RBCC Red Blood Cell Collection

PRICKLE1 (RILP) [Confidence: low (only semi-automatic identification from reviews)]
Prickle-like protein 1 (REST/NRSF-interacting LIM domain protein 1; Flags: Precursor)

UniProt Q96MT3
ID PRIC1_HUMAN Reviewed; 831 AA.
AC Q96MT3; Q14C83; Q71QF8; Q96N00;
DT 01-FEB-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-2005, sequence version 2.
DT 22-JAN-2014, entry version 103.
DE RecName: Full=Prickle-like protein 1;
DE AltName: Full=REST/NRSF-interacting LIM domain protein 1;
DE Flags: Precursor;
GN Name=PRICKLE1; Synonyms=RILP;
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], TISSUE SPECIFICITY, ISOPRENYLATION AT
RP CYS-828, MUTAGENESIS OF 828-CYS--SER-831, SUBCELLULAR LOCATION, AND
RP INTERACTION WITH REST.
RC TISSUE=Brain;
RX PubMed=14645515; DOI=10.1128/MCB.23.24.9025-9031.2003;
RA Shimojo M., Hersh L.B.;
RT "REST/NRSF-interacting LIM domain protein, a putative nuclear
RT translocation receptor.";
RL Mol. Cell. Biol. 23:9025-9031(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 IDENTIFICATION, AND TISSUE SPECIFICITY.
RX PubMed=12525887;
RA Katoh M., Katoh M.;
RT "Identification and characterization of human PRICKLE1 and PRICKLE2
RT genes as well as mouse Prickle1 and Prickle2 genes homologous to
RT Drosophila tissue polarity gene prickle.";
RL Int. J. Mol. Med. 11:249-256(2003).
RN [5]
RP ISOPRENYLATION AT CYS-828.
RX PubMed=17411337; DOI=10.1371/journal.pcbi.0030066;
RA Maurer-Stroh S., Koranda M., Benetka W., Schneider G., Sirota F.L.,
RA Eisenhaber F.;
RT "Towards complete sets of farnesylated and geranylgeranylated
RT proteins.";
RL PLoS Comput. Biol. 3:634-648(2007).
RN [6]
RP TISSUE SPECIFICITY, VARIANT EPM1B GLN-104, AND CHARACTERIZATION OF
RP VARIANT EPM1B GLN-104.
RX PubMed=18976727; DOI=10.1016/j.ajhg.2008.10.003;
RA Bassuk A.G., Wallace R.H., Buhr A., Buller A.R., Afawi Z., Shimojo M.,
RA Miyata S., Chen S., Gonzalez-Alegre P., Griesbach H.L., Wu S.,
RA Nashelsky M., Vladar E.K., Antic D., Ferguson P.J., Cirak S., Voit T.,
RA Scott M.P., Axelrod J.D., Gurnett C., Daoud A.S., Kivity S.,
RA Neufeld M.Y., Mazarib A., Straussberg R., Walid S., Korczyn A.D.,
RA Slusarski D.C., Berkovic S.F., El-Shanti H.I.;
RT "A homozygous mutation in human PRICKLE1 causes an autosomal-recessive
RT progressive myoclonus epilepsy-ataxia syndrome.";
RL Am. J. Hum. Genet. 83:572-581(2008).
RN [7]
RP FUNCTION, POSSIBLE INVOLVEMENT IN NTD, AND VARIANTS THR-69; HIS-81;
RP ILE-121; THR-124; MET-275; CYS-682; PHE-739; ASN-771 AND CYS-799.
RX PubMed=21901791; DOI=10.1002/humu.21589;
RA Bosoi C.M., Capra V., Allache R., Trinh V.Q., De Marco P., Merello E.,
RA Drapeau P., Bassuk A.G., Kibar Z.;
RT "Identification and characterization of novel rare mutations in the
RT planar cell polarity gene PRICKLE1 in human neural tube defects.";
RL Hum. Mutat. 32:1371-1375(2011).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [9]
RP VARIANTS EPM1B GLN-104; HIS-144 AND HIS-472.
RX PubMed=21276947; DOI=10.1016/j.ajhg.2010.12.012;
RA Tao H., Manak J.R., Sowers L., Mei X., Kiyonari H., Abe T.,
RA Dahdaleh N.S., Yang T., Wu S., Chen S., Fox M.H., Gurnett C.,
RA Montine T., Bird T., Shaffer L.G., Rosenfeld J.A., McConnell J.,
RA Madan-Khetarpal S., Berry-Kravis E., Griesbach H., Saneto R.P.,
RA Scott M.P., Antic D., Reed J., Boland R., Ehaideb S.N., El-Shanti H.,
RA Mahajan V.B., Ferguson P.J., Axelrod J.D., Lehesjoki A.E.,
RA Fritzsch B., Slusarski D.C., Wemmie J., Ueno N., Bassuk A.G.;
RT "Mutations in prickle orthologs cause seizures in flies, mice, and
RT humans.";
RL Am. J. Hum. Genet. 88:138-149(2011).
CC -!- FUNCTION: Involved in the planar cell polarity pathway that
CC controls convergent extension during gastrulation and neural tube
CC closure. Convergent extension is a complex morphogenetic process
CC during which cells elongate, move mediolaterally, and intercalate
CC between neighboring cells, leading to convergence toward the
CC mediolateral axis and extension along the anteroposterior axis.
CC Necessary for nuclear localization of REST. May serve as nuclear
CC receptor.
CC -!- SUBUNIT: Interacts with REST.
CC -!- SUBCELLULAR LOCATION: Nucleus membrane. Cytoplasm, cytosol. Note=A
CC smaller amount is detected in the cytosol.
CC -!- TISSUE SPECIFICITY: Expressed at highest levels in placenta and at
CC lower levels in lung, liver, kidney and pancreas. Expressed in
CC thalamus, hippocampus, cerebral cortex, and cerebellum (in neurons
CC rather than glia).
CC -!- DISEASE: Epilepsy, progressive myoclonic 1B (EPM1B) [MIM:612437]:
CC An autosomal recessive disorder characterized by myoclonus that
CC progressed in severity over time, tonic-clonic seizures and
CC ataxia. Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Neural tube defects (NTD) [MIM:182940]: Congenital
CC malformations of the central nervous system and adjacent
CC structures related to defective neural tube closure during the
CC first trimester of pregnancy. Failure of neural tube closure can
CC occur at any level of the embryonic axis. Common NTD forms include
CC anencephaly, myelomeningocele and spina bifida, which result from
CC the failure of fusion in the cranial and spinal region of the
CC neural tube. NTDs have a multifactorial etiology encompassing both
CC genetic and environmental components. Note=Disease susceptibility
CC is associated with variations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the prickle / espinas / testin family.
CC -!- SIMILARITY: Contains 3 LIM zinc-binding domains.
