Full text data of DIS3L2
DIS3L2
(FAM6A)
[Confidence: low (only semi-automatic identification from reviews)]
DIS3-like exonuclease 2; hDIS3L2; 3.1.13.-
Note: presumably soluble (membrane word is not in UniProt keywords or features)
DIS3-like exonuclease 2; hDIS3L2; 3.1.13.-
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q8IYB7
ID DI3L2_HUMAN Reviewed; 885 AA.
AC Q8IYB7; Q53S79; Q580W6; Q5XKH0; Q69YG5; Q6AW99; Q7Z4T6; Q8N9K9;
read moreDT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 4.
DT 22-JAN-2014, entry version 90.
DE RecName: Full=DIS3-like exonuclease 2;
DE Short=hDIS3L2;
DE EC=3.1.13.-;
GN Name=DIS3L2; Synonyms=FAM6A;
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 3).
RC TISSUE=Cerebellum;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4), AND NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 71-885 (ISOFORM 5).
RC TISSUE=Testis, and Uterus;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RA Zan Q., Guo J.H., Li D., Yu L.;
RL Submitted (NOV-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT
RP SER-12.
RC TISSUE=Testis;
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 [6]
RP IDENTIFICATION.
RX PubMed=11352565; DOI=10.1006/geno.2000.6504;
RA Rump A., Kasper G., Hayes C., Wen G., Starke H., Liehr T., Lehmann R.,
RA Lagemann D., Rosenthal A.;
RT "Complex arrangement of genes within a 220-kb region of double-
RT duplicated DNA on human 2q37.1.";
RL Genomics 73:50-55(2001).
RN [7]
RP CHROMOSOMAL TRANSLOCATION.
RX PubMed=17373680; DOI=10.1002/humu.20511;
RA Bocciardi R., Giorda R., Buttgereit J., Gimelli S., Divizia M.T.,
RA Beri S., Garofalo S., Tavella S., Lerone M., Zuffardi O., Bader M.,
RA Ravazzolo R., Gimelli G.;
RT "Overexpression of the C-type natriuretic peptide (CNP) is associated
RT with overgrowth and bone anomalies in an individual with balanced
RT t(2;7) translocation.";
RL Hum. Mutat. 28:724-731(2007).
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-252, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-31, 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 [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [11]
RP SUBCELLULAR LOCATION, VARIANT PRLMNS TYR-489, VARIANTS GLY-483 AND
RP HIS-576, AND CHARACTERIZATION OF VARIANTS GLY-483 AND HIS-576.
RX PubMed=22306653; DOI=10.1038/ng.1071;
RA Astuti D., Morris M.R., Cooper W.N., Staals R.H., Wake N.C.,
RA Fews G.A., Gill H., Gentle D., Shuib S., Ricketts C.J., Cole T.,
RA van Essen A.J., van Lingen R.A., Neri G., Opitz J.M., Rump P.,
RA Stolte-Dijkstra I., Muller F., Pruijn G.J., Latif F., Maher E.R.;
RT "Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth
RT and Wilms tumor susceptibility.";
RL Nat. Genet. 44:277-284(2012).
RN [12]
RP FUNCTION, COFACTOR, SUBCELLULAR LOCATION, MUTAGENESIS OF ASP-391, AND
RP INTERACTION WITH XRN1.
RX PubMed=23756462; DOI=10.1038/emboj.2013.135;
RA Lubas M., Damgaard C.K., Tomecki R., Cysewski D., Jensen T.H.,
RA Dziembowski A.;
RT "Exonuclease hDIS3L2 specifies an exosome-independent 3'-5'
RT degradation pathway of human cytoplasmic mRNA.";
RL EMBO J. 32:1855-1868(2013).
CC -!- FUNCTION: 3'-5'-exoribonuclease that specifically recognizes RNAs
CC polyuridylated at their 3' end and mediates their degradation.
CC Component of an exosome-independent RNA degradation pathway that
CC mediates degradation of both mRNAs and miRNAs that have been
CC polyuridylated by a terminal uridylyltransferase, such as
CC ZCCHC11/TUT4. Mediates degradation of cytoplasmic mRNAs that have
CC been deadenylated and subsequently uridylated at their 3'.
CC Mediates degradation of uridylated pre-let-7 miRNAs, contributing
CC to the maintenance of embryonic stem (ES) cells. Essential for
CC correct mitosis, and negatively regulates cell proliferation.
CC -!- COFACTOR: Magnesium or manganese (Probable).
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, P-body.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=Q8IYB7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8IYB7-2; Sequence=VSP_030376, VSP_030378;
CC Note=May be produced at very low levels due to a premature stop
CC codon in the mRNA, leading to nonsense-mediated mRNA decay;
CC Name=3;
CC IsoId=Q8IYB7-3; Sequence=VSP_030375, VSP_030377;
CC Note=May be produced at very low levels due to a premature stop
CC codon in the mRNA, leading to nonsense-mediated mRNA decay;
CC Name=4;
CC IsoId=Q8IYB7-4; Sequence=VSP_030372, VSP_030373;
CC Name=5;
CC IsoId=Q8IYB7-5; Sequence=VSP_030371, VSP_030374;
CC Note=No experimental confirmation available;
CC -!- POLYMORPHISM: Disrupted by a t(2;7)(q37.1;q21.3) chromosomal
CC translocation found in a patient suffering from Marfanoid habitus
CC and skeletal anomalies. However, its absence does not seem to be
CC the cause of the disease.
CC -!- DISEASE: Perlman syndrome (PRLMNS) [MIM:267000]: An autosomal
CC recessive congenital overgrowth syndrome. Affected children are
CC large at birth, are hypotonic, and show organomegaly,
CC characteristic facial dysmorphisms (inverted V-shaped upper lip,
CC prominent forehead, deep-set eyes, broad and flat nasal bridge,
CC and low-set ears), renal anomalies (nephromegaly and
CC hydronephrosis), frequent neurodevelopmental delay, and high
CC neonatal mortality. Perlman syndrome is associated with a high
CC risk of Wilms tumor. Histologic examination of the kidneys in
CC affected children shows frequent nephroblastomatosis, which is a
CC precursor lesion for Wilms tumor. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the RNR ribonuclease family. DIS3L2
CC subfamily.
CC -!- CAUTION: Although assigned as two separate genes (DIS3L2 and
CC FAM6A), it is quite clear that the gene FAM6A described by
CC PubMed:11352565 is a fragmentary prediction of DIS3L2.
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DR EMBL; AK094293; BAC04324.1; -; mRNA.
DR EMBL; AL834174; CAH10694.1; -; mRNA.
