RBCC Red Blood Cell Collection

VRK1 [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Serine/threonine-protein kinase VRK1; 2.7.11.1 (Vaccinia-related kinase 1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00019640
IPI00019640 Serine/threonine-protein kinase VRK1 PKC soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight

UniProt Q99986
ID VRK1_HUMAN Reviewed; 396 AA.
AC Q99986; Q3SYL2;
DT 10-OCT-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-1997, sequence version 1.
DT 22-JAN-2014, entry version 132.
DE RecName: Full=Serine/threonine-protein kinase VRK1;
DE EC=2.7.11.1;
DE AltName: Full=Vaccinia-related kinase 1;
GN Name=VRK1;
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], AND TISSUE SPECIFICITY.
RC TISSUE=Fetal liver;
RX PubMed=9344656; DOI=10.1006/geno.1997.4938;
RA Nezu J., Oku A., Jones M.H., Shimane M.;
RT "Identification of two novel human putative serine/threonine kinases,
RT VRK1 and VRK2, with structural similarity to Vaccinia virus B1R
RT kinase.";
RL Genomics 45:327-331(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Lung;
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 [3]
RP FUNCTION, SUBCELLULAR LOCATION, AUTOPHOSPHORYLATION, AND MUTAGENESIS
RP OF SER-14; THR-102; SER-125; SER-150; SER-158; SER-239; THR-305;
RP THR-312; THR-355 AND THR-390.
RX PubMed=10951572; DOI=10.1038/sj.onc.1203709;
RA Lopez-Borges S., Lazo P.A.;
RT "The human vaccinia-related kinase 1 (VRK1) phosphorylates threonine-
RT 18 within the mdm-2 binding site of the p53 tumour suppressor
RT protein.";
RL Oncogene 19:3656-3664(2000).
RN [4]
RP AUTOPHOSPHORYLATION, AND ENZYME REGULATION.
RX PubMed=11883897; DOI=10.1006/abbi.2001.2746;
RA Barcia R., Lopez-Borges S., Vega F.M., Lazo P.A.;
RT "Kinetic properties of p53 phosphorylation by the human vaccinia-
RT related kinase 1.";
RL Arch. Biochem. Biophys. 399:1-5(2002).
RN [5]
RP FUNCTION, SUBCELLULAR LOCATION, AND PHOSPHORYLATION.
RX PubMed=14645249; DOI=10.1074/jbc.M310813200;
RA Nichols R.J., Traktman P.;
RT "Characterization of three paralogous members of the Mammalian
RT vaccinia related kinase family.";
RL J. Biol. Chem. 279:7934-7946(2004).
RN [6]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=15105425; DOI=10.1074/jbc.M401009200;
RA Sevilla A., Santos C.R., Vega F.M., Lazo P.A.;
RT "Human vaccinia-related kinase 1 (VRK1) activates the ATF2
RT transcriptional activity by novel phosphorylation on Thr-73 and Ser-62
RT and cooperates with JNK.";
RL J. Biol. Chem. 279:27458-27465(2004).
RN [7]
RP SUBCELLULAR LOCATION.
RX PubMed=16704422; DOI=10.1111/j.1742-4658.2006.05256.x;
RA Blanco S., Klimcakova L., Vega F.M., Lazo P.A.;
RT "The subcellular localization of vaccinia-related kinase-2 (VRK2)
RT isoforms determines their different effect on p53 stability in tumour
RT cell lines.";
RL FEBS J. 273:2487-2504(2006).
RN [8]
RP FUNCTION.
RX PubMed=16495336; DOI=10.1091/mbc.E05-12-1179;
RA Nichols R.J., Wiebe M.S., Traktman P.;
RT "The vaccinia-related kinases phosphorylate the N' terminus of BAF,
RT regulating its interaction with DNA and its retention in the
RT nucleus.";
RL Mol. Biol. Cell 17:2451-2464(2006).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH RAN, AND ENZYME
RP REGULATION.
RX PubMed=18617507; DOI=10.1074/mcp.M700586-MCP200;
RA Sanz-Garcia M., Lopez-Sanchez I., Lazo P.A.;
RT "Proteomics identification of nuclear Ran GTPase as an inhibitor of
RT human VRK1 and VRK2 (vaccinia-related kinase) activities.";
RL Mol. Cell. Proteomics 7:2199-2214(2008).
RN [10]
RP INVOLVEMENT IN PCH1A.
RX PubMed=19646678; DOI=10.1016/j.ajhg.2009.07.006;
RA Renbaum P., Kellerman E., Jaron R., Geiger D., Segel R., Lee M.,
RA King M.C., Levy-Lahad E.;
RT "Spinal muscular atrophy with pontocerebellar hypoplasia is caused by
RT a mutation in the VRK1 gene.";
RL Am. J. Hum. Genet. 85:281-289(2009).
RN [11]
RP FUNCTION, PHOSPHORYLATION AT SER-342, AND MUTAGENESIS OF LYS-179 AND
RP SER-342.
RX PubMed=19103756; DOI=10.1128/MCB.01341-08;
RA Lopez-Sanchez I., Sanz-Garcia M., Lazo P.A.;
RT "Plk3 interacts with and specifically phosphorylates VRK1 in Ser342, a
