RBCC

Full text data of KCTD7

KCTD7 [Confidence: low (only semi-automatic identification from reviews)]
BTB/POZ domain-containing protein KCTD7

UniProt Q96MP8
ID KCTD7_HUMAN Reviewed; 289 AA.
AC Q96MP8; A4D2M4; Q8IVR0;
DT 03-OCT-2006, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-DEC-2001, sequence version 1.
DT 22-JAN-2014, entry version 91.
DE RecName: Full=BTB/POZ domain-containing protein KCTD7;
GN Name=KCTD7;
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 [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S.,
RA Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z.,
RA Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C.,
RA Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J.,
RA Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F.,
RA Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F.,
RA Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H.,
RA Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G.,
RA Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P.,
RA Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J.,
RA Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F.,
RA Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B.,
RA Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W.,
RA Mural R.J., Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [3]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
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 [5]
RP INVOLVEMENT IN EPM3.
RX PubMed=17455289; DOI=10.1002/ana.21121;
RA Van Bogaert P., Azizieh R., Desir J., Aeby A., De Meirleir L.,
RA Laes J.-F., Christiaens F., Abramowicz M.J.;
RT "Mutation of a potassium channel-related gene in progressive myoclonic
RT epilepsy.";
RL Ann. Neurol. 61:579-586(2007).
RN [6]
RP SUBCELLULAR LOCATION, INTERACTION WITH CUL3, VARIANT EPM3 CYS-184, AND
RP CHARACTERIZATION OF VARIANT EPM3 CYS-184.
RX PubMed=22748208; DOI=10.1016/j.ajhg.2012.05.023;
RA Staropoli J.F., Karaa A., Lim E.T., Kirby A., Elbalalesy N.,
RA Romansky S.G., Leydiker K.B., Coppel S.H., Barone R., Xin W.,
RA MacDonald M.E., Abdenur J.E., Daly M.J., Sims K.B., Cotman S.L.;
RT "A homozygous mutation in KCTD7 links neuronal ceroid lipofuscinosis
RT to the ubiquitin-proteasome system.";
RL Am. J. Hum. Genet. 91:202-208(2012).
RN [7]
RP SUBCELLULAR LOCATION, AND VARIANTS EPM3 TRP-94; MET-108; TYR-115 AND
RP ILE-273.
RX PubMed=22693283; DOI=10.1136/jmedgenet-2012-100859;
RA Kousi M., Anttila V., Schulz A., Calafato S., Jakkula E., Riesch E.,
RA Myllykangas L., Kalimo H., Topcu M., Gokben S., Alehan F., Lemke J.R.,
RA Alber M., Palotie A., Kopra O., Lehesjoki A.E.;
RT "Novel mutations consolidate KCTD7 as a progressive myoclonus epilepsy
RT gene.";
RL J. Med. Genet. 49:391-399(2012).
RN [8]
RP INVOLVEMENT IN OPSOCLONUS-MYOCLONUS ATAXIA-LIKE SYNDROME, AND VARIANT
RP TRP-84.
RX PubMed=22638565; DOI=10.1007/s00415-012-6545-z;
RA Blumkin L., Kivity S., Lev D., Cohen S., Shomrat R., Lerman-Sagie T.,
RA Leshinsky-Silver E.;
