K.; Nakamori, M.;
Eichinger, K.; Moxley, R. T.; Dirksen, R. T.; Thornton, C. A.: Muscle
weakness in myotonic dystrophy associated with misregulated splicing
and altered gating of CaV1.1 calcium channel. Hum. Molec. Genet. 21:
1312-1324, 2012.
31. Thornton, C. A.; Griggs, R. C.; Moxley, R. T., III: Myotonic
dystrophy with no trinucleotide repeat expansion. Ann. Neurol. 35:
269-272, 1994.
32. Todd, P. K.; Paulson, H. L.: RNA-mediated neurodegeneration in
repeat expansion disorders. Ann. Neurol. 67: 291-300, 2010.
33. Udd, B.; Meola, G.; Krahe, R.; Thornton, C.; Ranum, L.; Day, J.;
Bassez, G.; Ricker, K.: Report of the 115th ENMC workshop: DM2/PROMM
and other myotonic dystrophies. 3rd Workshop, 14-16 February 2003,
Naarden, The Netherlands. Neuromusc. Disord. 13: 589-596, 2003.
34. Vihola, A.; Bassez, G.; Meola, G.; Zhang, S.; Haapasalo, H.; Paetau,
A.; Mancinelli, E.; Rouche, A.; Hogrel, J. Y.; Laforet, P.; Maisonobe,
T.; Pellissier, J. F.; Krahe, R.; Eymard, B.; Udd, B.: Histopathological
differences of myotonic dystrophy type 1 (DM1) and PROMM/DM2. Neurology 60:
1854-1857, 2003.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Cataracts, posterior, subcapsular, iridescent
CARDIOVASCULAR:
[Heart];
Cardiac conduction abnormalities;
Palpitations;
Tachycardia
GENITOURINARY:
[Internal genitalia, male];
Hypogonadism;
Oligospermia
SKIN, NAILS, HAIR:
[Skin];
Hyperhydrosis;
[Hair];
Frontal balding (male pattern baldness)
MUSCLE, SOFT TISSUE:
Muscle pain;
Myotonia;
Proximal muscle weakness;
Deep finger muscle weakness;
Neck flexor weakness;
Myotonia seen on EMG;
Centrally located nuclei seen on muscle biopsy;
Angulated atrophic muscle fibers;
Nuclear clumps;
Type 2 fiber atrophy
NEUROLOGIC:
[Central nervous system];
No mental retardation
ENDOCRINE FEATURES:
Insulin insensitivity;
Low testosterone;
Elevated follicle stimulating hormone (FSH);
Diabetes mellitus
IMMUNOLOGY:
Decreased serum IgG and IgM;
Decreased absolute lymphocytes
LABORATORY ABNORMALITIES:
Elevated serum creatine kinase;
Elevated gamma-glutamyltransferase (GGT);
Increased cholesterol;
Increased lactate dehydrogenase;
Increased ALT;
Decreased creatine;
Decreased total protein
MISCELLANEOUS:
Variable age of onset (range 13 to 67 years, median 48 years);
No congenital form;
Pathogenic alleles contain 75-11,000 repeats;
Normal alleles contain up to 30 repeats;
Repeat tracts may expand as patient ages (somatic instability);
Smaller repeat lengths in younger generations (reverse anticipation);
See myotonic dystonia 1 (DM1, 160900) for a disorder with a similar
phenotype
MOLECULAR BASIS:
Caused by a (CCTG)n repeat expansion in the zinc finger protein 9
gene (ZNF9, 116955.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 5/3/2012
Cassandra L. Kniffin - updated: 8/3/2010
*FIELD* CD
Cassandra L. Kniffin: 9/2/2003
*FIELD* ED
joanna: 05/08/2012
ckniffin: 5/3/2012
ckniffin: 8/3/2010
joanna: 2/18/2009
ckniffin: 9/2/2003
*FIELD* CN
Cassandra L. Kniffin - updated: 10/30/2013
Patricia A. Hartz - updated: 7/17/2013
Cassandra L. Kniffin - updated: 2/13/2013
Cassandra L. Kniffin - updated: 5/3/2012
Cassandra L. Kniffin - updated: 9/6/2011
Cassandra L. Kniffin - updated: 8/3/2010
Cassandra L. Kniffin - updated: 4/6/2009
Cassandra L. Kniffin - updated: 3/18/2008
Cassandra L. Kniffin - updated: 6/25/2007
Cassandra L. Kniffin - updated: 2/13/2007
Cassandra L. Kniffin - updated: 3/21/2005
Cassandra L. Kniffin - reorganized: 9/11/2003
Cassandra L. Kniffin - updated: 9/2/2003
Stylianos E. Antonarakis - updated: 9/10/2002
George E. Tiller - updated: 2/11/2002
Victor A. McKusick - updated: 9/4/2001
Ada Hamosh - updated: 8/27/2001
Victor A. McKusick - updated: 4/27/1999
*FIELD* CD
Victor A. McKusick: 5/29/1998
*FIELD* ED
carol: 10/31/2013
ckniffin: 10/30/2013
mgross: 7/17/2013
carol: 4/4/2013
carol: 2/26/2013
ckniffin: 2/13/2013
carol: 5/4/2012
terry: 5/3/2012
ckniffin: 5/3/2012
carol: 9/7/2011
ckniffin: 9/6/2011
carol: 3/21/2011
wwang: 8/4/2010
ckniffin: 8/3/2010
wwang: 4/13/2009
ckniffin: 4/6/2009
wwang: 4/16/2008
ckniffin: 3/18/2008
wwang: 6/28/2007
ckniffin: 6/25/2007
carol: 2/23/2007
ckniffin: 2/13/2007
joanna: 5/23/2005
ckniffin: 3/21/2005
carol: 10/3/2003
carol: 9/11/2003
ckniffin: 9/2/2003
carol: 2/24/2003
tkritzer: 2/11/2003
mgross: 9/10/2002
cwells: 2/19/2002
cwells: 2/11/2002
terry: 9/4/2001
alopez: 8/28/2001
terry: 8/27/2001
terry: 10/31/2000
carol: 6/19/2000
alopez: 5/10/1999
terry: 4/27/1999
dholmes: 7/22/1998
alopez: 6/11/1998
alopez: 6/1/1998
*RECORD*
*FIELD* NO
602668
*FIELD* TI
#602668 MYOTONIC DYSTROPHY 2; DM2
;;DYSTROPHIA MYOTONICA 2;;
PROXIMAL MYOTONIC MYOPATHY; PROMM;;
read moreMYOTONIC MYOPATHY, PROXIMAL;;
RICKER SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because myotonic dystrophy-2
(DM2/PROMM) is caused by heterozygous expansion of a CCTG repeat in
intron 1 of the zinc finger protein-9 gene (ZNF9; 116955).