RT downstream target in a pathway that induces Golgi fragmentation.";
RL Mol. Cell. Biol. 29:1189-1201(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-342, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 3-364 IN COMPLEX WITH
RP INHIBITOR.
RG Structural genomics consortium (SGC);
RT "Human vaccinia-related kinase 1.";
RL Submitted (SEP-2010) to the PDB data bank.
RN [15]
RP STRUCTURE BY NMR, CATALYTIC ACTIVITY, MUTAGENESIS OF SER-342 AND
RP THR-353, AND AUTOPHOSPHORYLATION.
RX PubMed=21543316; DOI=10.1074/jbc.M110.200162;
RA Shin J., Chakraborty G., Bharatham N., Kang C., Tochio N., Koshiba S.,
RA Kigawa T., Kim W., Kim K.T., Yoon H.S.;
RT "NMR solution structure of human vaccinia-related kinase 1 (VRK1)
RT reveals the C-terminal tail essential for its structural stability and
RT autocatalytic activity.";
RL J. Biol. Chem. 286:22131-22138(2011).
CC -!- FUNCTION: Serine/threonine kinase involved in Golgi disassembly
CC during the cell cycle: following phosphorylation by PLK3 during
CC mitosis, required to induce Golgi fragmentation. Acts by mediating
CC phosphorylation of downstream target protein. Phosphorylates 'Thr-
CC 18' of p53/TP53 and may thereby prevent the interaction between
CC p53/TP53 and MDM2. Phosphorylates casein and histone H3.
CC Phosphorylates BANF1: disrupts its ability to bind DNA, reduces
CC its binding to LEM domain-containing proteins and causes its
CC relocalization from the nucleus to the cytoplasm. Phosphorylates
CC ATF2 which activates its transcriptional activity.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- ENZYME REGULATION: Active in presence of Mn(2+), Mg(2+) and
CC Zn(2+), but is not functional with Ca(2+) or Cu(2+). Has a higher
CC affinity for Mn(2+) than for Mg(2+). RAN inhibits its
CC autophosphorylation and its ability to phosphorylate histone H3.
CC -!- INTERACTION:
CC P15336:ATF2; NbExp=5; IntAct=EBI-1769146, EBI-1170906;
CC P38432:COIL; NbExp=9; IntAct=EBI-1769146, EBI-945751;
CC P05412:JUN; NbExp=4; IntAct=EBI-1769146, EBI-852823;
CC Q9H4B4:PLK3; NbExp=12; IntAct=EBI-1769146, EBI-751877;
CC P62826:RAN; NbExp=12; IntAct=EBI-1769146, EBI-286642;
CC Q12888:TP53BP1; NbExp=8; IntAct=EBI-1769146, EBI-396540;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Cytoplasm, cytoskeleton,
CC spindle (By similarity). Note=Dispersed throughout the cell but
CC not located on mitotic spindle or chromatids during mitosis.
CC -!- TISSUE SPECIFICITY: Widely expressed. Highly expressed in fetal
CC liver, testis and thymus.
CC -!- PTM: Autophosphorylated at various serine and threonine residues.
CC Autophosphorylation does not impair its ability to phosphorylate
CC p53/TP53. Phosphorylation by PLK3 leads to induction of Golgi
CC fragmentation during mitosis.
CC -!- DISEASE: Pontocerebellar hypoplasia 1A (PCH1A) [MIM:607596]: A
CC disorder characterized by an abnormally small cerebellum and
CC brainstem, central and peripheral motor dysfunction from birth,
CC gliosis and spinal cord anterior horn cells degeneration
CC resembling infantile spinal muscular atrophy. Additional features
CC include muscle hypotonia, congenital contractures and respiratory
CC insufficiency that is evident at birth. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CK1 Ser/Thr
CC protein kinase family. VRK subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/VRK1ID43556ch14q32.html";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AB000449; BAA19108.1; -; mRNA.
DR EMBL; BC103761; AAI03762.1; -; mRNA.
DR EMBL; BC112075; AAI12076.1; -; mRNA.
DR EMBL; BC113510; AAI13511.1; -; mRNA.
DR RefSeq; NP_003375.1; NM_003384.2.
DR UniGene; Hs.422662; -.
DR PDB; 2KTY; NMR; -; A=1-360.
DR PDB; 2KUL; NMR; -; A=1-360.
DR PDB; 2LAV; NMR; -; A=1-361.
DR PDB; 3OP5; X-ray; 2.40 A; A/B/C/D=3-364.
DR PDBsum; 2KTY; -.
DR PDBsum; 2KUL; -.
DR PDBsum; 2LAV; -.
DR PDBsum; 3OP5; -.
DR ProteinModelPortal; Q99986; -.
DR SMR; Q99986; 1-361.
DR IntAct; Q99986; 14.
DR MINT; MINT-3060185; -.
DR STRING; 9606.ENSP00000216639; -.
DR BindingDB; Q99986; -.
DR ChEMBL; CHEMBL1293199; -.
DR GuidetoPHARMACOLOGY; 2275; -.