RT "A compound heterozygous missense mutation and a large deletion in the
RT KCTD7 gene presenting as an opsoclonus-myoclonus ataxia-like
RT syndrome.";
RL J. Neurol. 259:2590-2598(2012).
RN [9]
RP VARIANT EPM3 TRP-94.
RX PubMed=22606975; DOI=10.1111/j.1469-1809.2012.00710.x;
RA Krabichler B., Rostasy K., Baumann M., Karall D., Scholl-Burgi S.,
RA Schwarzer C., Gautsch K., Spreiz A., Kotzot D., Zschocke J., Fauth C.,
RA Haberlandt E.;
RT "Novel mutation in potassium channel related gene KCTD7 and
RT progressive myoclonic epilepsy.";
RL Ann. Hum. Genet. 76:326-331(2012).
CC -!- FUNCTION: May be involved in the control of excitability of
CC cortical neurons (By similarity).
CC -!- SUBUNIT: Interacts with CUL3.
CC -!- SUBCELLULAR LOCATION: Cell membrane. Cytoplasm, cytosol.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q96MP8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96MP8-2; Sequence=VSP_020760;
CC Note=No experimental confirmation available;
CC -!- DISEASE: Epilepsy, progressive myoclonic 3, with or without
CC intracellular inclusions (EPM3) [MIM:611726]: An autosomal
CC recessive, severe, progressive myoclonic epilepsy with early
CC onset. Multifocal myoclonic seizures begin between 16 and 24
CC months of age after normal initial development. Neurodegeneration
CC and regression occur with seizure onset. Other features include
CC mental retardation, dysarthria, truncal ataxia, and loss of fine
CC finger movements. EEG shows slow dysrhythmia, multifocal and
CC occasionally generalized epileptiform discharges. In some
CC patients, ultrastructural findings on skin biopsies identify
CC intracellular accumulation of autofluorescent lipopigment storage
CC material, consistent with neuronal ceroid lipofuscinosis. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Note=Defects in KCTD7 are a cause of opsoclonus-myoclonus
CC ataxia-like syndrome. Opsoclonus myoclonus ataxia syndrome (OMS)
CC is a rare pervasive and frequently permanent disorder that usually
CC develops in previously healthy children with normal premorbid
CC psychomotor development and characterized by association of
CC abnormal eye movements (opsoclonus), severe dyskinesia
CC (myoclonus), cerebellar ataxia, functional regression, and
CC behavioral problems. The syndrome is considered to be an immune-
CC mediated disorder and may be tumor-associated or idiopathic. OMS
CC is one of a few steroid responsive disorders of childhood. KCTD7
CC mutations have been found in a patient with an atypical clinical
CC presentation characterized by non-epileptic myoclonus and ataxia
CC commencing in early infancy, abnormal opsoclonus-like eye
CC movements, improvement of clinical symptoms under steroid
CC treatment, and subsequent development of generalized epilepsy
CC (PubMed:22638565).
CC -!- SIMILARITY: Contains 1 BTB (POZ) domain.
CC -----------------------------------------------------------------------
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DR EMBL; AK056631; BAB71236.1; -; mRNA.