Normal ZNF9 alleles have up to 30 repeats; pathogenic alleles contain
from 75 to 11,000 repeats (Todd and Paulson, 2010).
DESCRIPTION
Myotonic dystrophy (DM) is a multisystem disorder and the most common
form of muscular dystrophy in adults. Individuals with DM2 have muscle
pain and stiffness, progressive muscle weakness, myotonia, male
hypogonadism, cardiac arrhythmias, diabetes, and early cataracts. Other
features may include cognitive dysfunction, hypersomnia, tremor, and
hearing loss (summary by Heatwole et al., 2011).
See also myotonic dystrophy-1 (DM1; 160900), caused by an expanded CTG
repeat in the dystrophia myotonica protein kinase gene (DMPK; 605377) on
19q13.
Although originally reported as 2 disorders, myotonic dystrophy-2 and
proximal myotonic myopathy are now referred to collectively as DM2 (Udd
et al., 2003).
CLINICAL FEATURES
Thornton et al. (1994) reported patients with clinical characteristics
consistent with classic myotonic dystrophy, but without the CTG repeat
in the DMPK gene (see also Rowland, 1994).
Ricker et al. (1994) described 15 affected individuals in 3 pedigrees
showing segregation of a novel autosomal dominant disorder, termed
proximal myotonic myopathy (PROMM). Affected individuals showed features
of myotonia, typically appearing between the third and fourth decade of
life, and mild proximal weakness, which did not appear until the fifth
to seventh decade. The severity of this disease was quite variable. None
of the patients had hypersomnia, gonadal atrophy, hearing deficits,
gastrointestinal hypermotility, ptosis, cardiac arrhythmia, or
respiratory weakness, features often present in cases of classic
myotonic dystrophy-1. Muscle biopsy demonstrated a nonspecific mild
myopathy with hypertrophy of type 2 fibers with variation in diameter,
but no ringbinden or subsarcolemmal masses. Physiologic studies of
muscle fiber bundles taken from 2 patients demonstrated long-lasting
runs of repetitive action potentials which were abolished by
tetrodotoxin and/or consistently diminished by increasing the potassium
concentration, a finding distinct from that present in myotonic
dystrophy. Chloride conductance was normal. The number of CTG repeats in
the DMPK gene was normal in the proband from each of the families.
Linkage analysis performed on each of the 3 kindreds gave a significant
negative lod score for DM1, chloride channel-1 (CLCN1; 118425) on
chromosome 7q, and muscle sodium channel (SCN4A; 603967) on 17q,
excluding allelism with DM1, myotonia congenita, and paramyotonia.
Ricker et al. (1995) reported 27 patients with proximal myotonic
myopathy from 14 families. Of the 27, 21 had proximal without distal
weakness of the legs. Although only 17 of them had clinical myotonia, 23
had myotonia demonstrated electromyographically. Twenty-four had
cataracts, several of which were similar to those seen in DM1. Fourteen
patients complained of a burning, tearing muscle pain. Muscle atrophy
was not a major feature. Ricker et al. (1995) concluded that PROMM is a
multisystem disorder similar to DM1 with involvement of skeletal muscle,
lens, and heart. However, it appeared to have a more favorable long-term
prognosis inasmuch as none of these patients demonstrated late
deterioration in mental status, hypersomnia, dysphagia, or other
respiratory complications. Clinically, PROMM could be distinguished from
myotonic dystrophy by the proximal, rather than distal, weakness and
sparing of the facial muscles. Ricker (1999) concluded that PROMM is a
more benign disorder than DM1, and suggested that, in Germany, the
frequency of PROMM may be almost equal to that of DM. Abbruzzese et al.