DR PhosphoSite; Q99986; -.
DR DMDM; 45593726; -.
DR PaxDb; Q99986; -.
DR PeptideAtlas; Q99986; -.
DR PRIDE; Q99986; -.
DR DNASU; 7443; -.
DR Ensembl; ENST00000216639; ENSP00000216639; ENSG00000100749.
DR GeneID; 7443; -.
DR KEGG; hsa:7443; -.
DR UCSC; uc001yft.3; human.
DR CTD; 7443; -.
DR GeneCards; GC14P097263; -.
DR HGNC; HGNC:12718; VRK1.
DR HPA; HPA000660; -.
DR HPA; HPA017929; -.
DR MIM; 602168; gene.
DR MIM; 607596; phenotype.
DR neXtProt; NX_Q99986; -.
DR Orphanet; 2254; Pontocerebellar hypoplasia type 1.
DR PharmGKB; PA37330; -.
DR eggNOG; NOG330134; -.
DR HOGENOM; HOG000069991; -.
DR HOVERGEN; HBG007532; -.
DR InParanoid; Q99986; -.
DR KO; K08816; -.
DR OMA; YCMVQWL; -.
DR OrthoDB; EOG7KSX83; -.
DR PhylomeDB; Q99986; -.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_21300; Mitotic M-M/G1 phases.
DR SignaLink; Q99986; -.
DR EvolutionaryTrace; Q99986; -.
DR GeneWiki; VRK1; -.
DR GenomeRNAi; 7443; -.
DR NextBio; 29150; -.
DR PRO; PR:Q99986; -.
DR Bgee; Q99986; -.
DR CleanEx; HS_VRK1; -.
DR Genevestigator; Q99986; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005795; C:Golgi stack; IDA:UniProtKB.
DR GO; GO:0005730; C:nucleolus; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005819; C:spindle; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0090166; P:Golgi disassembly; IDA:UniProtKB.
DR GO; GO:0007067; P:mitosis; IEA:UniProtKB-KW.
DR GO; GO:0007077; P:mitotic nuclear envelope disassembly; TAS:Reactome.
DR GO; GO:0007084; P:mitotic nuclear envelope reassembly; TAS:Reactome.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Cell cycle; Cell division;
KW Complete proteome; Cytoplasm; Cytoskeleton; Kinase; Mitosis;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase.
FT CHAIN 1 396 Serine/threonine-protein kinase VRK1.
FT /FTId=PRO_0000086803.
FT DOMAIN 37 317 Protein kinase.
FT NP_BIND 43 51 ATP (By similarity).
FT ACT_SITE 177 177 Proton acceptor (By similarity).
FT BINDING 71 71 ATP (By similarity).
FT MOD_RES 342 342 Phosphoserine; by PLK3.
FT MOD_RES 355 355 Phosphothreonine; by autocatalysis.
FT MUTAGEN 14 14 S->A: Does not abolish
FT autophosphorylation.
FT MUTAGEN 102 102 T->A: Does not abolish
FT autophosphorylation.
FT MUTAGEN 125 125 S->A: Does not abolish
FT autophosphorylation.
FT MUTAGEN 150 150 S->A: Does not abolish
FT autophosphorylation.
FT MUTAGEN 158 158 S->A: Does not abolish
FT autophosphorylation.
FT MUTAGEN 179 179 K->A: Does not affect phosphorylation at
FT S-342.
FT MUTAGEN 239 239 S->A: Does not abolish
FT autophosphorylation.
FT MUTAGEN 305 305 T->A: Does not abolish
FT autophosphorylation.
FT MUTAGEN 312 312 T->A: Does not abolish
FT autophosphorylation.
FT MUTAGEN 342 342 S->A: Abolishes phosphorylation by PLK3
FT and induction of Golgi fragmentation
FT during mitosis. Strongly reduced
FT autophosphorylation.
FT MUTAGEN 353 353 T->A: Strongly reduced
FT autophosphorylation.
FT MUTAGEN 355 355 T->A: Does not abolish
FT autophosphorylation.
FT MUTAGEN 390 390 T->A: Does not abolish
FT autophosphorylation.
FT TURN 2 4
FT STRAND 11 13
FT STRAND 22 24
FT STRAND 28 30
FT STRAND 36 42
FT STRAND 46 49
FT STRAND 50 56
FT STRAND 59 61
FT STRAND 67 74
FT HELIX 78 90
FT HELIX 93 102
FT STRAND 113 121
FT STRAND 124 132
FT STRAND 134 137
FT HELIX 138 144
FT TURN 145 147
FT HELIX 151 170
FT HELIX 180 182
FT STRAND 183 188
FT STRAND 193 195
FT HELIX 198 200
FT STRAND 202 205
FT HELIX 206 208
FT TURN 225 227
FT HELIX 230 233
FT HELIX 240 256
FT HELIX 262 264
FT HELIX 268 280
FT HELIX 282 289
FT STRAND 291 294
FT HELIX 297 307
FT STRAND 311 313
FT HELIX 317 330
FT STRAND 355 357
SQ SEQUENCE 396 AA; 45476 MW; 5640C624BF059949 CRC64;
MPRVKAAQAG RQSSAKRHLA EQFAVGEIIT DMAKKEWKVG LPIGQGGFGC IYLADMNSSE
SVGSDAPCVV KVEPSDNGPL FTELKFYQRA AKPEQIQKWI RTRKLKYLGV PKYWGSGLHD
KNGKSYRFMI MDRFGSDLQK IYEANAKRFS RKTVLQLSLR ILDILEYIHE HEYVHGDIKA
SNLLLNYKNP DQVYLVDYGL AYRYCPEGVH KEYKEDPKRC HDGTIEFTSI DAHNGVAPSR
RGDLEILGYC MIQWLTGHLP WEDNLKDPKY VRDSKIRYRE NIASLMDKCF PEKNKPGEIA
KYMETVKLLD YTEKPLYENL RDILLQGLKA IGSKDDGKLD LSVVENGGLK AKTITKKRKK
EIEESKEPGV EDTEWSNTQT EEAIQTRSRT RKRVQK
//

