RBCC

Full text data of TBC1D24

TBC1D24 (KIAA1171) [Confidence: high (present in two of the MS resources)]
TBC1 domain family member 24

Comments
Isoform Q9ULP9-2 was detected.

UniProt Q9ULP9
ID TBC24_HUMAN Reviewed; 559 AA.
AC Q9ULP9; A0JNW3; Q2KJ08;
DT 29-MAY-2007, integrated into UniProtKB/Swiss-Prot.
read moreDT 29-MAY-2007, sequence version 2.
DT 22-JAN-2014, entry version 80.
DE RecName: Full=TBC1 domain family member 24;
GN Name=TBC1D24; Synonyms=KIAA1171;
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=10574461; DOI=10.1093/dnares/6.5.329;
RA Hirosawa M., Nagase T., Ishikawa K., Kikuno R., Nomura N., Ohara O.;
RT "Characterization of cDNA clones selected by the GeneMark analysis
RT from size-fractionated cDNA libraries from human brain.";
RL DNA Res. 6:329-336(1999).
RN [2]
RP SEQUENCE REVISION.
RX PubMed=12168954; DOI=10.1093/dnares/9.3.99;
RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.;
RT "Construction of expression-ready cDNA clones for KIAA genes: manual
RT curation of 330 KIAA cDNA clones.";
RL DNA Res. 9:99-106(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Retinoblastoma;
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 [4]
RP FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, INTERACTION WITH
RP ARF6, VARIANTS FIME HIS-147 AND VAL-515, AND CHARACTERIZATION OF
RP VARIANTS FIME HIS-147 AND VAL-515.
RX PubMed=20727515; DOI=10.1016/j.ajhg.2010.07.020;
RA Falace A., Filipello F., La Padula V., Vanni N., Madia F.,
RA De Pietri Tonelli D., de Falco F.A., Striano P., Dagna Bricarelli F.,
RA Minetti C., Benfenati F., Fassio A., Zara F.;
RT "TBC1D24, an ARF6-interacting protein, is mutated in familial
RT infantile myoclonic epilepsy.";
RL Am. J. Hum. Genet. 87:365-370(2010).
RN [5]
RP FUNCTION, VARIANT FIME LEU-251, AND CHARACTERIZATION OF VARIANT FIME
RP LEU-251.
RX PubMed=20797691; DOI=10.1016/j.ajhg.2010.08.001;
RA Corbett M.A., Bahlo M., Jolly L., Afawi Z., Gardner A.E., Oliver K.L.,
RA Tan S., Coffey A., Mulley J.C., Dibbens L.M., Simri W., Shalata A.,
RA Kivity S., Jackson G.D., Berkovic S.F., Gecz J.;
RT "A focal epilepsy and intellectual disability syndrome is due to a
RT mutation in TBC1D24.";
RL Am. J. Hum. Genet. 87:371-375(2010).
RN [6]
RP VARIANT EIEE16 SER-229, AND CHARACTERIZATION OF VARIANT EIEE16
RP SER-229.
RX PubMed=23526554; DOI=10.1002/humu.22318;
RA Milh M., Falace A., Villeneuve N., Vanni N., Cacciagli P.,
RA Assereto S., Nabbout R., Benfenati F., Zara F., Chabrol B.,
RA Villard L., Fassio A.;
RT "Novel compound heterozygous mutations in TBC1D24 cause familial
RT malignant migrating partial seizures of infancy.";
RL Hum. Mutat. 34:869-872(2013).
CC -!- FUNCTION: May act as a GTPase-activating protein for Rab family
CC protein(s). Involved in neuronal projections development, probably
CC through a negative modulation of ARF6 function.
CC -!- SUBUNIT: Interacts with ARF6.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Note=Partially expressed at the
CC plasma membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9ULP9-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9ULP9-2; Sequence=VSP_025701;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Highest expression in brain.
CC -!- DISEASE: Familial infantile myoclonic epilepsy (FIME)
CC [MIM:605021]: A subtype of idiopathic epilepsy starting in early
CC infancy and manifesting as myoclonic seizures, febrile
CC convulsions, and tonic-clonic seizures. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Epileptic encephalopathy, early infantile, 16 (EIEE16)
CC [MIM:615338]: A severe autosomal recessive neurologic disorder
CC characterized by onset of seizures in the first weeks or months of
CC life. Seizures can be of various types, are unresponsive to
CC medication, last for long periods of time, and occur frequently.
CC Affected infants show psychomotor regression or lack of
CC psychomotor development, as well as other neurologic features such
CC as extrapyramidal signs and hypotonia. Most die in childhood.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Contains 1 Rab-GAP TBC domain.
CC -!- SIMILARITY: Contains 1 TLD domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA86485.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -----------------------------------------------------------------------