CC -!- SIMILARITY: Contains 1 PET domain.
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DR EMBL; AF399844; AAQ03035.1; -; mRNA.
DR EMBL; AK056189; BAB71116.1; -; mRNA.
DR EMBL; AK056499; BAB71198.1; -; mRNA.
DR EMBL; BC114939; AAI14940.1; -; mRNA.
DR EMBL; BC114940; AAI14941.1; -; mRNA.
DR RefSeq; NP_001138353.1; NM_001144881.1.
DR RefSeq; NP_001138354.1; NM_001144882.1.
DR RefSeq; NP_001138355.1; NM_001144883.1.
DR RefSeq; NP_694571.2; NM_153026.2.
DR UniGene; Hs.524348; -.
DR UniGene; Hs.720221; -.
DR ProteinModelPortal; Q96MT3; -.
DR SMR; Q96MT3; 124-306.
DR IntAct; Q96MT3; 3.
DR STRING; 9606.ENSP00000345064; -.
DR PhosphoSite; Q96MT3; -.
DR DMDM; 59800163; -.
DR PaxDb; Q96MT3; -.
DR PRIDE; Q96MT3; -.
DR Ensembl; ENST00000345127; ENSP00000345064; ENSG00000139174.
DR Ensembl; ENST00000445766; ENSP00000398947; ENSG00000139174.
DR Ensembl; ENST00000455697; ENSP00000401060; ENSG00000139174.
DR Ensembl; ENST00000548696; ENSP00000448359; ENSG00000139174.
DR Ensembl; ENST00000552240; ENSP00000449819; ENSG00000139174.
DR GeneID; 144165; -.
DR KEGG; hsa:144165; -.
DR UCSC; uc001rnl.3; human.
DR CTD; 144165; -.
DR GeneCards; GC12M042852; -.
DR HGNC; HGNC:17019; PRICKLE1.
DR HPA; HPA001379; -.
DR MIM; 182940; phenotype.
DR MIM; 608500; gene.
DR MIM; 612437; phenotype.
DR neXtProt; NX_Q96MT3; -.
DR Orphanet; 308; Unverricht-Lundborg disease.
DR PharmGKB; PA134906946; -.
DR eggNOG; NOG314122; -.
DR HOGENOM; HOG000290649; -.
DR HOVERGEN; HBG053679; -.
DR InParanoid; Q96MT3; -.
DR KO; K04511; -.
DR OMA; CCLECET; -.
DR OrthoDB; EOG7P8P7M; -.
DR PhylomeDB; Q96MT3; -.
DR GenomeRNAi; 144165; -.
DR NextBio; 84850; -.
DR PRO; PR:Q96MT3; -.
DR ArrayExpress; Q96MT3; -.
DR Bgee; Q96MT3; -.
DR CleanEx; HS_PRICKLE1; -.
DR CleanEx; HS_RILP; -.
DR Genevestigator; Q96MT3; -.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0031965; C:nuclear membrane; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0090090; P:negative regulation of canonical Wnt receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:2000691; P:negative regulation of cardiac muscle cell myoblast differentiation; IDA:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-dependent; IDA:BHF-UCL.
DR GO; GO:0001843; P:neural tube closure; IMP:UniProtKB.
DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IDA:BHF-UCL.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IDA:BHF-UCL.
DR GO; GO:0006606; P:protein import into nucleus; IDA:UniProtKB.
DR Gene3D; 2.10.110.10; -; 3.
DR InterPro; IPR010442; PET_domain.
DR InterPro; IPR001781; Znf_LIM.
DR Pfam; PF00412; LIM; 3.
DR Pfam; PF06297; PET; 1.
DR SMART; SM00132; LIM; 3.
DR PROSITE; PS00478; LIM_DOMAIN_1; 2.
DR PROSITE; PS50023; LIM_DOMAIN_2; 3.
DR PROSITE; PS51303; PET; 1.
PE 1: Evidence at protein level;
KW Complete proteome; Cytoplasm; Disease mutation; Epilepsy; LIM domain;
KW Lipoprotein; Membrane; Metal-binding; Methylation; Nucleus;
KW Polymorphism; Prenylation; Reference proteome; Repeat; Zinc.
FT CHAIN 1 828 Prickle-like protein 1.
FT /FTId=PRO_0000075889.
FT PROPEP 829 831 Removed in mature form (Probable).
FT /FTId=PRO_0000396712.
FT DOMAIN 14 122 PET.
FT DOMAIN 124 189 LIM zinc-binding 1.
FT DOMAIN 189 249 LIM zinc-binding 2.
FT DOMAIN 249 313 LIM zinc-binding 3.
FT COMPBIAS 655 682 Arg/His-rich.
FT COMPBIAS 761 772 Ser-rich.
FT COMPBIAS 816 821 Poly-Lys.
FT MOD_RES 828 828 Cysteine methyl ester (Probable).
FT LIPID 828 828 S-farnesyl cysteine.
FT VARIANT 69 69 I -> T (may be associated with NTD;
FT dbSNP:rs141795695).
FT /FTId=VAR_066850.
FT VARIANT 81 81 N -> H (may be associated with NTD).
FT /FTId=VAR_066851.
FT VARIANT 104 104 R -> Q (in EPM1B; affects interaction
FT with REST).
FT /FTId=VAR_054663.
FT VARIANT 121 121 V -> I (may be associated with NTD).
FT /FTId=VAR_066852.
FT VARIANT 124 124 A -> T (in dbSNP:rs79087668).
FT /FTId=VAR_066853.
FT VARIANT 144 144 R -> H (in EPM1B).
FT /FTId=VAR_065580.
FT VARIANT 275 275 T -> M (may be associated with NTD).
FT /FTId=VAR_066854.
FT VARIANT 472 472 Y -> H (in EPM1B).
FT /FTId=VAR_065581.
FT VARIANT 682 682 R -> C (may be associated with NTD).
FT /FTId=VAR_066855.
FT VARIANT 739 739 S -> F (may be associated with NTD;
FT dbSNP:rs138452760).
FT /FTId=VAR_066856.
FT VARIANT 746 746 P -> S (in dbSNP:rs3827522).
FT /FTId=VAR_056164.
FT VARIANT 771 771 D -> N (may be associated with NTD).
FT /FTId=VAR_066857.
FT VARIANT 799 799 S -> C (may be associated with NTD).
FT /FTId=VAR_066858.
FT MUTAGEN 828 831 Missing: Abolishes localization to the
FT nuclear membrane.
FT CONFLICT 739 739 S -> P (in Ref. 2; BAB71198).
SQ SEQUENCE 831 AA; 94300 MW; 753D68BD5A4D0935 CRC64;
MPLEMEPKMS KLAFGCQRSS TSDDDSGCAL EEYAWVPPGL RPEQIQLYFA CLPEEKVPYV
NSPGEKHRIK QLLYQLPPHD NEVRYCQSLS EEEKKELQVF SAQRKKEALG RGTIKLLSRA
VMHAVCEQCG LKINGGEVAV FASRAGPGVC WHPSCFVCFT CNELLVDLIY FYQDGKIHCG
RHHAELLKPR CSACDEIIFA DECTEAEGRH WHMKHFCCLE CETVLGGQRY IMKDGRPFCC
GCFESLYAEY CETCGEHIGV DHAQMTYDGQ HWHATEACFS CAQCKASLLG CPFLPKQGQI
YCSKTCSLGE DVHASDSSDS AFQSARSRDS RRSVRMGKSS RSADQCRQSL LLSPALNYKF
PGLSGNADDT LSRKLDDLSL SRQGTSFASE EFWKGRVEQE TPEDPEEWAD HEDYMTQLLL
KFGDKSLFQP QPNEMDIRAS EHWISDNMVK SKTELKQNNQ SLASKKYQSD MYWAQSQDGL
GDSAYGSHPG PASSRRLQEL ELDHGASGYN HDETQWYEDS LECLSDLKPE QSVRDSMDSL
ALSNITGASV DGENKPRPSL YSLQNFEEME TEDCEKMSNM GTLNSSMLHR SAESLKSLSS
ELCPEKILPE EKPVHLPVLR RSKSQSRPQQ VKFSDDVIDN GNYDIEIRQP PMSERTRRRV
YNFEERGSRS HHHRRRRSRK SRSDNALNLV TERKYSPKDR LRLYTPDNYE KFIQNKSARE
IQAYIQNADL YGQYAHATSD YGLQNPGMNR FLGLYGEDDD SWCSSSSSSS DSEEEGYFLG
QPIPQPRPQR FAYYTDDLSS PPSALPTPQF GQRTTKSKKK KGHKGKNCII S
//