DR EMBL; BX648325; CAH10545.1; -; mRNA.
DR EMBL; AF443854; AAP97321.1; -; mRNA.
DR EMBL; AC019130; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC068134; AAY24086.1; -; Genomic_DNA.
DR EMBL; AC093374; AAX82031.1; -; Genomic_DNA.
DR EMBL; AC138658; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC026166; AAH26166.1; -; mRNA.
DR EMBL; BC036113; AAH36113.2; -; mRNA.
DR RefSeq; NP_001244210.1; NM_001257281.1.
DR RefSeq; NP_001244211.1; NM_001257282.1.
DR RefSeq; NP_689596.4; NM_152383.4.
DR UniGene; Hs.732236; -.
DR ProteinModelPortal; Q8IYB7; -.
DR SMR; Q8IYB7; 50-122, 182-800.
DR IntAct; Q8IYB7; 4.
DR MINT; MINT-1386910; -.
DR STRING; 9606.ENSP00000315569; -.
DR PhosphoSite; Q8IYB7; -.
DR DMDM; 296439471; -.
DR PaxDb; Q8IYB7; -.
DR PRIDE; Q8IYB7; -.
DR DNASU; 129563; -.
DR Ensembl; ENST00000273009; ENSP00000273009; ENSG00000144535.
DR Ensembl; ENST00000325385; ENSP00000315569; ENSG00000144535.
DR Ensembl; ENST00000360410; ENSP00000353584; ENSG00000144535.
DR Ensembl; ENST00000390005; ENSP00000374655; ENSG00000144535.
DR Ensembl; ENST00000409307; ENSP00000386799; ENSG00000144535.
DR Ensembl; ENST00000409401; ENSP00000386594; ENSG00000144535.
DR Ensembl; ENST00000433430; ENSP00000391175; ENSG00000144535.
DR Ensembl; ENST00000445090; ENSP00000388999; ENSG00000144535.
DR GeneID; 129563; -.
DR KEGG; hsa:129563; -.
DR UCSC; uc010fxz.3; human.
DR CTD; 129563; -.
DR GeneCards; GC02P232825; -.
DR H-InvDB; HIX0002923; -.
DR HGNC; HGNC:28648; DIS3L2.
DR HPA; HPA035797; -.
DR MIM; 267000; phenotype.
DR MIM; 614184; gene.
DR neXtProt; NX_Q8IYB7; -.
DR Orphanet; 654; Nephroblastoma.
DR Orphanet; 2849; Perlman syndrome.
DR PharmGKB; PA162383714; -.
DR eggNOG; COG0557; -.
DR HOVERGEN; HBG107810; -.
DR InParanoid; Q8IYB7; -.
DR OMA; DQAQFRH; -.
DR OrthoDB; EOG7WDN1X; -.
DR ChiTaRS; DIS3L2; human.
DR GeneWiki; DIS3L2_(gene); -.
DR GenomeRNAi; 129563; -.
DR NextBio; 82609; -.
DR PRO; PR:Q8IYB7; -.
DR ArrayExpress; Q8IYB7; -.
DR Bgee; Q8IYB7; -.
DR CleanEx; HS_DIS3L2; -.
DR Genevestigator; Q8IYB7; -.
DR GO; GO:0000932; C:cytoplasmic mRNA processing body; IDA:UniProtKB.
DR GO; GO:0005844; C:polysome; TAS:UniProtKB.
DR GO; GO:0000175; F:3'-5'-exoribonuclease activity; IDA:UniProtKB.
DR GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0010587; P:miRNA catabolic process; ISS:UniProtKB.
DR GO; GO:0051306; P:mitotic sister chromatid separation; IMP:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IMP:UniProtKB.
DR GO; GO:0000291; P:nuclear-transcribed mRNA catabolic process, exonucleolytic; IMP:UniProtKB.
DR GO; GO:1990074; P:polyuridylation-dependent mRNA catabolic process; ISS:UniProtKB.
DR GO; GO:0019827; P:stem cell maintenance; ISS:UniProtKB.
DR HAMAP; MF_03045; DIS3L2; 1; -.
DR InterPro; IPR028591; DIS3L2.
DR InterPro; IPR012340; NA-bd_OB-fold.
DR InterPro; IPR022966; RNase_II/R_CS.
DR SUPFAM; SSF50249; SSF50249; 4.
DR PROSITE; PS01175; RIBONUCLEASE_II; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Cell cycle; Cell division;
KW Complete proteome; Cytoplasm; Disease mutation; Exonuclease;
KW Hydrolase; Magnesium; Manganese; Mitosis; Nuclease; Phosphoprotein;
KW Polymorphism; Reference proteome; RNA-binding; Tumor suppressor.
FT CHAIN 1 885 DIS3-like exonuclease 2.
FT /FTId=PRO_0000314817.
FT MOD_RES 31 31 Phosphoserine.
FT MOD_RES 252 252 N6-acetyllysine.
FT MOD_RES 875 875 Phosphoserine (By similarity).
FT VAR_SEQ 201 356 GREDGDAPVTKDETTCISQDTRALSEKSLQRSAKVVYILEK
FT KHSRAATGFLKLLADKNSELFRKYALFSPSDHRVPRIYVPL
FT KDCPQDFVARPKDYANTLFICRIVDWKEDCNFALGQLAKSL
FT GQAGEIEPETEGILTEYGVDFSDFSSEVLECLP -> DNEI
FT EAQRSSWAYPVSHRKSEERMVMHRLQKMRPPAFHKTQELYR
FT RNPCKDQQRWFTSWRKNILEQQPASSNSWLIRTANCLGNTP
FT CFLPQTTECLEFMCLSRTVPRTLWHGLKIMPTHCSSAALWT
FT GRRTAILPWGSWLRVLGRLVKLSLKQKEY (in isoform
FT 5).
FT /FTId=VSP_030371.
FT VAR_SEQ 236 249 VYILEKKHSRAATG -> IAYRFSPRVQMAFT (in
FT isoform 4).
FT /FTId=VSP_030372.
FT VAR_SEQ 250 885 Missing (in isoform 4).
FT /FTId=VSP_030373.
FT VAR_SEQ 357 885 Missing (in isoform 5).
FT /FTId=VSP_030374.
FT VAR_SEQ 528 603 AVLNLHGIAKQLRQQRFVDGALRLDQLKLAFTLDHETGLPQ
FT GCHIYEYRESNKLVEEFMLLANMAVAHKIHRAFPE -> QN
FT ADKDGAAHLQASHSPSAEDAEAQPSTEERLPETRGICDRDP
FT DTRLFFLQQQSRVLEAKPQNTIRVEEQTTQLQI (in
FT isoform 3).