(1996) reported 6 patients from 2 families with myotonic dystrophy
characterized by multisystem manifestations that were indistinguishable
from those seen in DM1 and PROMM, but who did not have expansions of the
chromosome 19 repeat.
Among 50 patients with PROMM from 10 unrelated families in Italy, Meola
et al. (1998) found that 38 showed autosomal dominant inheritance and
the remainder were sporadic cases. Symptoms at onset included myotonia
in 30 to 60% of patients, muscle pain in 30 to 50% of patients, and
lower leg weakness. Cataracts identical to those found in myotonic
dystrophy-1 were identified in 15 to 30% of patients. Cardiac symptoms
were present in only 5 to 10% of patients and consisted mainly of
cardiac arrhythmias. Linkage analysis in the families of Meola et al.
(1998) excluded linkage to chromosomes 19, 17, 7, and 3.
Ranum et al. (1998) identified a 5-generation family with a form of
myotonic dystrophy with clinical features remarkably similar to those
found in classic DM1, without the chromosome 19 CTG expansion. The
authors named the locus for the disorder myotonic dystrophy-2 (DM2).
Clinical features included myotonia, proximal and distal limb weakness,
frontal balding, polychromatic cataracts, infertility, and cardiac
arrhythmias. Day et al. (1999) noted that the genetically distinct form
of myotonic dystrophy in this 5-generation kindred shared some of the
clinical features of previously reported families with proximal myotonic
myopathy.
Newman et al. (1999) reported a family in which proximal myopathy,
cataracts, intermittent myotonia, and myalgia occurred in several
members in an autosomal dominant pattern. The presentation was unusual
in the proband and her 2 sisters, all of whom presented with myotonia
during pregnancy which resolved after each delivery. Two of the sisters
experienced myalgia between each pregnancy.
Vihola et al. (2003) reported the pathologic findings in DM2. Muscle
biopsies from affected patients showed myopathic changes, including
increased fiber size variation and internalized nuclei. There were
scattered thin, angular, atrophic fibers, with preferential type 2 fiber
atrophy.
Bonsch et al. (2003) discussed PROMM and DM2 as one entity characterized
by myotonia, muscular dystrophy with proximal weakness, cardiac
conduction defects, endocrine disorders, and cataracts. They noted that
hearing loss had been described as one feature of PROMM. Day et al.
(2003) provided a detailed review of DM2.
Schoser et al. (2004) reported 4 DM2 patients from 3 families who died
of sudden cardiac death between ages 31 and 44 years. None of the 4 had
high blood pressure, diabetes, or arteriosclerosis, and all had only
mild symptoms of DM2. Only 1 patient had increasing cardiac
insufficiency 6 months before death. Cardiopathologic findings in 3
patients showed dilated cardiomyopathy, with conduction system fibrosis
in 2 patients. Two patients had accumulation of CCUG ribonuclear
inclusions in cardiomyocytes.
Maurage et al. (2005) identified tau (MAPT; 157140)-positive
neurofibrillary tangles (NFTs) in multiple brain regions of a patient
with DM2 originally reported by Udd et al. (2003). The findings were
similar to the NFTs identified in patients with DM1 who also had
cognitive impairment or mental retardation. However, the patient with
DM2 studied by Maurage et al. (2005) was mentally normal, demonstrated
no cognitive decline, and died at age 71 years from a bilateral renal
thrombosis. Maurage et al. (2005) suggested that the findings may be
related to abnormal processing of tau protein isoforms similar to the
mechanism observed in DM1.
Rudnik-Schoneborn et al. (2006) reported the clinical details of
pregnancy in 42 women with DM2 from 37 families. Nine women (21%) had
the first symptoms of DM2 during pregnancy and worsening of symptoms in
subsequent pregnancies. There was often a marked improvement in symptoms
after delivery. Of 96 pregnancies, 13% ended as early miscarriage and 4%
as late miscarriage. Women with overt DM2 symptoms in pregnancy had a
high risk of preterm labor (50%) and preterm births (27%). There was no
evidence of congenital DM2 in the offspring and the overall neonatal
outcome was favorable.
Heatwole et al. (2011) analyzed the laboratory abnormalities of 83
patients with genetically confirmed or clinically probable DM2. Among
1,442 laboratory studies performed, 10 tests showed abnormal values in
more than 40% of patients. These included increased serum creatine
kinase, decreased IgG, increased total cholesterol, decreased lymphocyte
count, increased lactate dehydrogenase, increased ALT, decreased
creatinine, increased basophils, variable glucose levels, and decreased
total protein. Only 33% of patients had increased GGT. Although
endocrine laboratory studies were limited, the trend suggested low
testosterone and increased FSH. The findings reinforced the idea that
DM2 is a multisystem disorder and provided a means for disease screening
and monitoring.
DIAGNOSIS
Moxley et al. (1998) reviewed the diagnostic criteria of PROMM that had
been delineated at the 54th European Neuromuscular Center International
Workshop in 1997, before the causative ZNF9 mutation had been
identified. Mandatory inclusion criteria included autosomal dominant
inheritance, proximal weakness, primarily in the thighs, myotonia
demonstrable by EMG, cataracts identical to those seen in DM1, and a
normal size of the CTG repeat in the DM1 gene.
Noting that the extremely large size and somatic instability of the DM2
expansion make molecular testing and interpretation difficult, Day et
al. (2003) developed a repeat assay that increased the molecular
detection rate of DM2 to 99%.