DR EMBL; CH236961; EAL23735.1; -; Genomic_DNA.
DR EMBL; CH471140; EAX07919.1; -; Genomic_DNA.
DR EMBL; BC042482; AAH42482.1; -; mRNA.
DR RefSeq; NP_001161433.1; NM_001167961.2.
DR RefSeq; NP_694578.1; NM_153033.4.
DR UniGene; Hs.546627; -.
DR ProteinModelPortal; Q96MP8; -.
DR SMR; Q96MP8; 51-136.
DR STRING; 9606.ENSP00000275532; -.
DR PhosphoSite; Q96MP8; -.
DR DMDM; 74732414; -.
DR PaxDb; Q96MP8; -.
DR PRIDE; Q96MP8; -.
DR DNASU; 154881; -.
DR Ensembl; ENST00000275532; ENSP00000275532; ENSG00000243335.
DR Ensembl; ENST00000443322; ENSP00000411624; ENSG00000243335.
DR GeneID; 154881; -.
DR KEGG; hsa:154881; -.
DR UCSC; uc003tvd.4; human.
DR CTD; 154881; -.
DR GeneCards; GC07P066093; -.
DR HGNC; HGNC:21957; KCTD7.
DR MIM; 611725; gene.
DR MIM; 611726; phenotype.
DR neXtProt; NX_Q96MP8; -.
DR Orphanet; 263516; Progressive myoclonic epilepsy type 3.
DR PharmGKB; PA134884591; -.
DR eggNOG; NOG284422; -.
DR HOGENOM; HOG000113201; -.
DR HOVERGEN; HBG052220; -.
DR InParanoid; Q96MP8; -.
DR OMA; KKARFAK; -.
DR OrthoDB; EOG790G15; -.
DR PhylomeDB; Q96MP8; -.
DR ChiTaRS; KCTD7; human.
DR GeneWiki; KCTD7; -.
DR GenomeRNAi; 154881; -.
DR NextBio; 87335; -.
DR PRO; PR:Q96MP8; -.
DR ArrayExpress; Q96MP8; -.
DR Bgee; Q96MP8; -.
DR CleanEx; HS_KCTD7; -.
DR Genevestigator; Q96MP8; -.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0051260; P:protein homooligomerization; IEA:InterPro.
DR Gene3D; 3.30.710.10; -; 1.
DR InterPro; IPR000210; BTB/POZ-like.
DR InterPro; IPR011333; BTB/POZ_fold.
DR InterPro; IPR003131; T1-type_BTB.
DR Pfam; PF02214; BTB_2; 1.
DR SMART; SM00225; BTB; 1.
DR SUPFAM; SSF54695; SSF54695; 1.
DR PROSITE; PS50097; BTB; FALSE_NEG.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Complete proteome; Cytoplasm;
KW Disease mutation; Epilepsy; Membrane; Neurodegeneration;
KW Neuronal ceroid lipofuscinosis; Reference proteome.
FT CHAIN 1 289 BTB/POZ domain-containing protein KCTD7.
FT /FTId=PRO_0000251476.
FT DOMAIN 51 149 BTB.
FT VAR_SEQ 289 289 Missing (in isoform 2).
FT /FTId=VSP_020760.
FT VARIANT 84 84 R -> W (probable disease-associated
FT mutation found in a patient with
FT opsoclonus-myoclonus ataxia-like
FT syndrome).
FT /FTId=VAR_068775.
FT VARIANT 94 94 R -> W (in EPM3).
FT /FTId=VAR_068776.
FT VARIANT 108 108 L -> M (in EPM3).
FT /FTId=VAR_068777.
FT VARIANT 115 115 D -> Y (in EPM3; uncertain pathological
FT significance).
FT /FTId=VAR_068778.
FT VARIANT 184 184 R -> C (in EPM3; results in markedly
FT diminished localization at the cell
FT membrane and appearence of prominent
FT cytoplasmic aggregates).
FT /FTId=VAR_068779.
FT VARIANT 273 273 N -> I (in EPM3).
FT /FTId=VAR_068780.
SQ SEQUENCE 289 AA; 33132 MW; 1F0D1F618CD5E459 CRC64;
MVVVTGREPD SRRQDGAMSS SDAEDDFLEP ATPTATQAGH ALPLLPQEFP EVVPLNIGGA
HFTTRLSTLR CYEDTMLAAM FSGRHYIPTD SEGRYFIDRD GTHFGDVLNF LRSGDLPPRE
RVRAVYKEAQ YYAIGPLLEQ LENMQPLKGE KVRQAFLGLM PYYKDHLERI VEIARLRAVQ
RKARFAKLKV CVFKEEMPIT PYECPLLNSL RFERSESDGQ LFEHHCEVDV SFGPWEAVAD
VYDLLHCLVT DLSAQGLTVD HQCIGVCDKH LVNHYYCKRP IYEFKITWW
//