FT /FTId=VSP_030375.
FT VAR_SEQ 581 619 LVEEFMLLANMAVAHKIHRAFPEQALLRRHPPPQTRMLS
FT -> PCCAGTPRPKQGCSVTWWNSATRWGCPWTSAPQEPSIK
FT A (in isoform 2).
FT /FTId=VSP_030376.
FT VAR_SEQ 604 885 Missing (in isoform 3).
FT /FTId=VSP_030377.
FT VAR_SEQ 620 885 Missing (in isoform 2).
FT /FTId=VSP_030378.
FT VARIANT 12 12 P -> S (in dbSNP:rs723044).
FT /FTId=VAR_038059.
FT VARIANT 483 483 R -> G (probable disease-associated
FT mutation found in a patient with Wilms
FT tumor; does not suppress anchorage-
FT independent cell growth;
FT dbSNP:rs186865544).
FT /FTId=VAR_067577.
FT VARIANT 489 489 C -> Y (in PRLMNS).
FT /FTId=VAR_067578.
FT VARIANT 576 576 R -> H (probable disease-associated
FT mutation found in a patient with Wilms
FT tumor; does not suppress anchorage-
FT independent cell growth).
FT /FTId=VAR_067579.
FT MUTAGEN 391 391 D->N: Loss of exoribonuclease activity.
FT CONFLICT 16 16 P -> H (in Ref. 5; AAH36113/AAH26166).
FT CONFLICT 96 96 I -> F (in Ref. 3; AAP97321).
SQ SEQUENCE 885 AA; 99279 MW; 0F6757DCD1975412 CRC64;
MSHPDYRMNL RPLGTPRGVS AVAGPHDIGA SPGDKKSKNR STRGKKKSIF ETYMSKEDVS
EGLKRGTLIQ GVLRINPKKF HEAFIPSPDG DRDIFIDGVV ARNRALNGDL VVVKLLPEEH
WKVVKPESND KETEAAYESD IPEELCGHHL PQQSLKSYND SPDVIVEAQF DGSDSEDGHG
ITQNVLVDGV KKLSVCVSEK GREDGDAPVT KDETTCISQD TRALSEKSLQ RSAKVVYILE
KKHSRAATGF LKLLADKNSE LFRKYALFSP SDHRVPRIYV PLKDCPQDFV ARPKDYANTL
FICRIVDWKE DCNFALGQLA KSLGQAGEIE PETEGILTEY GVDFSDFSSE VLECLPQGLP
WTIPPEEFSK RRDLRKDCIF TIDPSTARDL DDALSCKPLA DGNFKVGVHI ADVSYFVPEG
SDLDKVAAER ATSVYLVQKV VPMLPRLLCE ELCSLNPMSD KLTFSVIWTL TPEGKILDEW
FGRTIIRSCT KLSYEHAQSM IESPTEKIPA KELPPISPEH SSEEVHQAVL NLHGIAKQLR
QQRFVDGALR LDQLKLAFTL DHETGLPQGC HIYEYRESNK LVEEFMLLAN MAVAHKIHRA
FPEQALLRRH PPPQTRMLSD LVEFCDQMGL PVDFSSAGAL NKSLTQTFGD DKYSLARKEV
LTNMCSRPMQ MALYFCSGLL QDPAQFRHYA LNVPLYTHFT SPIRRFADVL VHRLLAAALG
YRERLDMAPD TLQKQADHCN DRRMASKRVQ ELSTSLFFAV LVKESGPLES EAMVMGILKQ
AFDVLVLRYG VQKRIYCNAL ALRSHHFQKV GKKPELTLVW EPEDMEQEPA QQVITIFSLV
EVVLQAESTA LKYSAILKRP GTQGHLGPEK EEEESDGEPE DSSTS
//
ID DI3L2_HUMAN Reviewed; 885 AA.
AC Q8IYB7; Q53S79; Q580W6; Q5XKH0; Q69YG5; Q6AW99; Q7Z4T6; Q8N9K9;
read moreDT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 4.
DT 22-JAN-2014, entry version 90.
DE RecName: Full=DIS3-like exonuclease 2;
DE Short=hDIS3L2;
DE EC=3.1.13.-;
GN Name=DIS3L2; Synonyms=FAM6A;
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 3).
RC TISSUE=Cerebellum;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4), AND NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 71-885 (ISOFORM 5).
RC TISSUE=Testis, and Uterus;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RA Zan Q., Guo J.H., Li D., Yu L.;
RL Submitted (NOV-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT
RP SER-12.
RC TISSUE=Testis;
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 [6]
RP IDENTIFICATION.
RX PubMed=11352565; DOI=10.1006/geno.2000.6504;
RA Rump A., Kasper G., Hayes C., Wen G., Starke H., Liehr T., Lehmann R.,
RA Lagemann D., Rosenthal A.;
RT "Complex arrangement of genes within a 220-kb region of double-
RT duplicated DNA on human 2q37.1.";
RL Genomics 73:50-55(2001).
RN [7]
RP CHROMOSOMAL TRANSLOCATION.
RX PubMed=17373680; DOI=10.1002/humu.20511;
RA Bocciardi R., Giorda R., Buttgereit J., Gimelli S., Divizia M.T.,
RA Beri S., Garofalo S., Tavella S., Lerone M., Zuffardi O., Bader M.,
RA Ravazzolo R., Gimelli G.;
RT "Overexpression of the C-type natriuretic peptide (CNP) is associated
RT with overgrowth and bone anomalies in an individual with balanced
RT t(2;7) translocation.";
RL Hum. Mutat. 28:724-731(2007).
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-252, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-31, 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 [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [11]
RP SUBCELLULAR LOCATION, VARIANT PRLMNS TYR-489, VARIANTS GLY-483 AND
RP HIS-576, AND CHARACTERIZATION OF VARIANTS GLY-483 AND HIS-576.
RX PubMed=22306653; DOI=10.1038/ng.1071;
RA Astuti D., Morris M.R., Cooper W.N., Staals R.H., Wake N.C.,
RA Fews G.A., Gill H., Gentle D., Shuib S., Ricketts C.J., Cole T.,
RA van Essen A.J., van Lingen R.A., Neri G., Opitz J.M., Rump P.,
RA Stolte-Dijkstra I., Muller F., Pruijn G.J., Latif F., Maher E.R.;
RT "Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth
RT and Wilms tumor susceptibility.";
RL Nat. Genet. 44:277-284(2012).