MIM 182940
*RECORD*
*FIELD* NO
182940
*FIELD* TI
#182940 NEURAL TUBE DEFECTS
;;NTD
SPINA BIFIDA, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because neural tube defects
read moreare complex traits with multifactorial etiology encompassing both
genetic and environmental components. An association has been reported
with variants in the T locus (601397) on chromosome 6q. Polymorphic
variants in genes have been associated with increased risk of neural
tube defects, including a common variant (677C-T) in the MTHFR gene
(607093.0003). Mutations in the VANGL1 (610132) and VANGL2 (600533)
genes have been found in individuals with familial and sporadic neural
tube defects. Mutations in FUZZY (610622) have also been described in
patients with neural tube defects. Variation in the DACT1 gene (607861)
may be associated with NTD.

DESCRIPTION

Neural tube defects are the second most common type of birth defect
after congenital heart defects. The 2 most common NTDs are open spina
bifida, also known as spina bifida cystica (SBC) or myelomeningocele,
and anencephaly (206500) (Detrait et al., 2005). Spina bifida occulta
(SBO) is a bony defect of the spine covered by normal skin. It is mild
form of spina bifida and is often asymptomatic. The term 'spinal
dysraphia' refers to both SBC and SBO (Botto et al., 1999; Fineman et
al., 1982). The most severe neural tube defect, craniorachischisis
(CRN), leaves the neural tube open from the midbrain or rostral
hindbrain to the base of the spine (summary by Robinson et al., 2012).

An X-linked form of spina bifida has been suggested; see 301410. See
also folate-sensitive neural tube defects (601634).

CLINICAL FEATURES

Fineman et al. (1982) studied 4 families in which multiple members had
spina bifida cystica and/or spina bifida occulta. Excluding the
probands, the frequency of all types of spinal/vertebral defects in
family members was found to be 30/58 (52%). Statistical analysis
indicated autosomal dominant inheritance with a penetrance of 75%. The
authors concluded that both forms of spina bifida are different
expressions of the same dominant gene in these kindreds. Spina bifida
occulta was present in 15% of 100 control individuals.

Fellous et al. (1982) reported a 5-generation family with spina bifida
associated with sacral agenesis (see 600145). Abnormalities ranged from
complete absence of the sacrum, with or without spina bifida aperta, to
spina bifida occulta. The condition appeared in a man with 4 children
who were all affected, and thereafter, to varying degrees, in 17 of his
28 descendants. The authors suggested autosomal dominant inheritance.
Linkage analysis suggested a locus on chromosome 6 loci near PGM3
(172100) (lod score = 1.85 at a recombination fraction of 0.087).

Nickel et al. (1994) reported 3 unrelated patients with 22q11 deletion
syndrome, 2 with VCFS (192430) and 1 with DiGeorge syndrome (188400),
who also had neural tube defects. However, in a follow-up study of 295
patients with spina bifida, Nickel and Magenis (1996) concluded that
22q11 deletion is an infrequent cause of NTD.

- Reviews

Botto et al. (1999) and Detrait et al. (2005) provided reviews of neural
tube defects. De Marco et al. (2006) provided a detailed review of
neurulation and the possible etiologies of neural tube defects.

OTHER FEATURES

Chiari malformation type II (CM2; 207950), also known as the
Arnold-Chiari malformation, is often associated with open spina bifida.
Lindenberg and Walker (1971) described the Arnold-Chiari malformation in
2 successively born daughters of nonconsanguineous parents. Both
children had associated hydrocephalus and lumbar meningomyelocele.

INHERITANCE

Record and McKeown (1950) estimated a recurrence risk of spina bifida in
sibs of affected children to be 4%. Lorber (1965) reported familial
occurrence of spina bifida. He suggested recessive inheritance with
reduced penetrance and estimated the risk of recurrence of spina bifida
cystica, anencephaly, or hydrocephalus in subsequently born offspring to
be about 8%. In England, Carter and Roberts (1967) estimated the risk of
a third child having spina bifida or anencephaly, 2 having previously
been affected, to be about 1 in 10. Lorber and Levick (1967) found spina
bifida occulta in 14.3% of 188 mothers and 26.8% of 179 fathers of
patients with spina bifida cystica, and in 5% of 200 controls. However,
spina bifida occulta was not more common among parents with more than 1
child with spina bifida cystica and neither parent had it in the
majority of families.

Carter et al. (1976) found as high a frequency of anencephaly and spina
bifida cystica among the sibs of patients with spinal dysraphism as
among the sibs with other open neural tube defects, suggesting a common
etiology of various spinal defects.

POPULATION GENETICS

Spina bifida and anencephaly are common birth defects, affecting 0.5 to
2 per 1,000 pregnancies worldwide. Craniorachischisis, the most severe
neural tube defect, is considered rare, although estimates of prevalence
range from 1 in 100,000 in the United States to 1 in 1,000 in northern
China (summary by Robinson et al., 2012).

MAPPING

From studies in a large kindred, Amos et al. (1975) concluded that there
may be a gene locus for spina bifida occulta linked to the HLA complex
on chromosome 6. Early interest in this possibility was stimulated by
the T region of the mouse (601397), which determines morphogenesis,
especially of the tail, and is linked to the H-2 region on mouse
chromosome 17. Mendell et al. (1979) studied 2 extensive North Carolina
kindreds suggesting that spina bifida occulta and/or asymmetry of the
facet joints was determined by a gene at a locus linked to HLA. The
total lod score was 2.21 at theta = 0.05.

Bobrow et al. (1975) and de Bruyere et al. (1977) found no linkage of
spina bifida with HLA. Vannier et al. (1981) found a high frequency of
spina bifida occulta and lateral asymmetry of the lumbosacral spine in
sibs and parents. However, Vannier et al. (1981) found no association
between these abnormalities and the HLA system. Jorde (1983) concluded
that linkage to 6p markers could be excluded.

Erickson (1988) reviewed arguments for the assertion that there is no
HLA-linked equivalent of the t-complex of the mouse. He emphasized that
the essential attributes of the murine t-complex are distortion of
prezygotic transmission ratios and suppression of crossover rather than
developmental recessive mutations leading to embryonic arrest.

MOLECULAR GENETICS

Morrison et al. (1996) reported that an allelic variant of the T locus,
referred to as TIVS7-2 (601637.0001), showed a bias in transmission from
heterozygous parents to offspring with neural tube defects in Dutch and
U.K. families. Shields et al. (2000) also found an association between
the TIVS7-2 allele and neural tube defects. However, Trembath et al.
(1999) and Speer et al. (2002) found no association.

Jensen et al. (2004) observed that individuals carrying 1 or more copies
of the TIVS7-2 allele have a 1.6-fold increased risk of spina bifida
compared with individuals with 0 copies.