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DR EMBL; AB032997; BAA86485.1; ALT_INIT; mRNA.
DR EMBL; BC112389; AAI12390.1; -; mRNA.
DR EMBL; BC127014; AAI27015.1; -; mRNA.
DR EMBL; BC127015; AAI27016.1; -; mRNA.
DR RefSeq; NP_001186036.1; NM_001199107.1.
DR RefSeq; NP_065756.1; NM_020705.2.
DR RefSeq; XP_005255506.1; XM_005255449.1.
DR UniGene; Hs.353087; -.
DR ProteinModelPortal; Q9ULP9; -.
DR SMR; Q9ULP9; 339-554.
DR STRING; 9606.ENSP00000293970; -.
DR PhosphoSite; Q9ULP9; -.
DR DMDM; 148887040; -.
DR PaxDb; Q9ULP9; -.
DR PRIDE; Q9ULP9; -.
DR Ensembl; ENST00000293970; ENSP00000293970; ENSG00000162065.
DR Ensembl; ENST00000434757; ENSP00000390106; ENSG00000162065.
DR Ensembl; ENST00000567020; ENSP00000454408; ENSG00000162065.
DR GeneID; 57465; -.
DR KEGG; hsa:57465; -.
DR UCSC; uc002cql.3; human.
DR CTD; 57465; -.
DR GeneCards; GC16P002526; -.
DR HGNC; HGNC:29203; TBC1D24.
DR HPA; HPA044712; -.
DR MIM; 605021; phenotype.
DR MIM; 613577; gene.
DR MIM; 615338; phenotype.
DR neXtProt; NX_Q9ULP9; -.
DR Orphanet; 352582; Familial infantile myoclonic epilepsy.
DR Orphanet; 352587; Focal epilepsy - intellectual deficit - cerebro-cerebellar malformation.
DR Orphanet; 293181; Malignant migrating partial seizures of infancy.
DR Orphanet; 352596; Progressive myoclonic epilepsy with dystonia.
DR PharmGKB; PA144596267; -.
DR eggNOG; NOG315027; -.
DR HOGENOM; HOG000273861; -.
DR HOVERGEN; HBG068667; -.
DR InParanoid; Q9ULP9; -.
DR OMA; YSDWQRW; -.
DR OrthoDB; EOG7R830Z; -.
DR ChiTaRS; TBC1D24; human.
DR GenomeRNAi; 57465; -.
DR NextBio; 63674; -.
DR PRO; PR:Q9ULP9; -.
DR ArrayExpress; Q9ULP9; -.
DR Bgee; Q9ULP9; -.
DR CleanEx; HS_TBC1D24; -.
DR Genevestigator; Q9ULP9; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005097; F:Rab GTPase activator activity; IEA:InterPro.
DR GO; GO:0031175; P:neuron projection development; IMP:UniProtKB.
DR GO; GO:0032851; P:positive regulation of Rab GTPase activity; IEA:GOC.
DR InterPro; IPR000195; Rab-GTPase-TBC_dom.
DR InterPro; IPR006571; TLDc.
DR Pfam; PF00566; RabGAP-TBC; 1.
DR Pfam; PF07534; TLD; 2.
DR SMART; SM00164; TBC; 1.
DR SMART; SM00584; TLDc; 1.
DR SUPFAM; SSF47923; SSF47923; 2.
DR PROSITE; PS50086; TBC_RABGAP; FALSE_NEG.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Cytoplasm; Disease mutation;
KW Epilepsy; GTPase activation; Reference proteome.
FT CHAIN 1 559 TBC1 domain family member 24.
FT /FTId=PRO_0000288504.
FT DOMAIN 47 262 Rab-GAP TBC.
FT DOMAIN 368 554 TLD.
FT VAR_SEQ 322 327 Missing (in isoform 2).
FT /FTId=VSP_025701.
FT VARIANT 147 147 D -> H (in FIME; signicantly impairs the
FT interaction with ARF6; partially induces
FT neurite overgrowth when overexpressed in
FT primary cortical neurons).
FT /FTId=VAR_064365.
FT VARIANT 229 229 F -> S (in EIEE16; loss of function
FT mutation; impairs the interaction with
FT ARF6; overexpression of the mutant
FT protein in primary cortical neurons
FT abolishes the ability to increase neurite
FT length and arborization).
FT /FTId=VAR_070102.
FT VARIANT 251 251 F -> L (in FIME; fails to induce neurite
FT overgrowth when overexpressed in primary
FT cortical neurons).
FT /FTId=VAR_064366.
FT VARIANT 515 515 A -> V (in FIME; does not affect the
FT interaction with ARF6; fails to induce
FT neurite overgrowth when overexpressed in
FT primary cortical neurons).
FT /FTId=VAR_064367.
FT CONFLICT 295 295 F -> L (in Ref. 1; BAA86485).
SQ SEQUENCE 559 AA; 62919 MW; 0F4EA43297ACC7F9 CRC64;
MDSPGYNCFV DKDKMDAAIQ DLGPKELSCT ELQELKQLAR QGYWAQSHAL RGKVYQRLIR
DIPCRTVTPD ASVYSDIVGK IVGKHSSSCL PLPEFVDNTQ VPSYCLNARG EGAVRKILLC
LANQFPDISF CPALPAVVAL LLHYSIDEAE CFEKACRILA CNDPGRRLID QSFLAFESSC
MTFGDLVNKY CQAAHKLMVA VSEDVLQVYA DWQRWLFGEL PLCYFARVFD VFLVEGYKVL
YRVALAILKF FHKVRAGQPL ESDSVKQDIR TFVRDIAKTV SPEKLLEKAF AIRLFSRKEI
QLLQMANEKA LKQKGITVKQ KSVSLSKRQF VHLAVHAENF RSEIVSVREM RDIWSWVPER
FALCQPLLLF SSLQHGYSLA RFYFQCEGHE PTLLLIKTTQ KEVCGAYLST DWSERNKFGG
KLGFFGTGEC FVFRLQPEVQ RYEWVVIKHP ELTKPPPLMA AEPTAPLSHS ASSDPADRLS
PFLAARHFNL PSKTESMFMA GGSDCLIVGG GGGQALYIDG DLNRGRTSHC DTFNNQPLCS
ENFLIAAVEA WGFQDPDTQ
//

MIM 605021
*RECORD*
*FIELD* NO
605021
*FIELD* TI
#605021 MYOCLONIC EPILEPSY, FAMILIAL INFANTILE; FIME
;;EIM
*FIELD* TX
A number sign (#) is used with this entry because familial infantile
read moremyoclonic epilepsy is caused by homozygous or compound heterozygous
mutation in the TBC1D24 gene (613577) on chromosome 16p13.