RN [12]
RP FUNCTION, COFACTOR, SUBCELLULAR LOCATION, MUTAGENESIS OF ASP-391, AND
RP INTERACTION WITH XRN1.
RX PubMed=23756462; DOI=10.1038/emboj.2013.135;
RA Lubas M., Damgaard C.K., Tomecki R., Cysewski D., Jensen T.H.,
RA Dziembowski A.;
RT "Exonuclease hDIS3L2 specifies an exosome-independent 3'-5'
RT degradation pathway of human cytoplasmic mRNA.";
RL EMBO J. 32:1855-1868(2013).
CC -!- FUNCTION: 3'-5'-exoribonuclease that specifically recognizes RNAs
CC polyuridylated at their 3' end and mediates their degradation.
CC Component of an exosome-independent RNA degradation pathway that
CC mediates degradation of both mRNAs and miRNAs that have been
CC polyuridylated by a terminal uridylyltransferase, such as
CC ZCCHC11/TUT4. Mediates degradation of cytoplasmic mRNAs that have
CC been deadenylated and subsequently uridylated at their 3'.
CC Mediates degradation of uridylated pre-let-7 miRNAs, contributing
CC to the maintenance of embryonic stem (ES) cells. Essential for
CC correct mitosis, and negatively regulates cell proliferation.
CC -!- COFACTOR: Magnesium or manganese (Probable).
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, P-body.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=Q8IYB7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8IYB7-2; Sequence=VSP_030376, VSP_030378;
CC Note=May be produced at very low levels due to a premature stop
CC codon in the mRNA, leading to nonsense-mediated mRNA decay;
CC Name=3;
CC IsoId=Q8IYB7-3; Sequence=VSP_030375, VSP_030377;
CC Note=May be produced at very low levels due to a premature stop
CC codon in the mRNA, leading to nonsense-mediated mRNA decay;
CC Name=4;
CC IsoId=Q8IYB7-4; Sequence=VSP_030372, VSP_030373;
CC Name=5;
CC IsoId=Q8IYB7-5; Sequence=VSP_030371, VSP_030374;
CC Note=No experimental confirmation available;
CC -!- POLYMORPHISM: Disrupted by a t(2;7)(q37.1;q21.3) chromosomal
CC translocation found in a patient suffering from Marfanoid habitus
CC and skeletal anomalies. However, its absence does not seem to be
CC the cause of the disease.
CC -!- DISEASE: Perlman syndrome (PRLMNS) [MIM:267000]: An autosomal
CC recessive congenital overgrowth syndrome. Affected children are
CC large at birth, are hypotonic, and show organomegaly,
CC characteristic facial dysmorphisms (inverted V-shaped upper lip,
CC prominent forehead, deep-set eyes, broad and flat nasal bridge,
CC and low-set ears), renal anomalies (nephromegaly and
CC hydronephrosis), frequent neurodevelopmental delay, and high
CC neonatal mortality. Perlman syndrome is associated with a high
CC risk of Wilms tumor. Histologic examination of the kidneys in
CC affected children shows frequent nephroblastomatosis, which is a
CC precursor lesion for Wilms tumor. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the RNR ribonuclease family. DIS3L2
CC subfamily.
CC -!- CAUTION: Although assigned as two separate genes (DIS3L2 and
CC FAM6A), it is quite clear that the gene FAM6A described by
CC PubMed:11352565 is a fragmentary prediction of DIS3L2.
CC -----------------------------------------------------------------------
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DR EMBL; AK094293; BAC04324.1; -; mRNA.
DR EMBL; AL834174; CAH10694.1; -; mRNA.
DR EMBL; BX648325; CAH10545.1; -; mRNA.
DR EMBL; AF443854; AAP97321.1; -; mRNA.
DR EMBL; AC019130; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC068134; AAY24086.1; -; Genomic_DNA.
DR EMBL; AC093374; AAX82031.1; -; Genomic_DNA.
DR EMBL; AC138658; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC026166; AAH26166.1; -; mRNA.
DR EMBL; BC036113; AAH36113.2; -; mRNA.
DR RefSeq; NP_001244210.1; NM_001257281.1.
DR RefSeq; NP_001244211.1; NM_001257282.1.
DR RefSeq; NP_689596.4; NM_152383.4.
DR UniGene; Hs.732236; -.
DR ProteinModelPortal; Q8IYB7; -.
DR SMR; Q8IYB7; 50-122, 182-800.
DR IntAct; Q8IYB7; 4.
DR MINT; MINT-1386910; -.
DR STRING; 9606.ENSP00000315569; -.
DR PhosphoSite; Q8IYB7; -.
DR DMDM; 296439471; -.
DR PaxDb; Q8IYB7; -.
DR PRIDE; Q8IYB7; -.
DR DNASU; 129563; -.
DR Ensembl; ENST00000273009; ENSP00000273009; ENSG00000144535.
DR Ensembl; ENST00000325385; ENSP00000315569; ENSG00000144535.
DR Ensembl; ENST00000360410; ENSP00000353584; ENSG00000144535.
DR Ensembl; ENST00000390005; ENSP00000374655; ENSG00000144535.
DR Ensembl; ENST00000409307; ENSP00000386799; ENSG00000144535.
DR Ensembl; ENST00000409401; ENSP00000386594; ENSG00000144535.
DR Ensembl; ENST00000433430; ENSP00000391175; ENSG00000144535.
DR Ensembl; ENST00000445090; ENSP00000388999; ENSG00000144535.
DR GeneID; 129563; -.
DR KEGG; hsa:129563; -.
DR UCSC; uc010fxz.3; human.
DR CTD; 129563; -.
DR GeneCards; GC02P232825; -.
DR H-InvDB; HIX0002923; -.
DR HGNC; HGNC:28648; DIS3L2.
DR HPA; HPA035797; -.
DR MIM; 267000; phenotype.
DR MIM; 614184; gene.
DR neXtProt; NX_Q8IYB7; -.
DR Orphanet; 654; Nephroblastoma.
DR Orphanet; 2849; Perlman syndrome.
DR PharmGKB; PA162383714; -.
DR eggNOG; COG0557; -.
DR HOVERGEN; HBG107810; -.
DR InParanoid; Q8IYB7; -.
DR OMA; DQAQFRH; -.
DR OrthoDB; EOG7WDN1X; -.
DR ChiTaRS; DIS3L2; human.
DR GeneWiki; DIS3L2_(gene); -.
DR GenomeRNAi; 129563; -.
DR NextBio; 82609; -.
DR PRO; PR:Q8IYB7; -.
DR ArrayExpress; Q8IYB7; -.