Volcik et al. (2002) used the transmission disequilibrium test (TDT) to
determine if genes in the PAX family play a role in the formation of
NTDs; they performed further analysis with SSCA and direct sequencing.
Although multiple variations were detected in each of the PAX genes with
significant TDT results, the authors concluded that it is unlikely that
these variations contribute to susceptibility for spina bifida. By
analysis of HOX genes in 459 spina bifida patients and their parents, as
well as within gene regions of 8 mouse models that exhibit NTDs, Volcik
et al. (2002) obtained no significant findings with the markers tested.

In a study of 144 patients with neural tube defects, Kibar et al. (2007)
found mutations in 3 patients, 2 with a familial and 1 with a sporadic
form of the disorder. The mutations were not found among 106 ancestrally
matched controls or 65 control samples obtained from CEPH (Centre
d'Etude du Polymorphisme Humain). The findings implicated variation in
VANGL1, a human homolog of a Drosophila gene involved in establishing
planar cell polarity, as a risk factor in neural tube defects.

Lei et al. (2010) identified 3 different heterozygous missense mutations
in the VANGL2 gene (see, e.g., 600533.0001 and 600533.0002) in 3 of 163
unrelated Chinese Han stillborn or miscarried fetuses with neural tube
defects, including anencephaly. The authors postulated that loss of
function defects in this gene have a lethal effect during in utero
development in humans, and noted that mouse studies have indicated the
loss of Vangl2 results in defects in neural tube closure.

Kibar et al. (2011) sequenced the VANGL2 gene in a population-based
study of 673 patients with various forms of neural tube defects. Six
potentially pathogenic heterozygous missense mutations were identified
in 7 patients, including 3 at positions that were absolutely conserved
through zebrafish and Drosophila (R135W, R177H, and R270H), and 3 at
positions that were highly conserved (L242V, T247M, and R482H). Two
patients had open NTDs with myelomeningocele and 5 had closed NTDs,
which was a statistically significant difference (p = 0.027). However, 2
unaffected parents carried 2 of the mutations, and another mutation
(R105C) was found in 1 of 287 controls. Functional studies of the
mutations were not performed. Kibar et al. (2011) suggested that
variation in the VANGL2 gene may predispose to neural tube defects, but
noted that the findings needed to be confirmed.

Seo et al. (2011) found 5 missense mutations in the FUZZY gene (610622)
among 234 Italian patients with neural tube defects. These sequence
variants were absent in 130 matching Italian controls and over 250
control subjects sequenced as a part of the 1000 Genomes project. One
mutation was found to interfere with ciliogenesis in 2 independent
assays but did not affect cell directional movement. Another was found
to have a striking effect on directional cell movement without affecting
ciliogenesis, and a third mutation was found to affect both functions.

For discussion of a possible role of variation in the PRICKLE1 gene in
neural tube defects, see 608500.

ANIMAL MODEL

Adalsteinsson and Basrur (1984) concluded that spina bifida in Icelandic
lambs is an autosomal recessive.

Helwig et al. (1995) reported that mice who are doubly heterozygous for
the mutants 'undulated' and 'Patch' have a phenotype reminiscent of an
extreme form of spina bifida occulta in humans. The unexpected phenotype
in double-mutant and not single-mutant mice showed that novel congenital
anomalies such as spina bifida can result from interaction between
products of independently segregating loci. This is an example of
digenic inheritance. (The 'undulated' mutation is related to the mouse
Pax1 gene (PAX1; 167411), and the 'Patch' mutation is related to
deletion of the mouse Pdgfra gene (PDGFRA; 173490).)

Juriloff and Harris (2000) reviewed the numerous mouse models of NTDs,
as well as the zonal pattern of neural tube closure and the effect of
maternal nutrients on neural tube closure.

*FIELD* SA
Bennett (1977); Fellous et al. (1979); Goodfellow and Andrews (1983);
Sever (1983); Sever (1974)
*FIELD* RF
1. Adalsteinsson, S.; Basrur, P. K.: Inheritance of spina bifida
in Icelandic lambs. J. Hered. 75: 378-382, 1984.

2. Amos, D. B.; Ruderman, N.; Mendell, N.; Johnson, A. H.: Linkage
between HLA and spinal development. Transplant. Proc. 7: 93-95,
1975.

3. Bennett, D.: L. C. Dunn and his contribution to T-locus genetics. Ann.
Rev. Genet. 11: 1-12, 1977.

4. Bobrow, M.; Bodmer, J. G.; Bodmer, W. F.; McDevitt, H. O.; Lorber,
J.; Swift, P. N.: The search for a human equivalent of the mouse
T-locus. Negative results from a study of HLA types in spina bifida. Tissue
Antigens 5: 234-237, 1975.

5. Botto, L. D.; Moore, C. A.; Khoury, M. J.; Erickson, J. D.: Neural-tube
defects. New Eng. J. Med. 341: 1509-1519, 1999.

6. Carter, C. O.; Evans, K. A.; Till, K.: Spinal dysraphism: genetic
relation to neural tube malformations. J. Med. Genet. 13: 343-350,
1976.

7. Carter, C. O.; Roberts, J. A. F.: The risk of recurrence after
two children with central-nervous-system malformations. Lancet 289:
306-308, 1967. Note: Originally Volume I.

8. de Bruyere, M.; Kulakowski, S.; Melchaire, J.; Delire, M.; Sokal,
G.: HLA gene and haplotype frequencies in spina bifida: population
and family studies. Tissue Antigens 10: 399-402, 1977.

9. De Marco, P.; Merello, E.; Mascelli, S.; Capra, V.: Current perspectives
on the genetic causes of neural tube defects. Neurogenetics 7: 201-221,
2006.

10. Detrait, E. R.; George, T. M.; Etchevers, H. C.; Gilbert, J. R.;
Vekemans, M.; Speer, M. C.: Human neural tube defects: developmental
biology, epidemiology, and genetics. Neurotox. Teratol. 27: 515-524,
2005.

11. Erickson, R. P.: The 6's and 17's of developmental mutants near
the major histocompatibility complex: the mouse t-complex does not
have a human equivalent. Am. J. Hum. Genet. 43: 115-118, 1988.

12. Fellous, M.; Boue, J.; Malbrunot, C.; Wollman, E.; Sasportes,
M.; Van Cong, N.; Marcelli, A.; Rebourcet, R.; Hubert, C.; Demenais,
F.; Elston, R. C.; Namboodiri, K. K.; Kaplan, E. B.: A five-generation
family with sacral agenesis and spina bifida: possible similarities
with the mouse T-locus. Am. J. Med. Genet. 12: 465-487, 1982.

13. Fellous, M.; Hors, J.; Bone, J.; Dausset, J.; Jacob, F.: Are
there human analogs of the mouse T-locus in central nervous system
malformations? Birth Defects Orig. Art. Ser. XV(3): 93-104, 1979.

14. Fineman, R. M.; Jorde, L. B.; Martin, R. A.; Hasstedt, S. J.;
Wing, S. D.; Walker, M. L.: Spinal dysraphia as an autosomal dominant
defect in four families. Am. J. Med. Genet. 12: 457-464, 1982.

15. Goodfellow, P. N.; Andrews, P. W.: Is there a human T/t locus? Nature 302:
657-658, 1983.

16. Helwig, U.; Imai, K.; Schmahl, W.; Thomas, B. E.; Varnum, D. S.;
Nadeau, J. H.; Balling, R.: Interaction between undulated and Patch
leads to an extreme form of spina bifida in double-mutant mice. Nature
Genet. 11: 60-63, 1995.