MAPPING
In a 5-generation family with myotonic dystrophy, Ranum et al. (1998)
found that the disease locus, DM2, mapped to a 10-cM region of 3q. In
addition to excluding the DM1 locus on chromosome 19 in the large family
reported by Ranum et al. (1998), Day et al. (1999) excluded the
chromosomal regions containing the genes for muscle sodium and chloride
channels that are involved in other myotonic disorders.
Ricker et al. (1999) performed linkage analysis in 9 German families
with PROMM using DNA markers D3S1541 and D3S1589 from the region of the
locus for DM2. Two-point analysis yielded a lod score of 5.9. Ricker et
al. (1999) concluded that a gene causing PROMM is located on 3q and that
PROMM and DM2 are either allelic disorders or caused by closely linked
genes.
Sun et al. (1999) reported a Norwegian PROMM family in which the proband
was clinically diagnosed with myotonic dystrophy but lacked the
pathognomonic (CTG)n expansion. Haplotype analysis suggested exclusion
of the DM2 locus as well, perhaps indicating further genetic
heterogeneity. Interestingly, all family members, affected and
unaffected, were heterozygous for the arg894-to-ter (R894X) mutation in
the CLCN1 gene (118425.0010). The authors noted that Mastaglia et al.
(1998) had reported the R894X mutation in only 1 of 2 children with
PROMM, indicating that it was not the disease-causing mutation in that
family: they had termed it an incidental finding. Sun et al. (1999)
suggested that their findings, combined with those of Mastaglia et al.
(1998), likely reflected a fairly high carrier frequency in the
population, and they presented preliminary data indicating an R894X
allele frequency of 0.87% (4/460) in northern Scandinavia.
MOLECULAR GENETICS
Liquori et al. (2001) reported that DM2 is caused by a CCTG expansion
located in intron 1 of the ZNF9 gene (116955.0001). Expanded allele
sizes ranged from 75 to approximately 11,000 CCTG repeats, with a mean
of approximately 5,000 repeats. Expansion sizes in the blood of affected
children were usually shorter than in their parents (reverse
anticipation), but the authors noted that the time-dependent somatic
variation of repeat size may complicate interpretation of this
difference. No significant correlation between the age of onset and
expansion size was observed.
Liquori et al. (2003) and Bachinski et al. (2003) provided evidence for
a founder effect of the CCTG(n) expansion in European populations.
Saito et al. (2008) reported a Japanese woman with DM2 who had a
heterozygous expanded ZNF2 CCTG allele of 3,400 repeats. Haplotype
analysis showed a background distinct from that observed in European
patients, indicating a different ancestral origin of the mutation in
this patient.
Bachinski et al. (2009) identified 3 classes of large non-DM2 repeat
alleles: short interrupted alleles of up to CCTG(24) with 2
interruptions, long interrupted alleles of up to CCTG(32) with up to 4
interruptions, and uninterrupted alleles of CCTG(22-33) with lengths of
92 to 132 bp. Large non-DM2 alleles above 40 repeats were more common
among African Americans (8.5%) than European Caucasians (less than 2%).
Uninterrupted alleles were significantly more unstable than interrupted
alleles (p = 10(-4) to 10(-7)). SNP analysis was consistent with the
hypothesis that all large alleles occurred on the same haplotype as the
DM2 expansion. Bachinski et al. (2009) concluded that unstable
uninterrupted CCTG(22-33) alleles may represent a premutation allele
pool for DM2 full mutations.
GENOTYPE/PHENOTYPE CORRELATIONS
Sun et al. (2011) reported a large 3-generation Norwegian family in
which 13 individuals had DM2 confirmed by genetic analysis. Six of the
13 patients also carried a heterozygous F413C substitution in the CLCN1
gene (118425.0001); the F413C mutation is usually associated with
autosomal recessive myotonia congenita (255700) when present in the
homozygous or compound heterozygous state. All family members,
regardless of genotype, had myotonic discharges on EMG, but the
discharges were more prominent in those with both mutations. Similarly,
most patients reported muscle stiffness and myalgia, and but those with
both mutations tended to report more stiffness than those with only the
ZNF9 expansion. These findings suggested that the CLCN1 mutation may
have exaggerated the myotonia phenotype in those with the ZNF9
expansion. A 64-year-old man with only the ZNF9 expansion had
generalized myalgia during his entire adult life, bilateral cataracts,
and cardiomyopathy with evidence of abnormal relaxation of the
myocardium. He had mild action myotonia. EMG showed myopathic changes
and myotonia runs consistent with DM2. His brother, who had both
mutations, had myalgia and complained of stiffness and mild muscle
weakness, but strength was normal. EMG and physical examination showed
myotonia. All of his 5 daughters, 3 of whom carried both mutations,
developed myotonia during pregnancy that persisted after delivery. The
most severely affected daughter also had cold-induced stiffness in the
perioral muscles. All patients had normal cognitive function. The
genetic findings helped to explain the clinical variability in this
family.