MIM 611725
*RECORD*
*FIELD* NO
611725
*FIELD* TI
*611725 POTASSIUM CHANNEL TETRAMERIZATION DOMAIN-CONTAINING PROTEIN 7; KCTD7
*FIELD* TX
read more
DESCRIPTION

Members of the KCTD gene family, including KCTD7, encode predicted
proteins containing an N-terminal domain that is homologous to the T1
domain in voltage-gated potassium channels (see KCNA1, 176260). KCTD7
displays a primary sequence and hydropathy profile indicating
intracytoplasmic localization. EST database analysis showed that KCTD7
is expressed in human and mouse brain (Van Bogaert et al., 2007).

CLONING

Staropoli et al. (2012) detected expression of a full-length 31-kD Kctd7
isoform in mouse brain. Other major immunoreactive bands included a
28-kD species in the spleen, liver, and kidneys, a 37-kD species in the
kidneys, and a 62-kD form most likely corresponding to a stable dimer.
The presence of multiple bands was consistent with alternative splicing
and tissue-specific regulation.

Kousi et al. (2012) found expression of the Kctd7 gene in cultured mouse
hippocampal cells. Expression was found in the cell soma, in neuritic
varicosities along the developing neuronal extensions, and in neurite
growth cones, but not in the nucleus. Kctd7 was widely expressed in
neurons throughout the intact mouse brain, including in cortical
neurons, in granular and pyramidal cell layers of the hippocampus, and
in cerebellar Purkinje cells. However, not all neuronal cells were
immunopositive for Kctd7, and expression was not seen in astrocytes or
microglial cells. Expression was constant from P5 to 2 months in
cerebellar lysates. Overexpression of KCTD7 in HeLa and COS-1 cells,
which do not express endogenous KCTD7, showed diffuse cytosolic
localization, with no colocalization with markers for endosomes, ER,
Golgi, lysosomes, or the cytoskeleton.

MAPPING

The KCTD7 gene maps to chromosome 7q11.2 (Van Bogaert et al., 2007).

GENE FUNCTION

Azizieh et al. (2011) demonstrated that KCTD7 expression hyperpolarizes
the cell membrane and reduces the excitability of transfected neurons in
patch clamp experiments. Kctd7 was expressed in hippocampal and Purkinje
cells of the murine brain. Immunoprecipitation assays showed that KCTD7
directly interacted with cullin-3 (CUL3; 603136), a component of the
ubiquitin ligase complex.

MOLECULAR GENETICS

In 3 affected members of a large consanguineous Moroccan family with
progressive myoclonic epilepsy-3 (EPM3; 611726), Van Bogaert et al.
(2007) identified a homozygous mutation in the KCTD7 gene (611725.0001).

In 2 Mexican sibs with infantile onset of progressive myoclonic epilepsy
and pathologic findings of neuronal ceroid lipofuscinosis in multiple
cell types, Staropoli et al. (2012) identified a homozygous mutation in
the KCTD7 gene (R184C; 611725.0002). The mutation was identified by
whole-exome sequencing and confirmed by Sanger sequencing. Staropoli et
al. (2012) designated the phenotype CLN14 (611726). KCTD7 mutations were
not found in 32 additional CLN samples.

In affected members of 7 unrelated families with progressive myoclonic
epilepsy-3, Kousi et al. (2012) identified 6 different mutations in the
KCTD7 gene (see, e.g., 611725.0003-611725.0007). All mutations were in
the homozygous or compound heterozygous state. The initial mutations
were found in 2 probands by homozygosity mapping followed by candidate
gene sequencing, and the other mutations were found by screening of the
gene in 108 Turkish patients and 1 Pakistani patient with the phenotype.
Four mutations were missense, 1 was an in-frame deletion, and 1 was
truncating. None of the patients with KCTD7 mutations tested had
evidence of neuronal ceroid lipofuscinosis on skin biopsy, and none of
22 additional patients with neuronal ceroid lipofuscinosis carried
mutations in the KCTD7 gene.

*FIELD* AV
.0001
EPILEPSY, PROGRESSIVE MYOCLONIC 3, WITHOUT INTRACELLULAR INCLUSIONS
KCTD7, ARG99TER

In 3 affected members of a large consanguineous Moroccan family with
progressive myoclonic epilepsy-3 (611726), Van Bogaert et al. (2007)
identified a homozygous C-to-T transition in exon 2 of the KCTD7 gene,
resulting in an arg99-to-ter (R99X) substitution. The patients had onset
of myoclonic seizures and neurodegeneration between 16 and 24 months of
age. The phenotype was severe and included mental retardation. The
unaffected parents were heterozygous for the mutation. Ultrastructural
analysis of a skin biopsy was normal.