MIM 602168
*RECORD*
*FIELD* NO
602168
*FIELD* TI
*602168 VACCINIA-RELATED KINASE 1; VRK1
;;VACCINIA VIRUS B1R-RELATED KINASE 1
*FIELD* TX
read more
CLONING

To identify novel genes involved in the regulation of cell division,
Nezu et al. (1997) constructed a cDNA library enriched for human fetal
liver-specific genes by suppressive subtractive hybridization. One
expressed sequence tag (EST) generated from this library was found to
represent a novel putative serine/threonine kinase. They isolated
full-length VRK1, which encodes a protein of 396 amino acids. The amino
acid sequence has 40% identity over 305 amino acids with the B1R
serine/threonine protein kinase of vaccinia virus. VRK1 was also found
to have sequence identity (62.0% over 481 nucleotides) to a database
EST. Conceptual translation of the EST predicted a protein of 508 amino
acids that, like VRK1, had similarity to B1R kinase. This gene was named
VRK2 (602169). Northern analysis showed that expression of both genes is
widespread and elevated in highly proliferative cells, such as those in
testis, thymus, and fetal liver. B1R kinase is essential for DNA
replication of vaccinia virus. The authors noted the similarity of VRK1
and VRK2 to B1R and predicted that these genes may have similar
functions. Renbaum et al. (2009) noted that VRK1 contains an N-terminal
ATP-binding site, a serine/threonine kinase domain, endosomal and
lysosomal targeting sequence, and C-terminal nuclear localization signal
and BAB motif.