PATHOGENESIS
Mankodi et al. (2001) investigated the possibility that DM2 is caused by
expansion of a CTG repeat or related sequence. Analysis of DNA by repeat
expansion detection methods and RNA by ribonuclease protection did not
show an expanded CTG or CUG repeat in DM2. However, hybridization of
muscle sections with fluorescence-labeled CAG-repeat oligonucleotides
showed nuclear foci in DM2 similar to those seen in DM1. Nuclear foci
were present in 9 patients with symptomatic DM1 and 9 patients with DM2,
but not in 23 disease controls or healthy subjects. The foci were not
seen with CUG- or GUC-repeat probes. Foci in DM2 were distinguished from
DM1 by lower stability of the probe-target duplex, suggesting that a
sequence related to the DM1 CUG expansion may accumulate in the DM2
nucleus. Muscleblind proteins (see MBNL1; 606516), which interact with
expanded CUG repeats in vitro, localized to the nuclear foci in both DM1
and DM2. The authors proposed that nuclear accumulation of mutant RNA is
pathogenic in DM1, a similar disease process may occur in DM2, and
muscleblind may play a role in the pathogenesis of both disorders.
In DM, expression of RNAs that contain expanded CUG or CCUG repeats is
associated with degeneration and repetitive action potentials (myotonia)
in skeletal muscle. Using skeletal muscle from a transgenic mouse model
of DM, Mankodi et al. (2002) showed that expression of expanded CUG
repeats reduces the transmembrane chloride conductance to levels well
below those expected to cause myotonia. The expanded CUG repeats trigger
aberrant splicing of pre-mRNA for CLC1 (118425), the main chloride
channel in muscle, resulting in loss of CLC1 protein from the surface
membrane. Mankodi et al. (2002) identified a similar defect in CLC1
splicing and expression in human DM1 and DM2. They proposed that a
transdominant effect of mutant RNA on RNA processing leads to chloride
channelopathy and membrane hyperexcitability in DM.
Fugier et al. (2011) demonstrated that alternative splicing of the BIN1
gene (601248) was disrupted in muscle cells derived from patients with
DM1 and DM2. Exon 11 of BIN1 mRNA was skipped, and the amount of skipped
mRNA correlated with disease severity. This splicing misregulation was
associated with sequestration of the splicing regulator MBNL1 due to
pathogenic expanded CUG or CCUG repeats. Expression of BIN1 without exon
11 resulted in little or no T tubule formation in cultured muscle cells,
since this splice variant lacks a phosphatidylinositol
5-phosphate-binding site necessary for membrane-tubulating activities.
Skeletal muscle biopsies from patients with DM1 showed disorganized BIN1
localization and irregular T tubule networks. Promotion of the skipping
of Bin1 exon 11 in mouse skeletal muscle resulted in abnormal T tubules
and decreased muscle strength, although muscle integrity was maintained.
There was also decreased expression of Cacna1s (114208), which plays a
role in the excitation-contraction coupling process. The findings
suggested a link between abnormal BIN1 expression and muscle weakness in
myotonic dystrophy.
Tang et al. (2012) observed altered splicing of the calcium channel
subunit CAV1.1 (CACNA1S) in muscle of patients with DM1 and DM2 compared
with normal adult muscle and muscle of patients with facioscapulohumeral
muscular dystrophy (FSHD; see 158900). A significant fraction of CAV1.1
transcripts in DM1 and DM2 muscle showed skipping of exon 29, which
represents a fetal splicing pattern. Forced exclusion of exon 29 in
normal mouse skeletal muscle altered channel gating properties and
increased current density and peak electrically evoked calcium transient
magnitude. Downregulation of Mbnl1 in mouse cardiac muscle or
overexpression of Cugbp1 (601074) in mouse tibialis anterior muscle
enhanced skipping of exon 29, suggesting that these splicing factors may
be involved in the CAV1.1 splicing defect in myotonic dystrophy.
POPULATION GENETICS
Suominen et al. (2011) found 2 DM2 mutations among 4,508 Finnish control
individuals. One of 988 Finnish patients with a neuromuscular disorder
also carried a DM2 mutation, but this patient also had genetically
verified tibial muscular dystrophy (TMD; 600334), but no myotonia. The
exact sizes of the expanded repeats could not be determined. Overall,
the DM2 mutation frequency was estimated to be 1 in 1,830 in the general
population. In addition, 1 of 93 Italian patients with proximal myopathy
or increased serum creatine kinase also carried a DM2 mutation. This
49-year-old patient had waddling gait, proximal weakness, and Gowers
sign, but normal serum creatine kinase. EMG showed a myopathic pattern
without myotonic discharges, possibly expanding the phenotypic spectrum
of DM2 or suggesting that patients with variant symptoms may not be
properly diagnosed. In the same study, the frequency of DM1 mutations
was estimated to be 1 in 2,760. Suominen et al. (2011) stated that the
estimates of DM1 and DM2 in their study were significantly higher than
previously reported estimates, which they cited as 1 in 8,000 for both
DM1 and DM2. They concluded that DM1 and DM2 are more frequent than
previously thought.
NOMENCLATURE
According to the Report of the 115th ENMC Workshop, the term myotonic
dystrophy type 2 refers to both DM2 and PROMM, which are essentially the
same disorder (Udd et al., 2003).