DR Bgee; Q8IYB7; -.
DR CleanEx; HS_DIS3L2; -.
DR Genevestigator; Q8IYB7; -.
DR GO; GO:0000932; C:cytoplasmic mRNA processing body; IDA:UniProtKB.
DR GO; GO:0005844; C:polysome; TAS:UniProtKB.
DR GO; GO:0000175; F:3'-5'-exoribonuclease activity; IDA:UniProtKB.
DR GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0010587; P:miRNA catabolic process; ISS:UniProtKB.
DR GO; GO:0051306; P:mitotic sister chromatid separation; IMP:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IMP:UniProtKB.
DR GO; GO:0000291; P:nuclear-transcribed mRNA catabolic process, exonucleolytic; IMP:UniProtKB.
DR GO; GO:1990074; P:polyuridylation-dependent mRNA catabolic process; ISS:UniProtKB.
DR GO; GO:0019827; P:stem cell maintenance; ISS:UniProtKB.
DR HAMAP; MF_03045; DIS3L2; 1; -.
DR InterPro; IPR028591; DIS3L2.
DR InterPro; IPR012340; NA-bd_OB-fold.
DR InterPro; IPR022966; RNase_II/R_CS.
DR SUPFAM; SSF50249; SSF50249; 4.
DR PROSITE; PS01175; RIBONUCLEASE_II; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Cell cycle; Cell division;
KW Complete proteome; Cytoplasm; Disease mutation; Exonuclease;
KW Hydrolase; Magnesium; Manganese; Mitosis; Nuclease; Phosphoprotein;
KW Polymorphism; Reference proteome; RNA-binding; Tumor suppressor.
FT CHAIN 1 885 DIS3-like exonuclease 2.
FT /FTId=PRO_0000314817.
FT MOD_RES 31 31 Phosphoserine.
FT MOD_RES 252 252 N6-acetyllysine.
FT MOD_RES 875 875 Phosphoserine (By similarity).
FT VAR_SEQ 201 356 GREDGDAPVTKDETTCISQDTRALSEKSLQRSAKVVYILEK
FT KHSRAATGFLKLLADKNSELFRKYALFSPSDHRVPRIYVPL
FT KDCPQDFVARPKDYANTLFICRIVDWKEDCNFALGQLAKSL
FT GQAGEIEPETEGILTEYGVDFSDFSSEVLECLP -> DNEI
FT EAQRSSWAYPVSHRKSEERMVMHRLQKMRPPAFHKTQELYR
FT RNPCKDQQRWFTSWRKNILEQQPASSNSWLIRTANCLGNTP
FT CFLPQTTECLEFMCLSRTVPRTLWHGLKIMPTHCSSAALWT
FT GRRTAILPWGSWLRVLGRLVKLSLKQKEY (in isoform
FT 5).
FT /FTId=VSP_030371.
FT VAR_SEQ 236 249 VYILEKKHSRAATG -> IAYRFSPRVQMAFT (in
FT isoform 4).
FT /FTId=VSP_030372.
FT VAR_SEQ 250 885 Missing (in isoform 4).
FT /FTId=VSP_030373.
FT VAR_SEQ 357 885 Missing (in isoform 5).
FT /FTId=VSP_030374.
FT VAR_SEQ 528 603 AVLNLHGIAKQLRQQRFVDGALRLDQLKLAFTLDHETGLPQ
FT GCHIYEYRESNKLVEEFMLLANMAVAHKIHRAFPE -> QN
FT ADKDGAAHLQASHSPSAEDAEAQPSTEERLPETRGICDRDP
FT DTRLFFLQQQSRVLEAKPQNTIRVEEQTTQLQI (in
FT isoform 3).
FT /FTId=VSP_030375.
FT VAR_SEQ 581 619 LVEEFMLLANMAVAHKIHRAFPEQALLRRHPPPQTRMLS
FT -> PCCAGTPRPKQGCSVTWWNSATRWGCPWTSAPQEPSIK
FT A (in isoform 2).
FT /FTId=VSP_030376.
FT VAR_SEQ 604 885 Missing (in isoform 3).
FT /FTId=VSP_030377.
FT VAR_SEQ 620 885 Missing (in isoform 2).
FT /FTId=VSP_030378.
FT VARIANT 12 12 P -> S (in dbSNP:rs723044).
FT /FTId=VAR_038059.
FT VARIANT 483 483 R -> G (probable disease-associated
FT mutation found in a patient with Wilms
FT tumor; does not suppress anchorage-
FT independent cell growth;
FT dbSNP:rs186865544).
FT /FTId=VAR_067577.
FT VARIANT 489 489 C -> Y (in PRLMNS).
FT /FTId=VAR_067578.
FT VARIANT 576 576 R -> H (probable disease-associated
FT mutation found in a patient with Wilms
FT tumor; does not suppress anchorage-
FT independent cell growth).
FT /FTId=VAR_067579.
FT MUTAGEN 391 391 D->N: Loss of exoribonuclease activity.
FT CONFLICT 16 16 P -> H (in Ref. 5; AAH36113/AAH26166).
FT CONFLICT 96 96 I -> F (in Ref. 3; AAP97321).
SQ SEQUENCE 885 AA; 99279 MW; 0F6757DCD1975412 CRC64;
MSHPDYRMNL RPLGTPRGVS AVAGPHDIGA SPGDKKSKNR STRGKKKSIF ETYMSKEDVS
EGLKRGTLIQ GVLRINPKKF HEAFIPSPDG DRDIFIDGVV ARNRALNGDL VVVKLLPEEH
WKVVKPESND KETEAAYESD IPEELCGHHL PQQSLKSYND SPDVIVEAQF DGSDSEDGHG
ITQNVLVDGV KKLSVCVSEK GREDGDAPVT KDETTCISQD TRALSEKSLQ RSAKVVYILE
KKHSRAATGF LKLLADKNSE LFRKYALFSP SDHRVPRIYV PLKDCPQDFV ARPKDYANTL
FICRIVDWKE DCNFALGQLA KSLGQAGEIE PETEGILTEY GVDFSDFSSE VLECLPQGLP
WTIPPEEFSK RRDLRKDCIF TIDPSTARDL DDALSCKPLA DGNFKVGVHI ADVSYFVPEG
SDLDKVAAER ATSVYLVQKV VPMLPRLLCE ELCSLNPMSD KLTFSVIWTL TPEGKILDEW
FGRTIIRSCT KLSYEHAQSM IESPTEKIPA KELPPISPEH SSEEVHQAVL NLHGIAKQLR
QQRFVDGALR LDQLKLAFTL DHETGLPQGC HIYEYRESNK LVEEFMLLAN MAVAHKIHRA
FPEQALLRRH PPPQTRMLSD LVEFCDQMGL PVDFSSAGAL NKSLTQTFGD DKYSLARKEV
LTNMCSRPMQ MALYFCSGLL QDPAQFRHYA LNVPLYTHFT SPIRRFADVL VHRLLAAALG
YRERLDMAPD TLQKQADHCN DRRMASKRVQ ELSTSLFFAV LVKESGPLES EAMVMGILKQ
AFDVLVLRYG VQKRIYCNAL ALRSHHFQKV GKKPELTLVW EPEDMEQEPA QQVITIFSLV
EVVLQAESTA LKYSAILKRP GTQGHLGPEK EEEESDGEPE DSSTS
//
MIM
267000
*RECORD*
*FIELD* NO
267000
*FIELD* TI
#267000 PERLMAN SYNDROME; PRLMNS
;;RENAL HAMARTOMAS, NEPHROBLASTOMATOSIS, AND FETAL GIGANTISM;;
read moreNEPHROBLASTOMATOSIS, FETAL ASCITES, MACROSOMIA, AND WILMS TUMOR
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
Perlman syndrome is caused by homozygous or compound heterozygous
mutation in the DIS3L2 gene (614184) on chromosome 2q37.2.