GENE STRUCTURE

The VRK1 gene contains 13 exons (Renbaum et al., 2009).

MAPPING

Nezu et al. (1997) designed PCR primers to amplify selectively human,
but not murine, DNA and screened the Genebridge 4 radiation hybrid
panel. They assigned VRK1 to chromosome 14q32 and VRK2 to chromosome
2p16-p15.

MOLECULAR GENETICS

By linkage analysis followed by candidate gene sequencing of an affected
Ashkenazi Jewish family with pontocerebellar hypoplasia-1A (PCH1A;
607596), Renbaum et al. (2009) identified a homozygous mutation in the
VRK1 gene (R358X; 602168.0001). The phenotype was characterized by
early-onset spinal muscular atrophy with death in late childhood.

Najmabadi et al. (2011) performed homozygosity mapping followed by exon
enrichment and next-generation sequencing in 136 consanguineous families
(over 90% Iranian and less than 10% Turkish or Arabic) segregating
syndromic or nonsyndromic forms of autosomal recessive intellectual
disability. In family M017N, they identified a homozygous missense
mutation in the VRK1 gene (602168.0002) in 4 sibs with moderate to
severe intellectual disability and a phenotype compatible with
pontocerebellar hypoplasia. The parents, who were first cousins once
removed, had 3 healthy children.

*FIELD* AV
.0001
PONTOCEREBELLAR HYPOPLASIA, TYPE 1A
VRK1, ARG358TER

In an Ashkenazi Jewish girl, born of consanguineous parents, with
pontocerebellar hypoplasia type 1A (PCH1A; 607596), Renbaum et al.
(2009) identified a homozygous 1072C-T transition in exon 12 of the VRK1
gene, resulting in an arg358-to-ter (R358X) substitution within the NLS.
There were 3 affected family members, all of whom died by age 12 years.
Clinical features included poor sucking, developmental delay,
progressive muscle weakness, ataxia, hyperreflexia, foot deformities,
and cerebellar hypoplasia. Skeletal muscle biopsy showed neurogenic
atrophy. The mutation was detected in heterozygosity in 2 of 449
unaffected Ashkenazi Jewish individuals.