17. Jensen, L. E.; Barbaux, S.; Hoess, K.; Fraterman, S.; Whitehead,
A. S.; Mitchell, L. E.: The human T locus and spina bifida risk. Hum.
Genet. 115: 475-482, 2004.

18. Jorde, L.: Personal Communication. Salt Lake City, Utah 9/27/1983.

19. Juriloff, D. M.; Harris, M. J.: Mouse models for neural tube
closure defects. Hum. Molec. Genet. 9: 993-1000, 2000.

20. Kibar, Z.; Salem, S.; Bosoi, C. M.; Pauwels, E.; De Marco, P.;
Merello, E.; Bassuk, A. G.; Capra, V.; Gros, P.: Contribution of
VANGL2 mutations to isolated neural tube defects. Clin. Genet. 80:
76-82, 2011.

21. Kibar, Z.; Torban, E.; McDearmid, J. R.; Reynolds, A.; Berghout,
J.; Mathieu, M.; Kirillova, I.; De Marco, P.; Merello, E.; Hayes,
J. M.; Wallingford, J. B.; Drapeau, P.; Capra, V.; Gros, P.: Mutations
in VANGL1 associated with neural-tube defects. New Eng. J. Med. 356:
1432-1437, 2007.

22. Lei, Y.-P.; Zhang, T.; Li, H.; Wu, B.-L.; Jin, L.; Wang, H.-Y.
: VANGL2 mutations in human cranial neural-tube defects. (Letter) New
Eng. J. Med. 362: 2232-2235, 2010.

23. Lindenberg, R.; Walker, B. A.: Arnold-Chiari malformation in
sibs. Birth Defects Orig. Art. Ser. VII(1): 234-236, 1971.

24. Lorber, J.: The family of spina bifida cystica. Pediatrics 35:
589-595, 1965.

25. Lorber, J.; Levick, K.: Spina bifida cystica: incidence of spina
bifida occulta in parents and in controls. Arch. Dis. Child. 42:
171-173, 1967.

26. Mendell, N. R.; Ruderman, R. J.; Demenais, F.; Ruderman, J. G.;
Johnson, A. H.; Amos, D. B.; Elston, R. C.: The genetics of spinal
development in man: similarities with the mouse T locus. (Abstract) Cytogenet.
Cell Genet. 25: 184 only, 1979.

27. Morrison, K.; Papapetrou, C.; Attwood, J.; Hol, F.; Lynch, S.
A.; Sampath, A.; Hamel, B.; Burn, J.; Sowden, J.; Stott, D.; Mariman,
E.; Edwards, Y. H.: Genetic mapping of the human homologue (T) of
mouse T(Brachyury) and a search for allele association between human
T and spina bifida. Hum. Molec. Genet. 5: 669-674, 1996.

28. Nickel, R. E.; Magenis, R. E.: Neural tube defects and deletions
of 22q11. Am. J. Med. Genet. 66: 25-27, 1996.

29. Nickel, R. E.; Pillers, D. A.; Merkens, M.; Magenis, R. E.; Driscoll,
D. A.; Emanuel, B. S.; Zonana, J.: Velo-cardio-facial syndrome and
DiGeorge sequence with meningomyelocele and deletions of the 22q11
region. Am. J. Med. Genet. 52: 445-449, 1994.

30. Record, R. G.; McKeown, T.: Congenital malformation of the central
nervous system. III. Risk of malformations in sibs of malformed individuals. Brit.
J. Prev. Soc. Med. 4: 217-220, 1950.

31. Robinson, A.; Escuin, S.; Doudney, K.; Vekemans, M.; Stevenson,
R. E.; Greene, N. D. E.; Copp, A. J.; Stanier, P.: Mutations in the
planar cell polarity genes CELSR1 and SCRIB are associated with the
severe neural tube defect craniorachischisis. Hum. Mutat. 33: 440-447,
2012.

32. Seo, J. H.; Zilber, Y.; Babayeva, S.; Liu, J.; Kyriakopoulos,
P.; De Marco, P.; Merello, E.; Capra, V.; Gros, P.; Torban, E.: Mutations
in the planar cell polarity gene, Fuzzy, are associated with neural
tube defects in humans. Hum. Molec. Genet. 20: 4324-4333, 2011.

33. Sever, L. E.: Spinal anomalies and neural tube defects. (Letter) Am.
J. Med. Genet. 15: 343-345, 1983.

34. Sever, L. E.: A case of meningomyelocele in a kindred with multiple
cases of spondylolisthesis and spina bifida occulta. J. Med. Genet. 11:
94-96, 1974.

35. Shields, D. C.; Ramsbottom, D.; Donoghue, C.; Pinjon, E.; Kirke,
P. N.; Molloy, A. M.; Edwards, Y. H.; Mills, J. L.; Mynett-Johnson,
L.; Weir, D. G.; Scott, J. M.; Whitehead, A. S.: Association between
historically high frequencies of neural tube defects and the human
T homologue of mouse T (Brachyury). Am. J. Med. Genet. 92: 206-211,
2000.

36. Speer, M. C.; Melvin, E. C.; Viles, K. D.; Bauer, K. A.; Rampersaud,
E.; Drake, C.; George, T. M.; Enterline, D. S.; Mackey, J. F.; Worley,
G.; Gilbert, J. R.; Nye, J. S.; NTD Collaborative Group: T locus
shows no evidence for linkage disequilibrium or mutation in American
Caucasian neural tube defect families. Am. J. Med. Genet. 110: 215-218,
2002.

37. Trembath, D.; Sherbondy, A. L.; Vandyke, D. C.; Shaw, G. M.; Todoroff,
K.; Lammer, E. J.; Finnell, R. H.; Marker, S.; Lerner, G.; Murray,
J. C.: Analysis of select folate pathway genes, PAX3, and human T
in a midwestern neural tube defect population. Teratology 59: 331-341,
1999.

38. Vannier, J. P.; Lefort, J.; Cavelier, B.; Ledosseur, P.; Assailly,
C.; Feingold, J.: Spina bifida cystica families x-ray examination
and HLA typing. Pediat. Res. 15: 326-329, 1981.

39. Volcik, K. A.; Blanton, S. H.; Kruzel, M. C.; Townsend, I. T.;
Tyerman, G. H.; Mier, R. J.; Northrup, H.: Testing for genetic associations
in a spina bifida population: analysis of the HOX gene family and
human candidate gene regions implicated by mouse models of neural
tube defects. Am. J. Med. Genet. 110: 203-207, 2002.

40. Volcik, K. A.; Blanton, S. H.; Kruzel, M. C.; Townsend, I. T.;
Tyerman, G. H.; Mier, R. J.; Northrup, H.: Testing for genetic associations
with the PAX gene family in a spina bifida population. Am. J. Med.
Genet. 110: 195-202, 2002.