Mutation in the TBC1D24 gene can also cause early infantile epileptic
encephalopathy-16 (EIEE16; 615338), a more severe disorder.

CLINICAL FEATURES

Zara et al. (2000) studied a large Italian pedigree segregating a
recessive idiopathic myoclonic epilepsy that started in early infancy
and manifest as myoclonic seizures, febrile convulsions, and
tonic-clonic seizures. There was a favorable response to antiepileptic
medication, and intellectual and neurologic development was normal.

- Clinical Variability

Corbett et al. (2010) reported a consanguineous Arab family from
northern Israel with early-onset seizures and intellectual disability.
Affected individuals had focal seizures with prominent eye blinking and
facial and limb jerking beginning around 2 months of age. Generalized
convulsive seizures also occurred. The disorder persisted throughout
life but could be controlled by antiepileptic medication. Some children
had mildly delayed early motor and speech development, and as adults,
they showed borderline to moderate intellectual disability associated
with mild dysarthria and ataxia. Brain MRI suggested abnormal cortical
thickening most obvious in the anteromesial frontal areas.

Afawi et al. (2013) reported the clinical and neuroradiologic features
of 4 of the Arab sibs with early-onset seizures and intellectual
disability reported by Corbett et al. (2010). The patients ranged in age
from 23 to 40 years. All had onset of eye blinking or twitching at 2
months of age and had seizures throughout life, with variably good
response to medication. The seizures tended to be focal, with a
perirolandic or perisylvian origin; convulsive seizures occurred
infrequently. All had delayed psychomotor development, and 2 were unable
to run. Additional features included cerebellar signs such as
dysarthria, clumsiness, and abnormal gait. Interictal EEG showed mild
slowing of background rhythms. Brain MRI of 2 patients showed atrophy of
the cerebellar ansiform lobule with signal abnormalities in the cortical
and subcortical white matter. There was also cerebral cortical
thickening and blurring of the gray/white matter interface. One patient
had right hippocampal sclerosis. Afawi et al. (2013) noted that the
phenotype in this Arab family differed from that reported by Zara et al.
(2000).

MAPPING

By linkage analysis, Zara et al. (2000) mapped the disease locus to
chromosome 16p13, with a maximum lod score of 4.48 for marker D16S3027
at a recombination fraction of 0.0. Haplotype analysis placed the
critical region within a 3.4-cM interval between D16S3024 and D16S423.
Zara et al. (2000) stated that this was the first report of an
idiopathic epilepsy inherited as an autosomal recessive trait.

INHERITANCE

The transmission patter of epilepsy in the families reported by Zara et
al. (2000) and Corbett et al. (2010) indicated autosomal recessive
inheritance.

MOLECULAR GENETICS

In affected members of a large Italian family with infantile myoclonic
epilepsy mapping to chromosome 16p13.3 (Zara et al., 2000), Falace et
al. (2010) identified compound heterozygosity for 2 mutations in the
TBC1D24 gene (613577.0001 and 613577.0002) that were shown to decrease
protein function. The identification of these mutations suggested
involvement of the ARF6 (600464)-dependent molecular pathway in the
generation of brain hyperexcitability and seizures. The findings also
suggested a critical role for TBC1D24 in developmentally regulated
events essential for the morphologic and functional maturation of
neuronal circuitry, disruption of which likely plays a role in the
etiology of epileptic disorders.

By genomewide linkage analysis followed by candidate gene sequencing of
a large consanguineous Arab family with seizures and intellectual
disability, Corbett et al. (2010) found linkage to chromosome 16p13 and
identified a homozygous loss-of-function mutation in the TBC1D24 gene
(F251L; 613577.0003). The findings suggested that TBC1D24 plays an
important role in normal human brain development.

*FIELD* RF
1. Afawi, Z.; Mandelstam, S.; Korczyn, A. D.; Kivity, S.; Walid, S.;
Shalata, A.; Oliver, K. L.; Corbett, M.; Gecz, J.; Berkovic, S. F.;
Jackson, G. D.: TBC1D24 mutation associated with focal epilepsy,
cognitive impairment and a distinctive cerebro-cerebellar malformation. Epilepsy
Res. 105: 240-244, 2013.

2. Corbett, M. A.; Bahlo, M.; Jolly, L.; Afawi, Z.; Gardner, A. E.;
Oliver, K. L.; Tan, S.; Coffey, A.; Mulley, J. C.; Dibbens, L. M.;
Simri, W.; Shalata, A.; Kivity, S.; Jackson, G. D.; Berkovic, S. F.;
Gecz, J.: A focal epilepsy and intellectual disability syndrome is
due to a mutation in TBC1D24. Am. J. Hum. Genet. 87: 371-375, 2010.

3. Falace, A.; Filipello, F.; La Padula, V.; Vanni, N.; Madia, F.;
De Pietri Tonelli, D.; de Falco, F. A.; Striano, P.; Dagna Bricarelli,
F.; Minetti, C.; Benfenati, F.; Fassio, A.; Zara, F.: TBC1D24, an
ARF6-interacting protein, is mutated in familial infantile myoclonic
epilepsy. Am. J. Hum. Genet. 87: 365-370, 2010.