DESCRIPTION
Perlman syndrome is an autosomal recessive congenital overgrowth
syndrome with similarities to Beckwith-Wiedemann syndrome (BWS; 130650).
Affected children are large at birth, are hypotonic, and show
organomegaly, characteristic facial dysmorphisms (inverted V-shaped
upper lip, prominent forehead, deep-set eyes, broad and flat nasal
bridge, and low-set ears), renal anomalies (nephromegaly and
hydronephrosis), frequent neurodevelopmental delay, and high neonatal
mortality. Perlman syndrome is associated with a high risk of Wilms
tumor, with a 64% incidence in infants surviving beyond the neonatal
period. The tumor is diagnosed at an earlier age in these individuals
compared with sporadic cases (less than 2 years and 3-4 years of age,
respectively), and there is a high frequency of bilateral tumors (55%).
Histologic examination of the kidneys in children with Perlman syndrome
shows frequent nephroblastomatosis, which is a precursor lesion for
Wilms tumor (summary by Astuti et al., 2012).
CLINICAL FEATURES
Liban and Kozenitzky (1970) and Perlman et al. (1973) described 5
offspring, of Jewish-Yemenite second-cousin parents, with a disorder
manifested by large birth size, bilateral renal hamartomas with or
without nephroblastomatosis, hypertrophy of the islets of Langerhans,
and unusual facies. The longest survival was 27 days. There are some
obvious similarities to the Beckwith-Wiedemann syndrome (130650) but the
facies is thought to be characteristic with depressed nasal bridge and
anteverted upper lip. Perlman et al. (1975) reported a sixth offspring
from the Jewish-Yemenite family with fetal gigantism, renal hamartomas,
and nephroblastomatosis, in whom Wilms tumor (194070) occurred. Perlman
(1986) published very instructive photographs of the 2 sibs that he and
his colleagues reported in 1973 and 1975. The remarkably similar and
distinctive facies consisted of round fullness, hypotonic appearance
with open mouth, a long upper lip with inverted V-shape, upsweep of
anterior scalp hair, and mild micrognathia.
Neri et al. (1984) reported an affected brother and sister with
unaffected, unrelated parents. The brother died suddenly at 8 months of
age after a seizure during an apneic episode. His sister, who underwent
surgery for Wilms tumor (194070) and removal of a recurrence at 4.5 and
5.5 years of age, respectively, with subsequent removal of a pulmonary
metastasis and hamartoma at 6.5 years of age, was alive at 12 years of
age. Hyperinsulinism is probably an important feature and may be a
preventable cause of death. The cases of Greenberg et al. (1984, 1985,
1986) were in 2 sibs with polyhydramnios, fetal ascites, abdominal
muscular hypoplasia, visceromegaly, and subsequent development of
bilateral Wilms tumor in one of them. This disorder should be considered
in the differential diagnosis of fetal ascites without hydrops.
Dao et al. (1987) studied chromosome 11p markers in a patient with this
syndrome and found the same loss of 11p DNA sequences that occurs in
Wilms tumor. Genetic differences between 2 tumors indicated that they
developed independently, the results of different genetic events.
Greenberg et al. (1988) reported an infant with manifestations of
Perlman syndrome, including polyhydramnios, macrosomia, bilateral
nephromegaly with nephroblastomatosis, visceromegaly, and
cryptorchidism. The patient also had diaphragmatic hernia and
interrupted aortic arch, suggesting that these may be findings of
Perlman syndrome.
Hamel et al. (1989) described additional features of volvulus and distal
ileal atresia as well as agenesis of the corpus callosum. From a study
of 11p markers, they found no evidence of rearrangements. Because of the
overlapping of clinical features with the Beckwith-Wiedemann syndrome,
the findings of a cytogenetic abnormality of chromosome 11 is of
interest.
Chernos et al. (1990) described a newborn with macroglossia and
bilateral hydronephrosis which had been diagnosed in utero. The infant
had prominent forehead, broad flat facies, hypertelorism, bilateral
epicanthic folds, deep-set eyes, a short upturned nose with wide
nostrils, and prominent upper lip. Cytogenetic studies demonstrated an
extra band on the tip of the short arm of one chromosome 11 which was
G-dark, Q-bright, and C-negative.
Henneveld et al. (1999) reported 4 patients from 3 Dutch families with
Perlman syndrome. All had typical manifestations, including macrosomia,
nephromegaly with renal dysplasia, hypotonia, and characteristic facies.
Additional features included dextroposition of the heart (1 patient),
hepatic fibrosis with porto-portal bridging (1 patient), volvulus and
intestinal atresia (1 patient), choroid plexus hemangiomas (2 patients),
agenesis of the corpus callosum (1 patient), and cleft palate (1
patient). All 4 died within the first year of life. Two patients were
brother and sister, supporting the hypothesis that this condition is
inherited in an autosomal recessive manner.
Schilke et al. (2000) described a neonate presenting with
polyhydramnios; macrosomia; macrocephaly; visceromegaly including
bilateral nephromegaly, hepatomegaly, and cardiomegaly; thymus
hyperplasia; cryptorchidism; generalized muscle hypotonia; and a
distinctive facial appearance. The clinical course was marked by severe
neurodevelopmental deficits combined with progressive respiratory
decompensation, leading to death at the age of 6 months. MRI disclosed a
generalized cerebral atrophy with a marked deficit of the white matter.