.0002
PONTOCEREBELLAR HYPOPLASIA, TYPE 1A
VRK1, ARG133CYS

In family M017N, Najmabadi et al. (2011) identified a homozygous C-to-T
transition in the VRK1 gene at genomic coordinate Chr14:96388943,
resulting in an arg133-to-cys (R133C) substitution, in 4 sibs with
moderate to severe intellectual disability and a phenotype compatible
with pontocerebellar hypoplasia (607596). The parents, who were first
cousins once removed, were heterozygous for the mutation and had 3
healthy children.

*FIELD* RF
1. Najmabadi, H.; Hu, H.; Garshasbi, M.; Zemojtel, T.; Abedini, S.
S.; Chen, W.; Hosseini, M.; Behjati, F.; Haas, S.; Jamali, P.; Zecha,
A.; Mohseni, M.; and 33 others: Deep sequencing reveals 50 novel
genes for recessive cognitive disorders. Nature 478: 57-63, 2011.

2. Nezu, J.; Oku, A.; Jones, M. H.; Shimane, M.: Identification of
two novel human putative serine/threonine kinases, VRK1 and VRK2,
with structural similarity to vaccinia virus B1R kinase. Genomics 45:
327-331, 1997.

3. Renbaum, P.; Kellerman, E.; Jaron, R.; Geiger, D.; Segel, R.; Lee,
M.; King, M. C.; Levy-Lahad, E.: Spinal muscular atrophy with pontocerebellar
hypoplasia is caused by a mutation in the VRK1 gene. Am. J. Hum.
Genet. 85: 281-289, 2009.

*FIELD* CN
Ada Hamosh - updated: 1/6/2012
Cassandra L. Kniffin - updated: 10/9/2009

*FIELD* CD
Victor A. McKusick: 12/11/1997

*FIELD* ED
carol: 06/08/2012
ckniffin: 6/7/2012
carol: 1/9/2012
terry: 1/6/2012
terry: 4/22/2011
wwang: 10/16/2009
ckniffin: 10/9/2009
dkim: 12/8/1998
mark: 12/11/1997

MIM 607596
*RECORD*
*FIELD* NO
607596
*FIELD* TI
#607596 PONTOCEREBELLAR HYPOPLASIA, TYPE 1A; PCH1A
;;PCH1;;
PONTOCEREBELLAR HYPOPLASIA WITH INFANTILE SPINAL MUSCULAR ATROPHY;;
read morePONTOCEREBELLAR HYPOPLASIA WITH ANTERIOR HORN CELL DISEASE
*FIELD* TX
A number sign (#) is used with this entry because pontocerebellar
hypoplasia type 1A (PCH1A) can be caused by homozygous mutation in the
VRK1 gene (602168) on chromosome 14q32.

DESCRIPTION

Pontocerebellar hypoplasia (PCH) refers to a group of severe
neurodegenerative disorders affecting growth and function of the
brainstem and cerebellum, resulting in little or no development.
Different types were classified based on the clinical picture and the
spectrum of pathologic changes. PCH type 1 is characterized by central
and peripheral motor dysfunction associated with anterior horn cell
degeneration resembling infantile spinal muscular atrophy (SMA; see
SMA1, 253300); death usually occurs early. In PCH type 2 (see PCH2A,
277470), there is progressive microcephaly from birth combined with
extrapyramidal dyskinesias. PCH3 (608027) is characterized by hypotonia,
hyperreflexia, microcephaly, optic atrophy, and seizures. PCH4 (225753)
is characterized by hypertonia, joint contractures, olivopontocerebellar
hypoplasia, and early death. Patients with PCH5 (610204) have cerebellar
hypoplasia apparent in the second trimester and show seizures. PCH6
(611523) is associated with mitochondrial respiratory chain defects
(summary by Graham et al., 2010). Also see PCH7 (614969) and PCH8
(614961).

- Genetic Heterogeneity of Pontocerebellar Hypoplasia

PCH1B (614678) is caused by mutation in the EXOSC3 gene (606489), PCH2A
(277470) is caused by mutation in the TSEN54 gene (608755), PCH2B
(612389) is caused by mutation in the TSEN2 gene (608753), PCH2C
(612390) is caused by mutation in the TSEN34 gene (608754), and PCH2D
(613811) is caused by mutation in the SEPSECS gene (613009). PCH4
(225753) is caused by mutation in the TSEN54 gene (608755), PCH6
(611523) is caused by mutation in the RARS2 gene (611524), and PCH8
(614961) is caused by mutation in the CHMP1A gene (164010).