4. Zara, F.; Gennaro, E.; Stabile, M.; Carbone, I.; Malacarne, M.;
Majello, L.; Santangelo, R.; Antonio de Falco, F.; Bricarelli, F.
D.: Mapping of a locus for a familial autosomal recessive idiopathic
myoclonic epilepsy of infancy to chromosome 16p13. Am. J. Hum. Genet. 66:
1552-1557, 2000. Note: Erratum: Am. J. Hum. Genet. 66: 1728 only,
2000.

*FIELD* CS
INHERITANCE:
Autosomal recessive

NEUROLOGIC:
[Central nervous system];
Delayed motor and speech development, mild (1 family);
Myoclonic seizures, frequent, long-lasting (many hours);
Focal seizures;
Febrile seizures;
Generalized tonic-clonic seizures;
Ictal EEG with bisynchronous spike waves;
Intellectual disabilities (in 1 family);
Ataxia, (1 family);
Dysarthria, mild (1 family);
Brain MRI shows abnormal cortical thickening in the anteromesial frontal
areas (1 family)

MISCELLANEOUS:
Two unrelated families have been reported (as of October 2010);
Variable severity;
Age of onset 2-8 months;
One family had normal cognitive and neurologic development;
A second family had mild intellectual disability;
Some patients have persistence of seizures to adulthood, but then
show remission;
Good response to medication

MOLECULAR BASIS:
Caused by mutation in the TBC1 domain family, member 24 gene (TBC1D24,
613577.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 10/20/2010

*FIELD* CD
Cassandra L. Kniffin: 11/11/2002

*FIELD* ED
joanna: 05/01/2012
joanna: 1/20/2012
ckniffin: 10/20/2010
ckniffin: 11/11/2002

*FIELD* CN
Cassandra L. Kniffin - updated: 7/25/2013
Cassandra L. Kniffin - updated: 10/20/2010

*FIELD* CD
Victor A. McKusick: 5/26/2000

*FIELD* ED
carol: 07/26/2013
ckniffin: 7/25/2013
wwang: 10/25/2010
ckniffin: 10/20/2010
ckniffin: 6/17/2010
ckniffin: 10/2/2009
mgross: 3/19/2004
mcapotos: 12/21/2001
mgross: 5/26/2000

MIM 613577
*RECORD*
*FIELD* NO
613577
*FIELD* TI
*613577 TBC1 DOMAIN FAMILY, MEMBER 24; TBC1D24
;;KIAA1171
*FIELD* TX

DESCRIPTION

read moreThe TBC1D24 gene encodes a member of the Tre2-Bub2-Cdc16 (TBC)
domain-containing RAB-specific GTPase-activating proteins, which
coordinate Rab proteins and other GTPases for the proper transport of
intracellular vesicles (summary by Campeau et al., 2013).

CLONING

By sequencing clones obtained from a size-fractionated brain cDNA
library, followed by RT-PCR, Hirosawa et al. (1999) obtained a cDNA
encoding TBC1D24, which they called KIAA1171. The deduced 595-amino acid
protein contains a TBC domain, suggesting it is involved in cell
signaling. RT-PCR ELISA detected low expression of TBC1D24 in all adult
and fetal tissues examined except spleen, which showed no expression.
Expression was moderate in amygdala and cerebellum and low in all other
adult brain regions examined.

Falace et al. (2010) stated that TBC1D24 encodes a 553-amino acid
protein. RT-PCR analysis showed TBC1D24 expression in multiple human
tissues, with highest expression in brain, followed by testis, skeletal
muscle, heart, kidney, lung, and liver. Tbc1d24 was expressed in the
cortex and hippocampus of developing mouse brain, with increased
expression during cortical development, particularly in the internal
part of the cortical plate and in the subventricular zone.

Corbett et al. (2010) stated that the TBC1D24 protein contains 559 amino
acids and contains an N-terminal TBC domain and a C-terminal TLD domain.
Alternative splicing can result in as many as 3 isoforms. They
demonstrated Tbc1d24 expression in mouse embryonic stem cell-derived
neurons, cultured embryonic day 18.5 (E18.5) mouse hippocampal neurons,
and developing mouse brain.

Guven and Tolun (2013) used Sanger sequencing and PCR to analyze the
structure and expression of 4 different TBC1D24 mRNA isoforms. Isoform 1
encodes a 559-residue protein that includes all 8 exons; isoform 2
encodes a 553-residue protein that lacks exon 3; isoform 3 encodes a
506-residue protein that lacks exon 4; and isoform 4 encodes a
424-residue protein that lacks exon 5 and is coded after exon 4 in a
frame different from that of the other isoforms. All isoforms were
observed in all brain regions investigated, including the cerebellum,
corpus callosum, frontal cortex, occipital cortex, striatum, parietal
cortex, and brainstem. In all brain samples, isoform 1 was more abundant
than the other isoforms. Of 5 nonneuronal tissues tested, isoform 2, was
much more abundant than the total of all the others in liver, blood,
adipose tissue, and bone marrow, but was less abundant than the other
isoforms in skeletal muscle.

Campeau et al. (2013) noted that TBC1D24 is the only TBC/RabGAP with a
TLDc domain, which is thought to be involved in oxidative stress
resistance.

Campeau et al. (2013) found high expression of the Tbc1d24 gene in
chondrocytes of the distal phalanges of the mouse forelimb and in the
calvarium of newborn mice.

GENE STRUCTURE

Corbett et al. (2010) noted that the TBC1D24 gene contains 7 exons.

A new 18-bp exon 3 was subsequently identified, indicating that the
TBC1D24 gene contains 8 exons (summary by Guven and Tolun, 2013).

MAPPING

Gross (2010) mapped the TBC1D24 gene to chromosome 16p13.3 based on an
alignment of the TBC1D24 sequence (GenBank GENBANK AB449911) with the
genomic sequence (GRCh37).