*FIELD* CS

Spine:
Spina bifida;
Anencephaly;
Spina bifida cystica;
Hydrocephalus;
Spina bifida occulta;
Spinal dysraphism;
Diastematomyelia;
Intradural/extradural lipoma;
Sacral hairy patch or dimple;
Asymmetry of spinal facet joints;
Sacral agenesis;
Caudal regression syndrome

Neuro:
Neurologic signs in legs;
Urinary incontinence

Inheritance:
Autosomal dominant form

*FIELD* CN
Cassandra L. Kniffin - updated: 11/4/2013
Cassandra L. Kniffin - updated: 11/1/2012
Ada Hamosh - updated: 6/25/2012
Cassandra L. Kniffin - updated: 4/2/2012
Cassandra L. Kniffin - updated: 8/16/2011
Cassandra L. Kniffin - updated: 6/10/2010
Victor A. McKusick - updated: 5/2/2007
Cassandra L. Kniffin - updated: 12/7/2006
Cassandra L. Kniffin - reorganized: 7/31/2006
Cassandra L. Kniffin - updated: 7/26/2006
George E. Tiller - updated: 5/2/2000
Iosif W. Lurie - updated: 8/5/1997
Iosif W. Lurie - updated: 9/22/1996

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 11/11/2013
ckniffin: 11/4/2013
carol: 11/1/2012
ckniffin: 11/1/2012
alopez: 6/27/2012
terry: 6/25/2012
carol: 4/4/2012
ckniffin: 4/2/2012
alopez: 8/19/2011
ckniffin: 8/16/2011
wwang: 6/11/2010
ckniffin: 6/10/2010
terry: 2/9/2009
alopez: 5/10/2007
terry: 5/2/2007
wwang: 12/7/2006
ckniffin: 12/7/2006
carol: 8/18/2006
ckniffin: 8/8/2006
carol: 7/31/2006
ckniffin: 7/27/2006
ckniffin: 7/26/2006
alopez: 6/9/2006
carol: 3/7/2005
carol: 1/5/2001
alopez: 5/2/2000
alopez: 11/16/1999
terry: 6/11/1999
jenny: 8/5/1997
carol: 9/22/1996
mark: 8/31/1995
mimadm: 3/25/1995
carol: 10/24/1994
terry: 7/15/1994
warfield: 4/14/1994
pfoster: 3/31/1994

MIM 608500
*RECORD*
*FIELD* NO
608500
*FIELD* TI
*608500 PRICKLE, DROSOPHILA, HOMOLOG OF, 1; PRICKLE1
;;PK1;;
PRICKLE-LIKE 1;;
REST-INTERACTING LIM DOMAIN PROTEIN; RILP
read more*FIELD* TX

DESCRIPTION

PRICKLE proteins, such as PRICKLE1, are core constituents of the planar
cell polarity signaling pathway that establishes cell polarity during
embryonic development (Liu et al., 2013).

CLONING

Using mouse Rest4 (see REST, 600571) as bait in a yeast 2-hybrid screen,
Shimojo and Hersh (2003) cloned rat Prickle1, which they designated
Rilp, from a rat brain cDNA library. By screening a human brain cDNA
library with rat Rilp cDNA fragments, followed by 5-prime and 3-prime
RACE, they obtained full-length human PRICKLE1. The deduced 831-amino
acid protein contains 3 N-terminal LIM domains and 3 C-terminal nuclear
localization signals. It also contains 4 N-glycosylation sites, 2 PKA
(see 176911) phosphorylation sites, and a C-terminal CIIS
(cys-ile-ile-ser) prenylation motif. Northern blot analysis detected a
single 4.4-kb transcript in all tissues examined, with the highest level
in placenta. Western blot analysis detected in vitro translated PRICKLE1
at an apparent molecular mass of 100 kD. SDS-PAGE and Western blot
analysis of HeLa cell extracts showed endogenous PRICKLE1 in the nuclear
fraction, with a smaller amount in the cytosolic extract.
Immunolocalization showed endogenous PRICKLE1 localized around HeLa cell
nuclei, and proteinase digestion indicated that at least a portion of
PRICKLE1 is localized to the outer nuclear membrane.

By searching an EST database for sequences similar to those of
Drosophila and Xenopus Prickle, Katoh and Katoh (2003) identified human
PRICKLE1. The deduced protein contains a PET domain N-terminal to the 3
LIM domains. PRICKLE1 and PRICKLE2 (608501) share 51.9% identity overall
and 79.3% identity within the N-terminal PET and LIM domains. EST
database analysis revealed coexpression of PRICKLE1 and PRICKLE2 in
brain, eye, and testis; additionally, PRICKLE1 is expressed in fetal
heart and in hematologic malignancies lymphoma and acute myelogenous
leukemia (601626).

Bassuk et al. (2008) detected Prickle1 expression in neurons of several
murine brain regions, including thalamus, hippocampus, cerebral cortex,
and cerebellum.

Tao et al. (2011) demonstrated diffuse Prickle staining in neurons and
neuronal structures in various regions of the Drosophila brain,
including the optic lobes, central brain structures, and ventral
segmental ganglia near the brain.

Using in situ hybridization and immunohistochemical analysis, Liu et al.
(2013) found that mouse Pk1 was expressed during middle and late stages
of cortical neurogenesis. In adult mouse brain, Pk1 was expressed
widely, but in distinct neuronal and glial cell populations. In retina,
highest Pk1 expression was detected in cholinergic amacrine neurons.

GENE STRUCTURE

Shimojo and Hersh (2003) and Katoh and Katoh (2003) determined that the
PRICKLE1 gene contains at least 8 exons. Katoh and Katoh (2003)
determined that the 5-prime untranslated region is interrupted by intron
1.

MAPPING

By genomic sequence analysis, Shimojo and Hersh (2003) mapped the
PRICKLE1 gene to chromosome 12q12. Katoh and Katoh (2003) mapped the
human PRICKLE1 gene to chromosome 12q11-q12 and the mouse Prickle1 gene
to chromosome 15.

GENE FUNCTION

By immunoprecipitation of transfected human embryonic kidney cells,
Shimojo and Hersh (2003) demonstrated that PRICKLE1 interacts directly
with REST. PRICKLE1 did not coimmunoprecipitate with a REST mutant in
which the zinc finger structures were disrupted. Deletion analysis
indicated that the C-terminal CIIS prenylation motif was necessary for
targeting PRICKLE1 to the nucleus. Furthermore, downregulation of
PRICKLE1 with small interfering RNAs (siRNAs) resulted in the
mislocalization of REST to the cytosol.

Liu et al. (2013) found that knockdown of Pk1 by short hairpin RNA or
expression of dominant-negative constructs reduced axonal and dendritic
extension in cultured mouse hippocampal neurons. Knockdown of Pk1 in
neonatal mouse retina led to defects in inner and outer segments and
axon terminals of photoreceptors.

MOLECULAR GENETICS

- Progressive Myoclonic Epilepsy 1B

In affected members of 3 Middle Eastern families with autosomal
recessive progressive myoclonic epilepsy-1B (EPM1B; 612437), Bassuk et
al. (2008) identified the same homozygous mutation in the PRICKLE1 gene
(R104Q; 608500.0001). The findings were consistent with a founder
effect.

Tao et al. (2011) identified 2 different heterozygous mutations in the
PRICKLE1 gene (R144H; 608500.0002 and Y472H; 608500.0003, respectively)
in 2 unrelated patients with myoclonic epilepsy. One patient had a more
severe phenotype with mild mental retardation. Mutations were also
identified in the homologous PRICKLE2 gene (608501.0001-608501.0002) in
different patients with myoclonic seizures (EPM5; 613832). Tao et al.
(2011) concluded that PRICKLE signaling is important in seizure
prevention, and presented 2 hypotheses: (1) that PRICKLE affects cell
polarity and contributes to the development of a functional neural
network and (2) that PRICKLE affects calcium signaling, which may play a
role in seizure genesis if disrupted.