.0002
EPILEPSY, PROGRESSIVE MYOCLONIC 3, WITH INTRACELLULAR INCLUSIONS
KCTD7, ARG184CYS

In 2 Mexican sibs with infantile onset of progressive myoclonic epilepsy
(611726) and intracellular inclusions, consistent with a diagnosis of
neuronal ceroid lipofuscinosis (designated CLN14), Staropoli et al.
(2012) identified a homozygous 550C-T transition in exon 4 of the KCTD7
gene, resulting in an arg184-to-cys (R184C) substitution. The mutation
was found by exome sequencing and confirmed by Sanger sequencing. Each
unaffected parent was heterozygous for the mutation, which was not found
in over 6,000 controls. In cerebellar cells, wildtype KCTD7 showed
broad, punctate cytoplasmic localization and distinct signal at the
plasma membrane, whereas mutant A184C showed more diffuse cytoplasmic
localization, markedly diminished signaling at the plasma membrane, and
prominent cytoplasmic aggregates. These results suggested that the
mutation affects the trafficking and/or solubility of KCTD7. Studies in
HEK293T cells showed that the R184C mutation abrogated the interaction
with cullin-3 (CUL3; 603136), which Staropoli et al. (2012) suggested
may lead to an accumulation of toxic intracellular proteins.

.0003
EPILEPSY, PROGRESSIVE MYOCLONIC 3, WITHOUT INTRACELLULAR INCLUSIONS
KCTD7, ARG94TRP

In a Turkish boy with progressive myoclonic epilepsy-3 (611726), Kousi
et al. (2012) identified a homozygous 280C-T transition in exon 2 of the
KCTD7 gene, resulting in an arg94-to-trp (R94W) substitution. The
mutation was not found in 150 Turkish control chromosomes.

.0004
EPILEPSY, PROGRESSIVE MYOCLONIC 3, WITHOUT INTRACELLULAR INCLUSIONS
KCTD7, 1-BP DEL, 594C

In 2 unrelated Turkish patients with EPM3 (611726), Kousi et al. (2012)
identified a homozygous 1-bp deletion (594delC) in exon 4 of the KCTD7
gene, resulting in a frameshift and premature termination
(Ile199SerfsTer74).

.0005
EPILEPSY, PROGRESSIVE MYOCLONIC 3, WITHOUT INTRACELLULAR INCLUSIONS
KCTD7, ASN273ILE

In a Turkish boy with EPM3 (611726), Kousi et al. (2012) identified a
homozygous 818A-T transversion in exon 4 of the KCTD7 gene, resulting in
an asn273-to-ile (N273I) substitution at a highly conserved residue.
Another Turkish boy with the disorder was compound heterozygous for
N273I and a 343G-T transversion, resulting in an asp115-to-tyr (D115Y;
611725.0006) substitution. The D115Y substitution did not occur at a
highly conserved residue and was predicted to be benign, but neither
mutation was found in 150 Turkish control chromosomes.

.0006
EPILEPSY, PROGRESSIVE MYOCLONIC 3, WITHOUT INTRACELLULAR INCLUSIONS
KCTD7, ASP115TYR

See 611725.0005 and Kousi et al. (2012).

.0007
EPILEPSY, PROGRESSIVE MYOCLONIC 3, WITHOUT INTRACELLULAR INCLUSIONS
KCTD7, LEU108MET

In 2 Pakistani sibs, born of consanguineous parents, with EPM3 (611726),
Kousi et al. (2012) identified a homozygous 322C-A transversion in exon
3 of the KCTD7 gene, resulting in a leu108-to-met (L108M) substitution
at a highly conserved residue. The mutation was not found in 150 Turkish
control chromosomes.