GENE FUNCTION

By coimmunoprecipitation studies in COS-7 cells, Falace et al. (2010)
found that TBC1D24 binds ARF6 (600464), a member of the Ras-related
family of small GTPases that regulate exo- and endocytosis. The
intensity of the coimmunoprecipitated band increased in the presence of
inactive GDP-locked ARF6, indicating a GDP-dependent interaction.
Overexpression of TBC1D24 in mouse embryo cortical neurons resulted in a
marked increase in neurite length and arborization compared to controls,
affecting both axonal and dendritic compartments. The findings were
consistent with TBC1D24 acting as a negative regulator of ARF6.

Corbett et al. (2010) found that overexpression of TBC1D24 in mouse
E18.5 primary hippocampal neurons resulted in significantly increased
length of primary axons and increased numbers of neurite termini at days
5 and 7 posttransfection, consistent with increased arborization. These
findings suggested that TBC1D24 has an important role in normal brain
development.

MOLECULAR GENETICS

- Familial Infantile Myoclonic Epilepsy

In affected members of a large Italian family with familial infantile
myoclonic epilepsy (FIME; 605021) mapping to chromosome 16p13.3 (Zara et
al., 2000), Falace et al. (2010) identified compound heterozygosity for
2 mutations in the TBC1D24 gene (613577.0001 and 613577.0002) that were
shown to decrease function. The identification of these mutations
suggested involvement of the ARF6-dependent molecular pathway in the
generation of brain hyperexcitability and seizures. The findings also
suggested a critical role for TBC1D24 in developmentally regulated
events essential for the morphologic and functional maturation of
neuronal circuitry, disruption of which likely plays a role in the
etiology of epileptic disorders.

By genomewide linkage analysis followed by candidate gene sequencing of
a large consanguineous Arab family with seizures and intellectual
disability, Corbett et al. (2010) found linkage to chromosome 16p13 and
identified a homozygous loss of function mutation in the TBC1D24 gene
(F251L; 613577.0003). The findings suggested that TBC1D24 plays an
important role in normal human brain development.

- Early Infantile Epileptic Encephalopathy 16

In affected members of a consanguineous Turkish family with early
infantile epileptic encephalopathy-16 (EIEE16; 615338), previously
reported by Duru et al. (2010), Guven and Tolun (2013) identified a
homozygous truncating mutation in the TBC1D24 gene (613577.0004). The
mutation was predicted to affect isoforms 1, 3, and 4, but not isoform
2, which lacks exon 3. The disorder was characterized by onset of
seizures in the first weeks or months of life. Seizures were
predominantly myoclonic but also focal, were unresponsive to medication,
and occurred frequently. Affected infants showed psychomotor regression
or lack of psychomotor development, as well as other neurologic features
such as extrapyramidal signs and hypotonia. All died in childhood. Guven
and Tolun (2013) noted that the severity of the mutation paralleled the
severity of the phenotype in this family.

In 2 sisters with EIEE16, Milh et al. (2013) identified compound
heterozygosity for 2 mutations in exon 2 of the TBC1D24 gene (F229S,
613577.0005 and C156X, 613577.0006). The mutations, which were found by
exome sequencing and confirmed by Sanger sequencing, were not present in
several large exome databases and segregated with the disorder in the
family. The patients developed clonic seizures early in the second month
of life and thereafter developed prolonged, almost continuous seizures
of different types with severe neurologic deterioration and lack of
psychomotor development. The clinical diagnosis was consistent with
malignant migrating partial seizures of infancy (MMPSI). Screening of
the TBC1D24 gene in 8 additional MMPSI patients did not identify any
mutations.

- Deafness, Onychodystrophy, Osteodystrophy, Mental Retardation,
and Seizures Syndrome

In affected individuals from 9 unrelated families with deafness,
onychodystrophy, osteodystrophy, mental retardation, and seizures
syndrome (DOORS; 220500), Campeau et al. (2013) identified homozygous or
compound heterozygous mutations in the TBC1D24 gene (see, e.g.,
613577.0007-613577.0011). The mutations in the first families were found
by whole-exome sequencing and confirmed by Sanger sequencing. Most of
the mutations were missense substitutions; functional studies were not
performed. The 9 families were ascertained from a larger cohort of 26
families with clinical features suggestive of the disorder. The
remaining families did not carry TBC1D24 mutations, indicating genetic
heterogeneity.

*FIELD* AV
.0001
MYOCLONIC EPILEPSY, INFANTILE, FAMILIAL
TBC1D24, ASP147HIS

In affected members of a large Italian family with infantile myoclonic
epilepsy (FIME; 605021) mapping to chromosome 16p13.3 (Zara et al.,
2000), Falace et al. (2010) identified compound heterozygosity for 2
mutations in the TBC1D24 gene: a 439G-C transversion in exon 2,
resulting in an asp147-to-his (D147H) substitution in the TBC domain,
and a 1526C-T transition in exon 7, resulting in an ala509-to-val
(A509V) substitution in the TLD domain. Neither mutation was found in
300 Italian controls. Affected individuals had myoclonic epilepsy that
started in early infancy as myoclonic seizures, febrile convulsions, and
tonic-clonic seizures, with normal mental and neurologic development. In
vitro studies in COS-7 cells showed that the D147H mutant impaired
normal interaction with ARF6 (600464), and that A509V mutant severely
affected ARF6-dependent TBC1D24 function without affecting the
interaction. Overexpression of wildtype TBC1D24 in mouse embryonic
cortical cells resulted in an increase in neurite length and branching,
whereas expression of the FIME-associated mutations significantly
reverted this phenotype, showing a partial (D147H) or complete (A509V)
loss of function.