- Associations Pending Confirmation

Bosoi et al. (2011) identified 7 different heterozygous missense
variants in the PRICKLE1 gene in 7 of 810 patients with a variety of
neural tube defects (NTD; 182940). None of the variants were found in
1,396 controls, but the variants were inherited from an unaffected
parent in 5 cases, suggesting incomplete penetrance. In silico analysis
using PolyPhen software predicted that only 3 of the variants were
probably damaging, whereas SIFT predicted that all were intolerant
substitutions. Overexpression of the wildtype zebrafish ortholog (pk1a)
results in defective convergent extension during gastrulation and neural
tube formation. In zebrafish, Bosoi et al. (2011) found that
overexpression of 5 of the variants found in humans resulted in more
severe defects in convergent extension compared to wildtype, suggesting
that they may act as hypermorphic alleles. Overexpression of 1 variant
(R682C) rescued the effects of overexpressed Prickle1, suggesting a
dominant-negative effect. Bosoi et al. (2011) hypothesized that
variation in the PRICKLE1 gene may contribute to the development of
neural tube defects in man.

ANIMAL MODEL

Tao et al. (2011) found that Prickle1-mutant mice that were heterozygous
for a C251X mutation, which truncates protein shortly after the PET and
LIM domains, showed a decreased seizure threshold compared to wildtype
mice. A similar phenotype was observed for Prickle1-mutant mice carrying
a heterozygous F141S mutation, which alters an amino acid in the PET/LIM
domain. These results suggested that disruption of the highly conserved
PET/LIM domain is sufficient to lower seizure threshold. Homozygous
Prickle1-null mice and homozygous C251X-mutant mice were embryonic
lethal. In the Drosophila prickle mutant 'spiny legs-1,'
pk(sple1)/pk(sple1) homozygous mutants showed severely decreased
recovery in the bang test (sensitivity to vortexing), suggesting a
decreased seizure threshold. A small percentage of pk(sple1)/pk(sple1)
flies also showed generalized disorganization of the peripheral nervous
system, with aberrant migration of neuronal processes resulting in
improper connections; these changes were not observed in controls.

*FIELD* AV
.0001
EPILEPSY, PROGRESSIVE MYOCLONIC 1B
PRICKLE1, ARG104GLN

In affected members of 3 unrelated consanguineous families with
progressive myoclonic epilepsy-1B (EPM1B; 612437), Bassuk et al. (2008)
identified a homozygous 311G-A transition in the PRICKLE1 gene,
resulting in an arg104-to-gln (R104Q) substitution in a highly conserved
region. The mutation was not detected in 1,354 control individuals. In
vitro functional expression studies showed that mutant PRICKLE1 failed
to bind REST (600571) and blocked transport of REST out of the nucleus,
resulting in constitutive activation of REST and inappropriate
downregulation of REST target genes.

.0002
EPILEPSY, PROGRESSIVE MYOCLONIC 1B
PRICKLE1, ARG144HIS

In a male patient with EPM1B (612437), Tao et al. (2011) identified a
heterozygous 431G-A transition in the PRICKLE1 gene, resulting in an
arg144-to-his (R144H) substitution. The patient had myoclonic seizures,
generalized EEG pattern, and mild mental retardation. The mutation was
not detected in 2,000 CEPH control chromosomes or 352 ethnically matched
chromosomes.

.0003
EPILEPSY, PROGRESSIVE MYOCLONIC 1B
PRICKLE1, TYR472HIS

In a female patient with juvenile myoclonic epilepsy (612437), Tao et
al. (2011) identified a heterozygous 1414T-C transition in the PRICKLE1
gene, resulting in a tyr472-to-his (Y472H) substitution. No other
clinical details were provided. The mutation was not detected in 2,000
CEPH control chromosomes or 352 ethnically matched chromosomes.

*FIELD* RF
1. Bassuk, A. G.; Wallace, R. H.; Buhr, A.; Buller, A. R.; Afawi,
Z.; Shimojo, M.; Miyata, S.; Chen, S.; Gonzalez-Alegre, P.; Griesbach,
H. L.; Wu, S.; Nashelsky, M.; and 18 others: A homozygous mutation
in human PRICKLE1 causes an autosomal-recessive progressive myoclonus
epilepsy-ataxia syndrome. Am. J. Hum. Genet. 83: 572-581, 2008.

2. Bosoi, C. M.; Capra, V.; Allache, R.; Trinh, V. Q.-H.; De Marco,
P.; Merello, E.; Drapeau, P.; Bassuk, A. G.; Kibar, Z.: Identification
and characterization of novel rare mutations in the planar cell polarity
gene PRICKLE1 in human neural tube defects. Hum. Mutat. 32: 1371-1375,
2011.

3. Katoh, M.; Katoh, M.: Identification and characterization of human
PRICKLE1 and PRICKLE2 genes as well as mouse Prickle1 and Prickle2
genes homologous to Drosophila tissue polarity gene prickle. Int.
J. Molec. Med. 11: 249-256, 2003.

4. Liu, C.; Lin, C.; Whitaker, D., T.; Bakeri, H.; Bulgakov, O. V.;
Liu, P.; Lei, J.; Dong, L.; Li, T.; Swaroop, A.: Prickle1 is expressed
in distinct cell populations of the central nervous system and contributes
to neuronal morphogenesis. Hum. Molec. Genet. 22: 2234-2246, 2013.

5. Shimojo, M.; Hersh, L. B.: REST/NRSF-interacting LIM domain protein,
a putative nuclear translocation receptor. Molec. Cell. Biol. 23:
9025-9031, 2003.

6. Tao, H.; Manak, J. R.; Sowers, L.; Mei, X.; Kiyonari, H.; Abe,
T.; Dahdaleh, N. S.; Yang, T.; Wu, S.; Chen, S.; Fox, M. H.; Gurnett,
C.; and 24 others: Mutations in prickle orthologs cause seizures
in flies, mice, and humans. Am. J. Hum. Genet. 88: 138-149, 2011.

*FIELD* CN
Patricia A. Hartz - updated: 10/11/2013
Cassandra L. Kniffin - updated: 4/2/2012
Cassandra L. Kniffin - updated: 3/25/2011
Cassandra L. Kniffin - updated: 11/24/2008

*FIELD* CD
Patricia A. Hartz: 3/1/2004

*FIELD* ED
mgross: 10/14/2013
mgross: 10/11/2013
carol: 4/4/2012
terry: 4/4/2012
ckniffin: 4/2/2012
terry: 4/28/2011
wwang: 3/29/2011
ckniffin: 3/25/2011
terry: 1/20/2010
wwang: 12/5/2008
ckniffin: 11/24/2008
alopez: 3/1/2004

MIM 612437
*RECORD*
*FIELD* NO
612437
*FIELD* TI
#612437 EPILEPSY, PROGRESSIVE MYOCLONIC 1B; EPM1B
*FIELD* TX
A number sign (#) is used with this entry because progressive myoclonic
read moreepilepsy-1B (EPM1B) is caused by homozygous or heterozygous mutation in
the PRICKLE1 gene (608500).

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

CLINICAL FEATURES

Berkovic et al. (2005) reported a consanguineous Israeli Arab family in
which 8 members had an early-onset form of progressive myoclonic
epilepsy. Age at seizure onset was 7.3 years (range, 5 to 10 years).
Five patients presented with myoclonic seizures, 1 with tonic-clonic
seizures, and 2 with both. In 4 cases, the parents reported delayed
walking in infancy with difficulty walking or running in childhood,
consistent with ataxia, before the onset of seizures. Myoclonic seizures
were aggravated by sunlight. The disorder was progressive, and 3
patients became wheelchair-bound. There was no significant progressive
dementia; brain MRI of 1 patient was normal. The clinical phenotype of
this family was similar to that of classic Unverricht-Lundborg disease,
but differed by early age of onset and a slightly more severe course.