*FIELD* RF
1. Abbruzzese, C.; Krahe, R.; Liguori, M.; Tessarolo, D.; Siciliano,
M. J.; Ashizawa, T.; Giacanelli, M.: Myotonic dystrophy phenotype
without expansion of (CTG)n repeat: an entity distinct from proximal
myotonic myopathy (PROMM)? J. Neurol. 243: 715-721, 1996.
2. Bachinski, L. L.; Czernuszewicz, T.; Ramagli, L. S.; Suominen,
T.; Shriver, M. D.; Udd, B.; Siciliano, M. J.; Krahe, R.: Premutation
allele pool in myotonic dystrophy type 2. Neurology 72: 490-497,
2009.
3. Bachinski, L. L.; Udd, B.; Meola, G.; Sansone, V.; Bassez, G.;
Eymard, B.; Thornton, C. A.; Moxley, R. T.; Harper, P. S.; Rogers,
M. T.; Jurkat-Rott, K.; Lehmann-Horn, F.; and 11 others: Confirmation
of the type 2 myotonic dystrophy (CCTG)n expansion mutation in patients
with proximal myotonic myopathy/proximal myotonic dystrophy of different
European origins: a single shared haplotype indicates an ancestral
founder effect. Am. J. Hum. Genet. 73: 835-848, 2003.
4. Bonsch, D.; Neumann, C.; Lang-Roth, R.; Witte, O.; Lamprecht-Dinnesen,
A.; Deufel, T.: PROMM and deafness: exclusion of ZNF9 as the disease
gene in DFNA18 suggests a polygenic origin of the PROMM/DM2 phenotype.
(Letter) Clin. Genet. 63: 73-75, 2003.
5. Day, J. W.; Ricker, K.; Jacobsen, J. F.; Rasmussen, L. J.; Dick,
K. A.; Kress, W.; Schneider, C.; Koch, M. C.; Beilman, G. J.; Harrison,
A. R.; Dalton, J. C.; Ranum, L. P. W.: Myotonic dystrophy type 2:
molecular, diagnostic and clinical spectrum. Neurology 60: 657-664,
2003.
6. Day, J. W.; Roelofs, R.; Leroy, B.; Pech, I.; Benzow, K.; Ranum,
L. P. W.: Clinical and genetic characteristics of a five-generation
family with a novel form of myotonic dystrophy (DM2). Neuromusc.
Disord. 9: 19-27, 1999.
7. Fugier, C.; Klein, A. F.; Hammer, C.; Vassilopoulos, S.; Ivarsson,
Y.; Toussaint, A.; Tosch, V.; Vignaud, A.; Ferry, A.; Messaddeq, N.;
Kokunai, Y.; Tsuburaya, R.; and 22 others: Misregulated alternative
splicing of BIN1 is associated with T tubule alterations and muscle
weakness in myotonic dystrophy. (Letter) Nature Med. 17: 720-725,
2011.
8. Heatwole, C.; Johnson, N.; Goldberg, B.; Martens, W.; Moxley, R.,
III: Laboratory abnormalities in patients with myotonic dystrophy
type 2. Arch. Neurol. 68: 1180-1184, 2011.
9. Liquori, C. L.; Ikeda, Y.; Weatherspoon, M.; Ricker, K.; Schoser,
B. G. H.; Dalton, J. C.; Day, J. W.; Ranum, L. P. W.: Myotonic dystrophy
type 2: human founder haplotype and evolutionary conservation of the
repeat tract. Am. J. Hum. Genet. 73: 849-862, 2003.
10. Liquori, C. L.; Ricker, K.; Moseley, M. L.; Jacobsen, J. F.; Kress,
W.; Naylor, S. L.; Day, J. W.; Ranum, L. P. W.: Myotonic dystrophy
type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293:
864-867, 2001.
11. Mankodi, A.; Takahashi, M. P.; Jiang, H.; Beck, C. L.; Bowers,
W. J.; Moxley, R. T.; Cannon, S. C.; Thornton, C. A.: Expanded CUG
repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA
and hyperexcitability of skeletal muscle in myotonic dystrophy. Molec.
Cell 10: 35-44, 2002.
12. Mankodi, A.; Urbinati, C. R.; Yuan, Q.-P.; Moxley, R. T.; Sansone,
V.; Krym, M.; Henderson, D.; Schalling, M.; Swanson, M. S.; Thornton,
C. A.: Muscleblind localizes to nuclear foci of aberrant RNA in myotonic
dystrophy types 1 and 2. Hum. Molec. Genet. 10: 2165-2170, 2001.
13. Mastaglia, F. L.; Harker, N.; Phillips, B. A.; Day, T. J.; Hankey,
G. J.; Laing, N. G.; Fabian, V.; Kakulas, B. A.: Dominantly inherited
proximal myotonic myopathy and leukoencephalopathy in a family with
an incidental CLCN1 mutation. J. Neurol. Neurosurg. Psychiat. 64:
543-547, 1998.
14. Maurage, C. A.; Udd, B.; Ruchoux, M. M.; Vermersch, P.; Kalimo,
H.; Krahe, R.; Delacourte, A.; Sergeant, N.: Similar brain tau pathology
in DM2/PROMM and DM1/Steinert disease. Neurology 65: 1636-1638,
2005.
15. Meola, G.; Sansone, V.; Rotondo, G.; Nobile-Orazio, E.; Mongini,
T.; Angelini, C.; Toscano, A.; Mancuso, M.; Siciliano, G.: PROMM
in Italy: clinical and biomolecular findings. Acta Myol. 2: 21-26,
1998.