.0002
MYOCLONIC EPILEPSY, INFANTILE, FAMILIAL
TBC1D24, ALA509VAL

See 613577.0001 and Falace et al. (2010).

.0003
MYOCLONIC EPILEPSY, INFANTILE, FAMILIAL
TBC1D24, PHE251LEU

In affected members of a consanguineous Arab family with infantile
myoclonic epilepsy (605021) and intellectual disability in some, Corbett
et al. (2010) identified a homozygous 751T-C transition in exon 2 of the
TBC1D24 gene, resulting in a phe251-to-leu (F251L) substitution within
the TBC domain. The mutation occurred in a highly conserved residue and
was not found in 210 ethnically matched control chromosomes.
Overexpression of wildtype TBC1D24 in mouse E18.5 primary hippocampal
neurons resulted in increased arborization, whereas overexpression of
the F251L mutant was no different than control, consistent with a loss
of function.

.0004
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 16
TBC1D24, 2-BP DEL, 969GT

In affected members of a consanguineous Turkish family with early
infantile epileptic encephalopathy-16 (EIEE16; 615338) previously
reported by Duru et al. (2010), Guven and Tolun (2013) identified a
homozygous 2-bp deletion (c.969delGT) in exon 3 of the TBC1D24 gene,
resulting in a frameshift and premature termination (Ser324ThrfsTer3),
yielding a protein 42% shorter than the native protein. The mutation
segregated with the disorder and was not found in 120 control samples.
The mutation was predicted to affect isoforms 1, 3, and 4, but not
isoform 2, which lacks exon 3. Guven and Tolun (2013) noted that the
severity of the mutation paralleled the severity of the phenotype in
this family.

.0005
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 16
TBC1D24, PHE229SER

In 2 sisters with EIEE16 (615338), Milh et al. (2013) identified
compound heterozygosity for 2 mutations in exon 2 of the TBC1D24 gene: a
c.686T-C transition, resulting in a phe229-to-ser (F229S) substitution
at a highly conserved residue in the TBC domain, and c.468C-A
transversion, resulting in a cys156-to-ter substitution (C156X;
613577.0006). The mutations, which were found by exome sequencing and
confirmed by Sanger sequencing, were not present in several large exome
databases and segregated with the disorder in the family. The patients
developed clonic seizures early in the second month of life and
thereafter developed prolonged, almost continuous seizures of different
types with severe neurologic deterioration and lack of psychomotor
development. The clinical diagnosis was consistent with malignant
migrating partial seizures of infancy (MMPSI). Coimmunoprecipitation
studies showed that the F229S mutation impaired the interaction of
TBC1D24 with ARF6 (600464), and overexpression of the mutant protein in
primary cortical neurons abolished the ability of TBC1D24 to increase
neurite length and arborization, consistent with a loss of function.

.0006
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 16
TBC1D24, CYS156TER

See 613577.0005 and Milh et al. (2013).

.0007
DEAFNESS, ONYCHODYSTROPHY, OSTEODYSTROPHY, MENTAL RETARDATION, AND
SEIZURES SYNDROME
TBC1D24, ARG242CYS

In 4 affected individuals from 3 unrelated families with deafness,
onychodystrophy, osteodystrophy, mental retardation, and seizures
syndrome (DOORS; 220500), Campeau et al. (2013) identified a homozygous
c.724C-T transition in the TBC1D24 gene, resulting in an arg242-to-cys
(R242C) substitution. The families were from the United States, India,
and Brazil. Three affected individuals from 2 additional families were
compound heterozygous for R242C and another mutation in the TBC1D24
gene: R40C (613577.0008) or Q20E (613577.0009). The mutations in the
first families were found by whole-exome sequencing and confirmed by
Sanger sequencing. All substitutions occurred at conserved residues and
were not found in the Exome Variant Server database.

.0008
DEAFNESS, ONYCHODYSTROPHY, OSTEODYSTROPHY, MENTAL RETARDATION, AND
SEIZURES SYNDROME
TBC1D24, ARG40CYS

In a Japanese patient with DOORS syndrome (220500), Campeau et al.
(2013) identified compound heterozygous mutations in the TBC1D24 gene: a
c.118C-T transition, resulting in an arg40-to-cys (R40C) substitution,
and R242C (613577.0007). Both substitutions occurred at conserved
residues and were not present in the Exome Variant Server database.

.0009
DEAFNESS, ONYCHODYSTROPHY, OSTEODYSTROPHY, MENTAL RETARDATION, AND
SEIZURES SYNDROME
TBC1D24, GLN20GLU

In 2 sibs from Chile with DOORS syndrome (220500), Campeau et al. (2013)
identified compound heterozygous mutations in the TBC1D24 gene: a
c.58C-G transversion, in a gln20-to-glu (Q20E) substitution, and R242C
(613577.0007). Both substitutions occurred at conserved residues and
were not present in the Exome Variant Server database.

.0010
DEAFNESS, ONYCHODYSTROPHY, OSTEODYSTROPHY, MENTAL RETARDATION, AND
SEIZURES SYNDROME
TBC1D24, 1-BP DEL, 1008T

In a German patient with DOORS syndrome (220500), Campeau et al. (2013)
identified compound heterozygosity for 2 mutations in the TBC1D24 gene:
a 1-bp deletion (c.1008delT), resulting in a frameshift and premature
termination (His336GlnfsTer12), and a splice site mutation in intron 5
(c.1206+5G-A; 613577.0011). The heterozygous c.1008delT mutation was
found in 2 of 6,118 individuals in the Exome Variant Server. Fibroblasts
from this patient showed 5% TBC1D24 mRNA and no detectable protein
compared to controls, consistent with a loss of function. An unrelated
French patient was heterozygous for the c.1008delT mutation, but a
second mutation was not identified.