*FIELD* RF
1. Azizieh, R.; Orduz, D.; Van Bogaert, P.; Bouschet, T.; Rodriguez,
W.; Schiffmann, S. N.; Pirson, I.; Abramowicz, M. J.: Progressive
myoclonic epilepsy-associated gene KCTD7 is a regulator of potassium
conductance in neurons. Molec. Neurobiol. 44: 111-121, 2011.

2. Kousi, M.; Anttila, V.; Schulz, A.; Calafato, S.; Jakkula, E.;
Riesch, E.; Myllykangas, L.; Kalimo, H.; Topcu, M.; Gokben, S.; Alehan,
F.; Lemke, J. R.; Alber, M.; Palotie, A.; Kopra, O.; Lehesjoki, A.-E.
: Novel mutations consolidate KCTD7 as a progressive myoclonus epilepsy
gene. J. Med. Genet. 49: 391-399, 2012.

3. Staropoli, J. F.; Karaa, A; Lim, E. T.; Kirby, A.; Elbalalesy,
N.; Romansky, S. G.; Leydiker, K. B.; Coppel, S. H.; Barone, R.; Xin,
W.; Macdonald, M. E.; Abdenur, J. E.; Daly, M. J.; Sims, K. B.; Cotman,
S. L.: A homozygous mutation in KCTD7 links neuronal ceroid lipofuscinosis
to the ubiquitin-proteasome system. Am. J. Hum. Genet. 91: 202-208,
2012.

4. Van Bogaert, P.; Azizieh, R.; Desir, J.; Aeby, A.; De Meirleir,
L.; Laes, J.-F.; Christiaens, F.; Abramowicz, M. J.: Mutation of
a potassium channel-related gene in progressive myoclonic epilepsy. Ann.
Neurol. 61: 579-586, 2007.

*FIELD* CN
Cassandra L. Kniffin - updated: 8/22/2012
Cassandra L. Kniffin - updated: 7/31/2012

*FIELD* CD
Cassandra L. Kniffin: 1/15/2008

*FIELD* ED
carol: 09/12/2013
carol: 8/22/2012
ckniffin: 8/22/2012
carol: 8/2/2012
ckniffin: 7/31/2012
wwang: 1/31/2008
ckniffin: 1/16/2008

MIM 611726
*RECORD*
*FIELD* NO
611726
*FIELD* TI
#611726 EPILEPSY, PROGRESSIVE MYOCLONIC 3, WITH OR WITHOUT INTRACELLULAR INCLUSIONS;
read moreEPM3
;;CEROID LIPOFUSCINOSIS, NEURONAL, 14; CLN14
*FIELD* TX
A number sign (#) is used with this entry because progressive myoclonic
epilepsy-3 with or without intracellular inclusions (EPM3) is caused by
homozygous or compound heterozygous mutation in the KCTD7 gene (611725)
on chromosome 7q11.

DESCRIPTION

Mutations in the KCTD7 gene cause a severe neurodegenerative phenotype
characterized by onset of intractable myoclonic seizures before age 2
years and accompanied by developmental regression. The initial
description was consistent with a form of progressive myoclonic epilepsy
(designated here as EPM3), whereas a later report identified
intracellular accumulation of autofluorescent lipopigment storage
material, consistent with neuronal ceroid lipofuscinosis (designated
CLN14). Ultrastructural findings on skin biopsies thus appear to be
variable. However, clinical features are generally consistent between
reports (summary by Staropoli et al., 2012).

For a general phenotypic description and a discussion of genetic
heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800).

For a general phenotypic description and a discussion of genetic
heterogeneity of neuronal ceroid lipofuscinosis, see CLN1 (256730).