16. Moxley, R. T., III; Udd, B.; Ricker, K.: Proximal myotonic myopathy
(PROMM) and other proximal myotonic syndromes. Neuromusc. Disord. 8:
519-520, 1998.
17. Newman, B.; Meola, G.; O'Donovan, D. G.; Schapira, A. H. V.; Kingston,
H.: Proximal myotonic myopathy (PROMM) presenting as myotonia during
pregnancy. Neuromusc. Disord. 9: 144-149, 1999.
18. Ranum, L. P. W.; Rasmussen, P. F.; Benzow, K. A.; Koob, M. D.;
Day, J. W.: Genetic mapping of a second myotonic dystrophy locus. Nature
Genet. 19: 196-198, 1998.
19. Ricker, K.: Myotonic dystrophy and proximal myotonic myopathy. J.
Neurol. 246: 334-338, 1999.
20. Ricker, K.; Grimm, T.; Koch, M. C.; Schneider, C.; Kress, W.;
Reimers, C. D.; Schulte-Mattler, W.; Mueller-Myhsok, B.; Toyka, K.
V.; Mueller, C. R.: Linkage of proximal myotonic myopathy to chromosome
3q. Neurology 52: 170-171, 1999.
21. Ricker, K.; Koch, M. C.; Lehmann-Horn, F.; Pongratz, D.; Otto,
M.; Heine, R.; Moxley, R. T., III: Proximal myotonic myopathy: a
new dominant disorder with myotonia, muscle weakness, and cataracts. Neurology 44:
1448-1452, 1994.
22. Ricker, K.; Koch, M. C.; Lehmann-Horn, F.; Pongratz, D.; Speich,
N.; Reiners, K.; Schneider, C.; Moxley, R. T., III: Proximal myotonic
myopathy: clinical features of a multisystem disorder similar to myotonic
dystrophy. Arch. Neurol. 52: 25-31, 1995.
23. Rowland, L. P.: Thornton-Griggs-Moxley disease: myotonic dystrophy
type 2. Ann. Neurol. 36: 803-804, 1994.
24. Rudnik-Schoneborn, S.; Schneider-Gold, C.; Raabe, U.; Kress, W.;
Zerres, K.; Schoser, B. G. H.: Outcome and effect of pregnancy in
myotonic dystrophy type 2. Neurology 66: 579-580, 2006.
25. Saito, T.; Amakusa, Y.; Kimura, T.; Yahara, O.; Aizawa, H.; Ikeda,
Y.; Day, J. W.; Ranum, L. P. W.; Ohno, K.; Matsuura, T.: Myotonic
dystrophy type 2 in Japan: ancestral origin distinct from Caucasian
families. Neurogenetics 9: 61-63, 2008.
26. Schoser, B. G. H.; Ricker, K.; Schneider-Gold, C.; Hengstenberg,
C.; Durre, J.; Bultmann, B.; Kress, W.; Day, J. W.; Ranum, L. P. W.
: Sudden cardiac death in myotonic dystrophy type 2. Neurology 63:
2402-2404, 2004.
27. Sun, C.; Henriksen, O. A.; Tranebjaerg, L.: Proximal myotonic
myopathy: clinical and molecular investigation of a Norwegian family
with PROMM. Clin. Genet. 56: 457-461, 1999.
28. Sun, C.; Van Ghelue, M.; Tranebjaerg, L.; Thyssen, F.; Nilssen,
O.; Torbergsen, T.: Myotonia congenita and myotonic dystrophy in
the same family: coexistence of a CLCN1 mutation and expansion in
the CNBP (ZNF9) gene. Clin. Genet. 80: 574-580, 2011.
29. Suominen, T.; Bachinski, L. L.; Auvinen, S.; Hackman, P.; Baggerly,
K. A.; Angelini, C.; Peltonen, L.; Krahe, R.; Udd, B.: Population
frequency of myotonic dystrophy: higher than expected frequency of
myotonic dystrophy type 2 (DM2) mutation in Finland. Europ. J. Hum.
Genet. 19: 776-782, 2011.
30. Tang, Z. Z.; Yarotskyy, V.; Wei, L.; Sobczak, K.; Nakamori, M.;
Eichinger, K.; Moxley, R. T.; Dirksen, R. T.; Thornton, C. A.: Muscle
weakness in myotonic dystrophy associated with misregulated splicing
and altered gating of CaV1.1 calcium channel. Hum. Molec. Genet. 21:
1312-1324, 2012.
31. Thornton, C. A.; Griggs, R. C.; Moxley, R. T., III: Myotonic
dystrophy with no trinucleotide repeat expansion. Ann. Neurol. 35:
269-272, 1994.
32. Todd, P. K.; Paulson, H. L.: RNA-mediated neurodegeneration in
repeat expansion disorders. Ann. Neurol. 67: 291-300, 2010.
33. Udd, B.; Meola, G.; Krahe, R.; Thornton, C.; Ranum, L.; Day, J.;
Bassez, G.; Ricker, K.: Report of the 115th ENMC workshop: DM2/PROMM
and other myotonic dystrophies. 3rd Workshop, 14-16 February 2003,
Naarden, The Netherlands. Neuromusc. Disord. 13: 589-596, 2003.