PCH3 (608027) has been mapped to chromosome 7q11-q21. PCH5 (610204) and
PCH7 (614969) have not yet been mapped.

CLINICAL FEATURES

The combination of autosomal recessive PCH and anterior horn cell
disease was first described by Norman (1961) and was extensively
reviewed by Chou et al. (1990) and Barth (1993).

Rudnik-Schoneborn et al. (2003) described a series of 6 families
exhibiting a relatively broad spectrum of clinical manifestations
related to PCH with infantile SMA (i.e., PCH1). Their findings suggested
an extended phenotype that can include major structural defects of the
cerebellum as well as mild cerebellar hypoplasia in combination with
anterior horn cell loss. In the 6 families reported by Rudnik-Schoneborn
et al. (2003), the onset of muscle weakness in 3 was within the first 6
months (SMA2; 253550), while the remaining 3 families had onset
prenatally or shortly after birth and were classified as SMA1. All
patients underwent testing for infantile SMA, and homozygous absence of
the SMN1 gene (600354) was excluded in all. Moreover, none of the
patients showed SMN1 values in the heterozygous range upon quantitative
analysis. At least 3 of the 6 parental pairs were consanguineous.

Renbaum et al. (2009) reported a consanguineous family of Ashkenazi
Jewish origin in which 3 children had SMA-PCH. Early features included
microcephaly, poor sucking, and developmental delay. In the first 2
years, the proband developed upper limb ataxia, brisk reflexes, and
bilateral equinovarus. She was found to have motor and sensory
neuropathy due to chronic denervation. Brain MRI showed a small
cerebellar vermis and a large cisterna magna, compatible with cerebellar
hypoplasia; she had mild mental retardation. Disease progression led to
severe weakness, and the child became wheelchair-bound and incontinent,
with sleep disturbance, increasing swallowing difficulties, severe
ataxia, and progressive intercostal muscle weakness. She died at age
11.5 years. A previously deceased older sister had a similar phenotype,
with tongue fasciculations, hypotonia with brisk reflexes, ataxia, and
equinovarus deformities. She died at age 9.5 years. Their cousin, also
the product of a consanguineous marriage within the extended family,
reportedly had a similar phenotype and died at age 8 years. Skeletal
muscle studies showed neurogenic atrophy.

MOLECULAR GENETICS

By linkage analysis followed by candidate gene sequencing of an affected
Ashkenazi Jewish family with SMA-PCH, Renbaum et al. (2009) identified a
homozygous mutation in the VRK1 gene (R358X; 602168.0001). The mutation
was detected in heterozygosity in 2 of 449 unaffected Ashkenazi Jewish
individuals.

Najmabadi et al. (2011) performed homozygosity mapping followed by exon
enrichment and next-generation sequencing in 136 consanguineous families
(over 90% Iranian and less than 10% Turkish or Arabic) segregating
syndromic or nonsyndromic forms of autosomal recessive intellectual
disability. In family M017N, they identified a homozygous missense
mutation in the VRK1 gene (602168.0002) in 4 sibs with moderate to
severe intellectual disability and a phenotype compatible with
pontocerebellar hypoplasia. The parents, who were first cousins once
removed, were heterozygous for the mutation and had 3 healthy children.

*FIELD* RF
1. Barth, P. G.: Pontocerebellar hypoplasias: an overview of a group
of inherited neurodegenerative disorders with fetal onset. Brain
Dev. 15: 411-422, 1993.

2. Chou, S. M.; Gilbert, E. F.; Chun, R. W. M.; Laxova, R.; Tuffli,
G. A.; Sufit, R. L.; Krassikot, N.: Infantile olivopontocerebellar
atrophy with spinal muscular atrophy (infantile OPCA + SMA). Clin.
Neuropath. 9: 21-32, 1990.