CLINICAL FEATURES

Van Bogaert et al. (2007) reported a consanguineous Moroccan family in
which 3 members had early-onset progressive myoclonic epilepsy.
Multifocal myoclonic seizures began between 16 and 24 months of age
after normal initial development. Two patients had secondary
generalization. Neurodegeneration and regression occurred with seizure
onset. Other features included mental retardation, dysarthria, truncal
ataxia, and loss of fine finger movements. One patient had several
episodes of myoclonic status epilepticus and developed permanent
myoclonus affecting the face, tongue, and limbs. Two patients showed
transient neurologic improvement when the epilepsy was controlled. EEG
showed slow dysrhythmia, multifocal and occasionally generalized
epileptiform discharges, and photosensitivity. Ultrastructural analysis
of a skin biopsy was normal.

Staropoli et al. (2012) reported 2 Mexican sibs with onset of severe
intractable myoclonic seizures at ages 9 and 8 months, respectively,
after normal development. Myoclonic movements involved mainly the face
and extremities, and were often precipitated or worsened by fevers.
Normal development occurred until about 18 months of age, at which point
motor and speech regression were noted. At ages 12 and 10 years, both
sibs had microcephaly, were nonverbal, and were without spontaneous
motor function. Neither showed a response to visual threat and both had
diminished pupillary light reflexes; 1 also had bilateral optic atrophy
without retinopathy. Brain imaging showed global cortical and cerebellar
atrophy and thinning of the corpus callosum. Skin biopsy of 1 patient
showed CLN-type storage material in fibroblasts, neurons, and eccrine
secretory epithelial cells. Electron microscopy of lymphocytes showed
lysosomal storage material containing fingerprint-like profiles and
granular osmiophilic deposits. The axon of a myelinated nerve contained
vacuole-bound rectilinear profiles. Immunoblot analysis of lymphocytes
showed increased levels of mitochondrial ATP synthase subunit C in
fingerprint, rectilinear, and curvilinear storage profiles, similar to
that observed in CLN3 (204200). Both sibs died from complications of
progressive disease in their mid-teens.

Kousi et al. (2012) reported 9 patients from 6 unrelated Turkish
families and 1 Pakistani family with EPM3. Three of the families were
consanguineous. All patients were alive at the time of the study and
were between 3.2 and 14 years of age. The mean age at presentation was
19 months, and most presented with myoclonic and/or tonic-clonic
seizures. One patient presented with ataxia. Six of the 9 patients had a
favorable response to antiepileptic drug treatment with multiple agents.
Psychomotor decline, including ataxia, became evident soon after onset
of seizures and resulted in severe motor and mental retardation. Some
patients developed scoliosis. All patients had abnormal EEG findings in
various brain regions. None had retinal findings, and none of the
patients tested had evidence of neuronal ceroid lipofuscinosis on skin
biopsy.

MAPPING

By linkage mapping, Van Bogaert et al. (2007) identified a locus for
EPM3 on chromosome 7q11.2 (maximum multipoint lod score of 4.0 at
D7S663).

MOLECULAR GENETICS

In affected members of a consanguineous Moroccan family with progressive
myoclonic epilepsy, Van Bogaert et al. (2007) identified a homozygous
mutation in the KCTD7 gene (R99X; 611725.0001).

In 2 Mexican sibs with progressive myoclonic epilepsy and pathologic
findings of neuronal ceroid lipofuscinosis in multiple cell types,
Staropoli et al. (2012) identified a homozygous mutation in the KCTD7
gene (R184C; 611725.0002). The mutation was identified by whole-exome
sequencing and confirmed by Sanger sequencing. KCTD7 mutations were not
found in 32 additional CLN samples.