.0011
DEAFNESS, ONYCHODYSTROPHY, OSTEODYSTROPHY, MENTAL RETARDATION, AND
SEIZURES SYNDROME
TBC1D24, IVS5DS, G-A, +5

See 613577.0010 and Campeau et al. (2013).

*FIELD* RF
1. Campeau, P. M.; Kasperaviciute, D.; Lu, J. T.; Burrage, L. C.;
Kim, C.; Hori, M.; Powell, B. R.; Stewart, F.; Felix, T. M.; van den
Ende, J.; Wisniewska, M.; Kayserili, H.; and 29 others: The genetic
basis of DOORS syndrome: an exome-sequencing study. Lancet Neurol. 28Nov,
2013. Note: Advance Electronic Publication.

2. Corbett, M. A.; Bahlo, M.; Jolly, L.; Afawi, Z.; Gardner, A. E.;
Oliver, K. L.; Tan, S.; Coffey, A.; Mulley, J. C.; Dibbens, L. M.;
Simri, W.; Shalata, A.; Kivity, S.; Jackson, G. D.; Berkovic, S. F.;
Gecz, J.: A focal epilepsy and intellectual disability syndrome is
due to a mutation in TBC1D24. Am. J. Hum. Genet. 87: 371-375, 2010.

3. Duru, N.; Iseri, S. A. U.; Selcuk, N.; Tolun, A.: Early-onset
progressive myoclonic epilepsy with dystonia mapping to 16pter-p13.3. J.
Neurogenet. 24: 207-215, 2010.

4. Falace, A.; Filipello, F.; La Padula, V.; Vanni, N.; Madia, F.;
De Pietri Tonelli, D.; de Falco, F. A.; Striano, P.; Dagna Bricarelli,
F.; Minetti, C.; Benfenati, F.; Fassio, A.; Zara, F.: TBC1D24, an
ARF6-interacting protein, is mutated in familial infantile myoclonic
epilepsy. Am. J. Hum. Genet. 87: 365-370, 2010.

5. Gross, M. B.: Personal Communication. Baltimore, Md. 9/28/2010.

6. Guven, A.; Tolun, A.: TBC1D24 truncating mutation resulting in
severe neurodegeneration. J. Med. Genet. 50: 199-202, 2013.

7. Hirosawa, M.; Nagase, T.; Ishikawa, K.; Kikuno, R.; Nomura, N.;
Ohara, O.: Characterization of cDNA clones selected by the GeneMark
analysis from size-fractionated cDNA libraries from human brain. DNA
Res. 6: 329-336, 1999.

8. Milh, M.; Falace, A.; Villeneuve, N.; Vanni, N.; Cacciagli, P.;
Assereto, S.; Nabbout, R.; Benfenati, F.; Zara, F.; Chabrol, B.; Villard,
L.; Fassio, A.: Novel compound heterozygous mutations in TBC1D24
cause familial malignant migrating partial seizures of infancy. Hum.
Mutat. 34: 869-872, 2013.

9. Zara, F.; Gennaro, E.; Stabile, M.; Carbone, I.; Malacarne, M.;
Majello, L.; Santangelo, R.; Antonio de Falco, F.; Bricarelli, F.
D.: Mapping of a locus for a familial autosomal recessive idiopathic
myoclonic epilepsy of infancy to chromosome 16p13. Am. J. Hum. Genet. 66:
1552-1557, 2000. Note: Erratum: Am. J. Hum. Genet. 66: 1728 only,
2000.

*FIELD* CN
Cassandra L. Kniffin - updated: 12/12/2013
Cassandra L. Kniffin - updated: 7/25/2013
Cassandra L. Kniffin - updated: 10/20/2010

*FIELD* CD
Matthew B. Gross: 9/28/2010

*FIELD* ED
carol: 01/30/2014
carol: 12/16/2013
ckniffin: 12/12/2013
carol: 8/29/2013
carol: 7/26/2013
ckniffin: 7/25/2013
wwang: 10/25/2010
ckniffin: 10/20/2010
mgross: 9/28/2010

MIM 615338
*RECORD*
*FIELD* NO
615338
*FIELD* TI
#615338 EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 16; EIEE16
*FIELD* TX
A number sign (#) is used with this entry because early infantile
read moreepileptic encephalopathy-16 (EIEE16) is caused by homozygous or compound
heterozygous mutation in the TBC1D24 gene (613577) on chromosome 16p13.

Mutation in the TBC1D24 gene can also cause familial infantile myoclonic
epilepsy (FIME; 605021), a less severe disorder.

DESCRIPTION

Early infantile epileptic encephalopathy-16 is a severe autosomal
recessive neurologic disorder characterized by onset of seizures in the
first weeks or months of life. Seizures can be of various types, are
unresponsive to medication, last for long periods of time, and occur
frequently. Affected infants show psychomotor regression or lack of
psychomotor development, as well as other neurologic features such as
extrapyramidal signs and hypotonia. Most die in childhood (summary by
Duru et al., 2010 and Milh et al., 2013).

For a general phenotypic description and a discussion of genetic
heterogeneity of EIEE, see EIEE1 (308350).