Renal ultrasound and MRI showed markedly enlarged kidneys with multiple
small cystic lesions, a pattern indistinguishable from polycystic kidney
disease. The postmortem kidney biopsy showed dysplastic changes,
microcysts, and a focal nephrogenic rest, characteristic features of the
Perlman syndrome. The parents were nonconsanguineous, healthy Albanians.
Piccione et al. (2005) reported the 9-year follow-up of a girl with
Perlman syndrome. She was born of nonconsanguineous parents by cesarean
section due to polyhydramnios and at birth was noted to have macrosomia,
macrocephaly, prominent forehead, full round face, deeply set eyes,
hypertelorism, epicanthic folds, broad flat nasal bridge, anteverted
upper lip, highly arched palate, dysplastic ears, and axial hypotonia,
but no organomegaly. At 6 months of age she was noted to have mild
hepatosplenomegaly and bilateral nephromegaly; Wilms tumor was diagnosed
at 20 months of age. When seen at age 9, she had macrocephaly, severe
right convex dorsal and left convex lumbar scoliosis, lumbar
hyperlordosis and asymmetry of the iliac crests, and prominent
xiphisternum. Psychomotor development was normal.
Alessandri et al. (2008) reported an infant with Perlman syndrome who
died at 2 days of age. Prenatal ultrasound showed enlarged kidneys and
marked ascites. After birth, she was found to have macrosomia, abdominal
distention, nephromegaly, hypoplastic thorax, characteristic face with
depressed nasal bridge, deep-set eyes, low-set dysplastic ears and
micrognathia. Renal biopsy showed bilateral nephroblastomatosis. A
previous pregnancy resulted in an infant who rapidly expired after birth
and probably had the same syndrome. Alessandri et al. (2008) reviewed 28
patients with typical Perlman syndrome and concluded that there is a
high neonatal mortality rate. Most affected infants developed
respiratory distress with refractory hypoxemia and/or renal failure and
died within the first hours or days of life.
MAPPING
In a consanguineous Pakistani kindred with Perlman syndrome, in which
mutation in the IGF2 (147470) and IGF2R (147280) candidate genes had
been excluded, Astuti et al. (2012) performed autozygosity mapping by
genomewide SNP genotyping and identified 8 regions of extended
homozygosity, including a 43-cM (28-Mb) region on chromosome 2q.
Analysis of 3 affected individuals from 2 potentially consanguineous
Dutch kindreds with Perlman syndrome, previously reported by Henneveld
et al. (1999), confirmed the autozygous region at 2q37 and narrowed it
to a 4.8-cM (2.1-Mb) interval between dbSNP rs1992188 and dbSNP
rs1104953.
MOLECULAR GENETICS
In a consanguineous Pakistani kindred and 2 Dutch kindreds with Perlman
syndrome mapping to chromosome 2q37, Astuti et al. (2012) analyzed 36
candidate genes and identified a failure to amplify exons 6 and 9,
respectively, of the DIS3L2 gene (614184). Further investigation
revealed that affected individuals in the Pakistani family were
homozygous for an 82.8-kb deletion in DIS3L2 (614184.0001), whereas
patients from the 2 Dutch families previously studied by Henneveld et
al. (1999), as well as an unrelated Dutch patient, were homozygous for
an approximately 22-kb deletion (614184.0002). Analysis of DIS3L2 in
cell lines from 2 additional unrelated children with Perlman syndrome, 1
of whom was the sister previously studied by Neri et al. (1984),
revealed compound heterozygous mutations (614184.0002-614184.0004).
*FIELD* RF
1. Alessandri, J.-L.; Cuillier, F.; Ramful, D.; Ernould, S.; Robin,
S.; de Napoli-Cocci, S.; Riviere, J.-P.; Rossignol, S.: Perlman syndrome:
report, prenatal findings and review. Am. J. Med. Genet. 146A: 2532-2537,
2008.
2. Astuti, D.; Morris, M. R.; Cooper, W. N.; Staals, R. H. J.; Wake,
N. C.; Fews, G. A.; Gill, H.; Gentle, D.; Shuib, S.; Ricketts, C.
J.; Cole, T.; van Essen, A. J.; and 9 others: Germline mutations
in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor
susceptibility. Nature Genet. 44: 277-284, 2012.
3. Chernos, J. E.; Fowlow, S. B.; Cox, D. M.: A case of Perlman syndrome
associated with a cytogenetic abnormality of chromosome 11. (Abstract) Am.
J. Hum. Genet. 47 (suppl.): A28 only, 1990.
4. Dao, D. D.; Schroeder, W. T.; Chao, L.-Y.; Kikuchi, H.; Strong,
L. C.; Riccardi, V. M.; Pathak, S.; Nichols, W. W.; Lewis, W. H.;
Saunders, G. F.: Genetic mechanisms of tumor-specific loss of 11p
DNA sequences in Wilms tumor. Am. J. Hum. Genet. 41: 202-217, 1987.
5. Greenberg, F.; Copeland, K.; Gresik, M. V.: Expanding the spectrum
of the Perlman syndrome. Am. J. Med. Genet. 29: 773-776, 1988.
6. Greenberg, F.; Stein, F.; Gresik, M. V.; Finegold, M. J.; Carpenter,
R. J.; Riccardi, V. M.; Beaudet, A. L.: Perlman syndrome: familial
nephroblastomatosis, fetal ascites, polyhydramnios, macrosomia, and
Wilms' tumor--follow-up. (Abstract) Proc. Greenwood Genet. Center 4:
150 only, 1985.
7. Greenberg, F.; Stein, F.; Gresik, M. V.; Finegold, M. J.; Carpenter,
R. J.; Riccardi, V. M.; Beaudet, A. L.: The Perlman familial nephroblastomatosis
syndrome. Am. J. Med. Genet. 24: 101-110, 1986.
8. Greenberg, F.; Stein, F.; Gresik, M. V.; Finegold, M. J.; Carpenter,
R. J.; Riccardi, V. M.; Beaudet, A. L.: Fetal ascites, 'prune belly'
sequence, hepatomegaly, and nephromegaly associated with Wilms tumor.
(Abstract) Proc. Greenwood Genet. Center 3: 133 only, 1984.
9. Hamel, B. C. J.; Mannens, M.; Bokkerink, J. P. M.: Perlman syndrome:
report of a case and results of molecular studies. (Abstract) Am.