34. Vihola, A.; Bassez, G.; Meola, G.; Zhang, S.; Haapasalo, H.; Paetau,
A.; Mancinelli, E.; Rouche, A.; Hogrel, J. Y.; Laforet, P.; Maisonobe,
T.; Pellissier, J. F.; Krahe, R.; Eymard, B.; Udd, B.: Histopathological
differences of myotonic dystrophy type 1 (DM1) and PROMM/DM2. Neurology 60:
1854-1857, 2003.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Cataracts, posterior, subcapsular, iridescent
CARDIOVASCULAR:
[Heart];
Cardiac conduction abnormalities;
Palpitations;
Tachycardia
GENITOURINARY:
[Internal genitalia, male];
Hypogonadism;
Oligospermia
SKIN, NAILS, HAIR:
[Skin];
Hyperhydrosis;
[Hair];
Frontal balding (male pattern baldness)
MUSCLE, SOFT TISSUE:
Muscle pain;
Myotonia;
Proximal muscle weakness;
Deep finger muscle weakness;
Neck flexor weakness;
Myotonia seen on EMG;
Centrally located nuclei seen on muscle biopsy;
Angulated atrophic muscle fibers;
Nuclear clumps;
Type 2 fiber atrophy
NEUROLOGIC:
[Central nervous system];
No mental retardation
ENDOCRINE FEATURES:
Insulin insensitivity;
Low testosterone;
Elevated follicle stimulating hormone (FSH);
Diabetes mellitus
IMMUNOLOGY:
Decreased serum IgG and IgM;
Decreased absolute lymphocytes
LABORATORY ABNORMALITIES:
Elevated serum creatine kinase;
Elevated gamma-glutamyltransferase (GGT);
Increased cholesterol;
Increased lactate dehydrogenase;
Increased ALT;
Decreased creatine;
Decreased total protein
MISCELLANEOUS:
Variable age of onset (range 13 to 67 years, median 48 years);
No congenital form;
Pathogenic alleles contain 75-11,000 repeats;
Normal alleles contain up to 30 repeats;
Repeat tracts may expand as patient ages (somatic instability);
Smaller repeat lengths in younger generations (reverse anticipation);
See myotonic dystonia 1 (DM1, 160900) for a disorder with a similar
phenotype
MOLECULAR BASIS:
Caused by a (CCTG)n repeat expansion in the zinc finger protein 9
gene (ZNF9, 116955.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 5/3/2012
Cassandra L. Kniffin - updated: 8/3/2010
*FIELD* CD
Cassandra L. Kniffin: 9/2/2003
*FIELD* ED
joanna: 05/08/2012
ckniffin: 5/3/2012
ckniffin: 8/3/2010
joanna: 2/18/2009
ckniffin: 9/2/2003
*FIELD* CN
Cassandra L. Kniffin - updated: 10/30/2013
Patricia A. Hartz - updated: 7/17/2013
Cassandra L. Kniffin - updated: 2/13/2013
Cassandra L. Kniffin - updated: 5/3/2012
Cassandra L. Kniffin - updated: 9/6/2011
Cassandra L. Kniffin - updated: 8/3/2010
Cassandra L. Kniffin - updated: 4/6/2009
Cassandra L. Kniffin - updated: 3/18/2008
Cassandra L. Kniffin - updated: 6/25/2007
Cassandra L. Kniffin - updated: 2/13/2007
Cassandra L. Kniffin - updated: 3/21/2005
Cassandra L. Kniffin - reorganized: 9/11/2003
Cassandra L. Kniffin - updated: 9/2/2003
Stylianos E. Antonarakis - updated: 9/10/2002
George E. Tiller - updated: 2/11/2002
Victor A. McKusick - updated: 9/4/2001
Ada Hamosh - updated: 8/27/2001
Victor A. McKusick - updated: 4/27/1999
*FIELD* CD
Victor A. McKusick: 5/29/1998
*FIELD* ED
carol: 10/31/2013
ckniffin: 10/30/2013
mgross: 7/17/2013
carol: 4/4/2013
carol: 2/26/2013
ckniffin: 2/13/2013
carol: 5/4/2012
terry: 5/3/2012
ckniffin: 5/3/2012
carol: 9/7/2011
ckniffin: 9/6/2011
carol: 3/21/2011
wwang: 8/4/2010
ckniffin: 8/3/2010
wwang: 4/13/2009
ckniffin: 4/6/2009
wwang: 4/16/2008
ckniffin: 3/18/2008
wwang: 6/28/2007
ckniffin: 6/25/2007
carol: 2/23/2007
ckniffin: 2/13/2007
joanna: 5/23/2005
ckniffin: 3/21/2005
carol: 10/3/2003
carol: 9/11/2003
ckniffin: 9/2/2003
carol: 2/24/2003
tkritzer: 2/11/2003
mgross: 9/10/2002
cwells: 2/19/2002
cwells: 2/11/2002
terry: 9/4/2001
alopez: 8/28/2001
terry: 8/27/2001
terry: 10/31/2000
carol: 6/19/2000
alopez: 5/10/1999
terry: 4/27/1999
dholmes: 7/22/1998
alopez: 6/11/1998
alopez: 6/1/1998