In affected members of 7 unrelated families with progressive myoclonic
epilepsy-3, Kousi et al. (2012) identified 6 different mutations in the
KCTD7 gene (see, e.g., 611725.0003-611725.0007). All mutations were in
the homozygous or compound heterozygous state. The initial mutations
were found in 2 probands by homozygosity mapping followed by candidate
gene sequencing, and the other mutations were found by screening of the
gene in 108 Turkish patients and 1 Pakistani patient with the phenotype.
Four mutations were missense, 1 was an in-frame deletion, and 1 was
truncating. None of the patients with KCTD7 mutations tested had
evidence of neuronal ceroid lipofuscinosis on skin biopsy, and none of
22 additional patients with neuronal ceroid lipofuscinosis carried
mutations in the KCTD7 gene.

*FIELD* RF
1. Kousi, M.; Anttila, V.; Schulz, A.; Calafato, S.; Jakkula, E.;
Riesch, E.; Myllykangas, L.; Kalimo, H.; Topcu, M.; Gokben, S.; Alehan,
F.; Lemke, J. R.; Alber, M.; Palotie, A.; Kopra, O.; Lehesjoki, A.-E.
: Novel mutations consolidate KCTD7 as a progressive myoclonus epilepsy
gene. J. Med. Genet. 49: 391-399, 2012.

2. Staropoli, J. F.; Karaa, A.; Lim, E. T.; Kirby, A.; Elbalalesy,
N.; Romansky, S. G.; Leydiker, K. B.; Coppel, S. H.; Barone, R.; Xin,
W.; Macdonald, M. E.; Abdenur, J. E.; Daly, M. J.; Sims, K. B.; Cotman,
S. L.: A homozygous mutation in KCTD7 links neuronal ceroid lipofuscinosis
to the ubiquitin-proteasome system. Am. J. Hum. Genet. 91: 202-208,
2012.

3. Van Bogaert, P.; Azizieh, R.; Desir, J.; Aeby, A.; De Meirleir,
L.; Laes, J.-F.; Christiaens, F.; Abramowicz, M. J.: Mutation of
a potassium channel-related gene in progressive myoclonic epilepsy. Ann.
Neurol. 61: 579-586, 2007.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Head];
Microcephaly (in 1 family);
[Eyes];
Visual loss (in 1 family);
Optic atrophy, mild (in 1 patient)

NEUROLOGIC:
[Central nervous system];
Myoclonic seizures;
Secondary generalization;
Initial normal development;
Neurologic regression following seizure onset;
Mental retardation;
Dysarthria;
Limited expressive language;
Truncal ataxia;
Loss of motor function;
EEG shows slowed dysrhythmia and multifocal discharges;
Cerebral atrophy (in 1 family);
Cerebellar atrophy (in 1 family);
Thinning of the corpus callosum (in 1 family)

LABORATORY ABNORMALITIES:
Granular osmiophilic cytoplasmic deposits ultrastructurally in cells;
'Fingerprint profiles' ultrastructurally in cells;
'Rectilinear profiles' ultrastructurally in cells

MISCELLANEOUS:
Onset before age 2 years;
Two unrelated families have been reported (last curated July 2012);
Only 1 family had ultrastructural cellular findings of neuronal ceroid
lipofuscinosis;
Progressive disorder;
Severe phenotype

MOLECULAR BASIS:
Caused by mutation in the potassium channel tetramerisation domain
containing 7 gene (KCTD7, 611725.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 7/31/2012

*FIELD* CD
Cassandra L. Kniffin: 1/15/2008

*FIELD* ED
joanna: 11/30/2012
ckniffin: 7/31/2012
joanna: 3/14/2008
ckniffin: 1/16/2008

*FIELD* CN
Cassandra L. Kniffin - updated: 8/22/2012
Cassandra L. Kniffin - updated: 7/31/2012

*FIELD* CD
Cassandra L. Kniffin: 1/15/2008

*FIELD* ED
carol: 08/22/2012
ckniffin: 8/22/2012
carol: 8/2/2012
ckniffin: 7/31/2012
wwang: 6/13/2011
wwang: 1/31/2008
ckniffin: 1/16/2008

RBCC Red Blood Cell Collection

Full text data of KCTD7