CLINICAL FEATURES

Duru et al. (2010) reported a large consanguineous Turkish family in
which 5 children had a severe early infantile epileptic encephalopathy
characterized by myoclonic seizures, alternating and migrating jerks of
the extremities, focal seizures, and neurologic deterioration with
permanent neurologic sequelae. Features included long-lasting myoclonic
seizures that were not responsive to medication, hemiparesis with
pyramidal signs, severe hypotonia, dystonia, and status epilepticus. EEG
in initial stages were characterized by multiple spikes, but later
showed a steady and progressive slowing of background activity. Brain
imaging showed progressive atrophic changes in the brain and cerebellum
and/or delayed myelination. The seizures occurred spontaneously or were
triggered by common infections. The patients became inattentive to
visual and acoustic stimuli as the disease progressed; 1 patient
examined late in the disease course showed optic atrophy and macular
degeneration. None of the patients had photosensitivity. All patients
died by age 7 years. Duru et al. (2010) referred to the disorder as
'progressive myoclonic epilepsy with dystonia (PMED).'

Milh et al. (2013) reported 2 sisters, born of unrelated parents, with a
severe early infantile epileptic encephalopathy presenting clinically as
malignant migrating partial seizures of infancy (MMPSI). Both had onset
of clonic seizures early in the second month of life that progressed to
a 'stormy' phase, with almost continuous clonic migrating seizures and
psychomotor regression. Both patients had severe neurologic impairment
with axial hypotonia, no voluntary movement, no eye contact, and
acquired microcephaly. Brain MRI at birth was normal in both patients,
but later showed brain atrophy. One sib died of seizures at age 18
months.

INHERITANCE

The transmission pattern in the families with EIEE16 reported by Duru et
al. (2010) and Milh et al. (2013) was consistent with autosomal
recessive inheritance.

MAPPING

By linkage analysis of a large consanguineous Turkish family with early
infantile epileptic encephalopathy, Duru et al. (2010) identified a
locus on chromosome 16pter-p13.3 (maximum multipoint lod score of 7.83
between markers TTTA028 and D16S3-26; maximum 2-point lod score of 4.25
at D16S2618). Haplotype analysis delineated a 6.73-Mb candidate
interval. Sequencing of the ATP6V0C gene (108745) did not reveal any
pathogenic mutations. The locus overlapped that reported by Zara et al.
(2000) for FIME, but Duru et al. (2010) noted that the phenotypes
differed significantly in severity.

MOLECULAR GENETICS

In affected members of the family reported by Duru et al. (2010), Guven
and Tolun (2013) identified a homozygous truncating mutation in the
TBC1D24 gene (613577.0004). The severity of the mutation paralleled the
severity of the phenotype.

In 2 sisters with EIEE16, Milh et al. (2013) identified compound
heterozygous mutations in the TBC1D24 gene (F229S, 613577.0005 and
C156X, 613577.0006). The mutations, which were found by exome sequencing
and confirmed by Sanger sequencing, were not present in several large
exome databases and segregated with the disorder in the family.

*FIELD* RF
1. Duru, N.; Iseri, S. A. U.; Selcuk, N.; Tolun, A.: Early-onset
progressive myoclonic epilepsy with dystonia mapping to 16pter-p13.3. J.
Neurogenet. 24: 207-215, 2010.

2. Guven, A.; Tolun, A.: TBC1D24 truncating mutation resulting in
severe neurodegeneration. J. Med. Genet. 50: 199-202, 2013.

3. Milh, M.; Falace, A.; Villeneuve, N.; Vanni, N.; Cacciagli, P.;
Assereto, S.; Nabbout, R.; Benfenati, F.; Zara, F.; Chabrol, B.; Villard,
L.; Fassio, A.: Novel compound heterozygous mutations in TBC1D24
cause familial malignant migrating partial seizures of infancy. Hum.
Mutat. 34: 869-872, 2013.

4. Zara, F.; Gennaro, E.; Stabile, M.; Carbone, I.; Malacarne, M.;
Majello, L.; Santangelo, R.; Antonio de Falco, F.; Bricarelli, F.
D.: Mapping of a locus for a familial autosomal recessive idiopathic
myoclonic epilepsy of infancy to chromosome 16p13. Am. J. Hum. Genet. 66:
1552-1557, 2000. Note: Erratum: Am. J. Hum. Genet. 66: 1728 only,
2000.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Head];
Microcephaly, acquired (in some patients);
[Eyes];
Loss of eye contact;
Visual loss;
Optic atrophy (rare)

MUSCLE, SOFT TISSUE:
Hypotonia, severe

NEUROLOGIC:
[Central nervous system];
Epileptic encephalopathy;
Seizures, tonic, clonic, focal;
Prolonged seizures;
Status epilepticus;
Migrating clonic jerks (in some patients);
Myoclonus;
Psychomotor regression;
Psychomotor retardation, severe;
Hypotonia;
Dystonia;
Hemiparesis;
Extrapyramidal signs;
Hemiparesis;
Multifocal spikes and progressive slowing of background activity seen
on EEG;
Progressive cerebral atrophy seen on MRI;
Delayed myelination

MISCELLANEOUS:
Onset in early infancy;
Progressive disorder;
High frequency seizures;
Seizures may be triggered by infection;
Seizures are refractory to medication;
Most patients die in childhood

MOLECULAR BASIS:
Caused by mutation in the TBC1 domain family, member 24 gene (TBC1D24,
613577.0004)

*FIELD* CD
Cassandra L. Kniffin: 7/25/2013

*FIELD* ED
joanna: 10/01/2013
ckniffin: 7/25/2013

*FIELD* CD
Cassandra L. Kniffin: 7/25/2013

*FIELD* ED
carol: 07/29/2013
carol: 7/26/2013
ckniffin: 7/25/2013

RBCC Red Blood Cell Collection

Full text data of TBC1D24