3. Graham, J. M., Jr.; Spencer, A. H.; Grinberg, I.; Niesen, C. E.;
Platt, L. D.; Maya, M.; Namavar, Y.; Baas, F.; Dobyns, W. B.: Molecular
and neuroimaging findings in pontocerebellar hypoplasia type 2 (PCH2):
is prenatal diagnosis possible? Am. J. Med. Genet. 152A: 2268-2276,
2010.

4. Najmabadi, H.; Hu, H.; Garshasbi, M.; Zemojtel, T.; Abedini, S.
S.; Chen, W.; Hosseini, M.; Behjati, F.; Haas, S.; Jamali, P.; Zecha,
A.; Mohseni, M.; and 33 others: Deep sequencing reveals 50 novel
genes for recessive cognitive disorders. Nature 478: 57-63, 2011.

5. Norman, R. M.: Cerebellar hypoplasia in Werdnig-Hoffmann disease. Arch.
Dis. Child. 36: 96-101, 1961.

6. Renbaum, P.; Kellerman, E.; Jaron, R.; Geiger, D.; Segel, R.; Lee,
M.; King, M. C.; Levy-Lahad, E.: Spinal muscular atrophy with pontocerebellar
hypoplasia is caused by a mutation in the VRK1 gene. Am. J. Hum.
Genet. 85: 281-289, 2009.

7. Rudnik-Schoneborn, S.; Sztriha, L.; Aithala, G. R.; Houge, G.;
Laegreid, L. M.; Seeger, J.; Huppke, M.; Wirth, B.; Zerres, K.: Extended
phenotype of pontocerebellar hypoplasia with infantile spinal muscular
atrophy. Am. J. Med. Genet. 117A: 10-17, 2003.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Poor feeding

RESPIRATORY:
Respiratory insufficiency

SKELETAL:
Congenital contractures;
[Feet];
Foot deformities

MUSCLE, SOFT TISSUE:
Muscle weakness;
Fasciculations

NEUROLOGIC:
[Central nervous system];
Psychomotor retardation;
Hypotonia;
Weakness;
Hyperreflexia;
Ataxia;
Mental retardation;
Spinal cord anterior horn cell degeneration;
EMG shows neurogenic changes;
Pontocerebellar hypoplasia;
Hypoplasia of the ventral pons;
Neuronal loss in the brainstem;
Neuronal loss in basal ganglia;
Gliosis in the brainstem;
Gliosis in the basal ganglia

MISCELLANEOUS:
Onset prenatally or at birth;
Progressive disorder;
Death often occurs in childhood;
Clinically resembles spinal muscular atrophy-1 (SMA1, 253300)

MOLECULAR BASIS:
Caused by mutation in the vaccinia-related kinase 1 gene (VRK1, 602168.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 11/4/2009

*FIELD* CD
Cassandra L. Kniffin: 8/25/2003

*FIELD* ED
joanna: 10/22/2013
joanna: 12/3/2009
ckniffin: 11/4/2009
ckniffin: 8/25/2003

*FIELD* CN
Ada Hamosh - updated: 1/9/2012
Cassandra L. Kniffin - updated: 10/9/2009
Marla J. F. O'Neill - updated: 6/20/2006

*FIELD* CD
Victor A. McKusick: 3/4/2003

*FIELD* ED
carol: 12/06/2012
carol: 12/5/2012
ckniffin: 12/5/2012
ckniffin: 12/4/2012
carol: 6/8/2012
ckniffin: 6/7/2012
carol: 1/9/2012
wwang: 7/1/2011
ckniffin: 6/21/2011
carol: 4/23/2011
terry: 4/22/2011
wwang: 10/16/2009
ckniffin: 10/9/2009
alopez: 11/6/2008
alopez: 11/5/2008
alopez: 10/12/2007
wwang: 6/22/2006
terry: 6/20/2006
alopez: 3/17/2004
joanna: 8/26/2003
carol: 8/15/2003
ckniffin: 8/12/2003
terry: 7/31/2003
mgross: 3/4/2003