Straussberg et al. (2005) described a consanguineous Israeli Arab family
in which 3 sibs had early-onset ataxia, dysarthria, upward gaze palsy,
extensor plantar reflexes, axonal sensory neuropathy, and normal
cognition. Onset of progressive ataxia was noted around age 4 years. The
2 older sibs, ages 11 and 9 years, developed myoclonic and generalized
tonic-clonic seizures that were photosensitive. The youngest had not
developed seizures at age 4. Specific features of all patients included
tremor, dysmetria, impaired vibration and position sense, and extensor
plantar responses. Genetic analysis excluded known loci for autosomal
recessive ataxia.

El-Shanti et al. (2006) reported a consanguineous Jordanian family in
which 4 sibs had onset of gait ataxia at age 15 months, followed by fine
tremor progressing to coarse action tremor at age 4 years, and atonic
seizures at about age 8 to 10 years. Brain MRI showed no evidence of
cerebellar hypoplasia, and cognitive function was spared. The seizures
and tremor were responsive to medication. El-Shanti et al. (2006) noted
that none of the patients had frank myoclonic seizures, and concluded
that the action tremor was related to appendicular ataxia rather than to
action myoclonus. The tremor started with fine movement early in the
disease process, worsened as the hand approached the target, and
continued for a few seconds after the target was reached. However, the
authors thought it was possible that the tremor was composed of 2
components consisting of ataxic tremor and action myoclonus. Bassuk et
al. (2008) noted that affected members of the family reported by
El-Shanti et al. (2006) had developed progressive myoclonic seizures,
and that some patients had also developed upward gaze palsy.

MAPPING

By homozygosity mapping of a consanguineous family with autosomal
recessive myoclonic epilepsy and ataxia, Berkovic et al. (2005)
identified linkage to chromosome 12 (maximum lod score of 6.32 at marker
D12S1663). Haplotype analysis narrowed the disease locus, termed EPM1B,
to a 15-Mb pericentromeric region on chromosome 12 defined by markers
D12S345 and D12S1661.

By linkage analysis of a Jordanian family with autosomal recessive
ataxia and tremor, El-Shanti et al. (2006) found linkage to chromosome
12 (multipoint maximum lod score of 3.3). Haplotype analysis delineated
a minimal 18.67-cM (23-Mb) pericentromeric region on chromosome 12.

MOLECULAR GENETICS

In affected members of the families reported by Berkovic et al. (2005),
Straussberg et al. (2005), and El-Shanti et al. (2006), Bassuk et al.
(2008) identified the same homozygous mutation in the PRICKLE1 gene
(R104Q; 608500.0001). The findings were consistent with a founder
effect.

Tao et al. (2011) identified 2 different heterozygous mutations in the
PRICKLE1 gene (R144H; 608500.0002 and Y472H; 608500.0003, respectively)
in 2 unrelated patients with myoclonic epilepsy. One patient had a more
severe phenotype with mild mental retardation. The authors noted that
both homozygous (Bassuk et al., 2008) and heterozygous mutations can
result in seizures, suggesting a dosage effect. Heterozygous mutations
were also identified in the homologous PRICKLE2 gene
(608501.0001-608501.0002) in different patients with myoclonic seizures
(EPM5; 613832). Tao et al. (2011) concluded that PRICKLE signaling is
important in seizure prevention, and presented 2 hypotheses: (1) that
PRICKLE affects cell polarity and contributes to the development of a
functional neural network and (2) that PRICKLE affects calcium
signaling, which may play a role in seizure genesis if disrupted.

ANIMAL MODEL

Tao et al. (2011) demonstrated that disruption of the Prickle genes in
zebrafish, Drosophila, and mice resulted in aberrant protein function
and clinical features consistent with seizures.

*FIELD* RF
1. Bassuk, A. G.; Wallace, R. H.; Buhr, A.; Buller, A. R.; Afawi,
Z.; Shimojo, M.; Miyata, S.; Chen, S.; Gonzalez-Alegre, P.; Griesbach,
H. L.; Wu, S.; Nashelsky, M.; and 18 others: A homozygous mutation
in human PRICKLE1 causes an autosomal-recessive progressive myoclonus
epilepsy-ataxia syndrome. Am. J. Hum. Genet. 83: 572-581, 2008.

2. Berkovic, S. F.; Mazarib, A.; Walid, S.; Neufeld, M. Y.; Manelis,
J.; Nevo, Y.; Korczyn, A. D.; Yin, J.; Xiong, L.; Pandolfo, M.; Mulley,
J. C.; Wallace, R. H.: A new clinical and molecular form of Unverricht-Lundborg
disease localized by homozygosity mapping. Brain 128: 652-658, 2005.

3. El-Shanti, H.; Daoud, A.; Sadoon, A. A.; Leal, S. M.; Chen, S.;
Lee, K.; Spiegel, R.: A distinct autosomal recessive ataxia maps
to chromosome 12 in an inbred family from Jordan. Brain Dev. 28:
353-357, 2006.

4. Straussberg, R.; Basel-Vanagaite, L.; Kivity, S.; Dabby, R.; Cirak,
S.; Nurnberg, P.; Voit, T.; Mahajnah, M.; Inbar, D.; Saifi, G. M.;
Lupski, J. R.; Delague, V.; Megarbane, A.; Richter, A.; Leshinsky,
E.; Berkovic, S. F.: An autosomal recessive cerebellar ataxia syndrome
with upward gaze palsy, neuropathy, and seizures. Neurology 64:
142-144, 2005.

5. Tao, H.; Manak, J. R.; Sowers, L.; Mei, X.; Kiyonari, H.; Abe,
T.; Dahdaleh, N. S.; Yang, T.; Wu, S.; Chen, S.; Fox, M. H.; Gurnett,
C.; and 24 others: Mutations in prickle orthologs cause seizures
in flies, mice, and humans. Am. J. Hum. Genet. 88: 138-149, 2011.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Eyes];
Upward gaze palsy

NEUROLOGIC:
[Central nervous system];
Delayed walking and running in early childhood;
Ataxia, cerebellar, limb and gait;
Myoclonic seizures, progressive;
Tonic-clonic seizures;
Atonic seizures;
Dysarthria;
Dysmetria;
Disdiadochokinesia;
Tremor, fine;
Tremor, action, progressive;
Extensor plantar responses;
Cognition is spared;
[Peripheral nervous system];
Axonal sensory neuropathy

MISCELLANEOUS:
Onset of ataxia in early childhood (range 15 months to 3 years);
Onset of seizures in later childhood (5 to 10 years);
Progressive disorder

MOLECULAR BASIS:
Caused by mutation in the prickle-like 1 gene (PRICKLE1, 608500.0001)

*FIELD* CD
Cassandra L. Kniffin: 11/21/2008

*FIELD* ED
ckniffin: 11/24/2008

*FIELD* CN
Cassandra L. Kniffin - updated: 3/25/2011

*FIELD* CD
Cassandra L. Kniffin: 11/21/2008

*FIELD* ED
carol: 08/02/2012
carol: 3/7/2012
terry: 4/28/2011
wwang: 3/29/2011
ckniffin: 3/25/2011
terry: 1/21/2010
wwang: 12/5/2008
ckniffin: 11/24/2008