J. Hum. Genet. 45 (suppl.): A48 only, 1989.
10. Henneveld, H. T.; van Lingen, R. A.; Hamel, B. C. J.; Stolte-Dijkstra,
I.; van Essen, A. J.: Perlman syndrome: four additional cases and
review. Am. J. Med. Genet. 86: 439-446, 1999.
11. Liban, E.; Kozenitzky, I. L.: Metanephric hamartomas and nephroblastomatosis
in siblings. Cancer 25: 885-888, 1970.
12. Neri, G.; Martini-Neri, M. E.; Katz, B. E.; Opitz, B. E.: The
Perlman syndrome: familial renal dysplasia with Wilms tumor, fetal
gigantism and multiple congenital anomalies. Am. J. Med. Genet. 19:
195-207, 1984.
13. Perlman, M.: Perlman syndrome: familial renal dysplasia with
Wilms tumor, fetal gigantism, and multiple congenital anomalies. (Letter) Am.
J. Med. Genet. 25: 793-795, 1986.
14. Perlman, M.; Goldberg, G. M.; Bar-Ziv, J.; Danovitch, G.: Renal
hamartomas and nephroblastomatosis with fetal gigantism: a familial
syndrome. J. Pediat. 83: 414-418, 1973.
15. Perlman, M.; Levin, M.; Wittels, B.: Syndrome of fetal gigantism,
renal hamartomas and nephroblastomatosis with Wilms' tumour. Cancer 35:
1212-1217, 1975.
16. Piccione, M.; Cecconi, M.; Giuffre, M.; Lo Curto, M.; Malacarne,
M.; Piro, E.; Riccio, A.; Corsello, G.: Perlman syndrome: clinical
report and nine-year follow-up. Am. J. Med. Genet. 139A: 131-135,
2005.
17. Schilke, K.; Schaefer, F.; Waldherr, R.; Rohrschneider, W.; John,
C.; Himbert, U.; Mayatepek, E.; Tariverdian, G.: A case of Perlman
syndrome: fetal gigantism, renal dysplasia, and severe neurological
deficits. Am. J. Med. Genet. 91: 29-33, 2000.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Large birth size;
Macrosomia
HEAD AND NECK:
[Face];
Unusual facies;
Round facial fullness;
Micrognathia;
[Ears];
Low-set ears;
[Nose];
Depressed nasal bridge;
Broad nasal bridge;
[Mouth];
Anteverted upper lip;
Open mouth;
Long upper lip;
Inverted V-shaped upper lip
CARDIOVASCULAR:
[Vascular];
Interrupted aortic arch
CHEST:
[Diaphragm];
Diaphragmatic hernia
ABDOMEN:
[External features];
Abdominal muscular hypoplasia;
Visceromegaly;
[Pancreas];
Islets of Langerhans hypertrophy;
[Gastrointestinal];
Volvulus;
Distal ileal atresia
GENITOURINARY:
[External genitalia, male];
Cryptorchidism;
[Kidneys];
Bilateral renal hamartomas;
Nephroblastomatosis;
Wilms tumor
SKIN, NAILS, HAIR:
[Hair];
Upsweep of anterior scalp hair
NEUROLOGIC:
[Central nervous system];
Corpus callosum agenesis;
Developmental delay
ENDOCRINE FEATURES:
Hyperinsulinism
PRENATAL MANIFESTATIONS:
Fetal ascites without hydrops;
[Amniotic fluid];
Polyhydramnios
MISCELLANEOUS:
Fatal in the neonatal period (in some patients)
MOLECULAR BASIS:
Caused by mutation in the Dis3 mitotic control, S. cerevisiae, homolog-like
2 gene (DIS3L2, 614184.0001)
*FIELD* CN
Marla J. F. O'Neill - revised: 3/16/2012
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 11/30/2012
joanna: 3/16/2012
*FIELD* CN
Marla J. F. O'Neill - updated: 3/16/2012
Cassandra L. Kniffin - updated: 4/15/2009
Marla J. F. O'Neill - updated: 1/12/2006
Victor A. McKusick - updated: 3/15/2000
Sonja A. Rasmussen - updated: 12/2/1999
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 03/16/2012
terry: 3/16/2012
wwang: 5/7/2009
ckniffin: 4/15/2009
wwang: 1/19/2006
terry: 1/12/2006
mgross: 3/17/2004
joanna: 8/15/2001
mcapotos: 3/28/2000
terry: 3/15/2000
mgross: 12/2/1999
davew: 6/7/1994
mimadm: 3/12/1994
carol: 2/24/1993
supermim: 3/17/1992
carol: 3/2/1992
supermim: 3/20/1990
*RECORD*
*FIELD* NO
267000
*FIELD* TI
#267000 PERLMAN SYNDROME; PRLMNS
;;RENAL HAMARTOMAS, NEPHROBLASTOMATOSIS, AND FETAL GIGANTISM;;
read moreNEPHROBLASTOMATOSIS, FETAL ASCITES, MACROSOMIA, AND WILMS TUMOR
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
Perlman syndrome is caused by homozygous or compound heterozygous
mutation in the DIS3L2 gene (614184) on chromosome 2q37.2.
DESCRIPTION
Perlman syndrome is an autosomal recessive congenital overgrowth
syndrome with similarities to Beckwith-Wiedemann syndrome (BWS; 130650).
Affected children are large at birth, are hypotonic, and show
organomegaly, characteristic facial dysmorphisms (inverted V-shaped
upper lip, prominent forehead, deep-set eyes, broad and flat nasal
bridge, and low-set ears), renal anomalies (nephromegaly and
hydronephrosis), frequent neurodevelopmental delay, and high neonatal
mortality. Perlman syndrome is associated with a high risk of Wilms
tumor, with a 64% incidence in infants surviving beyond the neonatal
period. The tumor is diagnosed at an earlier age in these individuals
compared with sporadic cases (less than 2 years and 3-4 years of age,
respectively), and there is a high frequency of bilateral tumors (55%).
Histologic examination of the kidneys in children with Perlman syndrome
shows frequent nephroblastomatosis, which is a precursor lesion for
Wilms tumor (summary by Astuti et al., 2012).
CLINICAL FEATURES
Liban and Kozenitzky (1970) and Perlman et al. (1973) described 5
offspring, of Jewish-Yemenite second-cousin parents, with a disorder
manifested by large birth size, bilateral renal hamartomas with or
without nephroblastomatosis, hypertrophy of the islets of Langerhans,
and unusual facies. The longest survival was 27 days. There are some
obvious similarities to the Beckwith-Wiedemann syndrome (130650) but the
facies is thought to be characteristic with depressed nasal bridge and
anteverted upper lip. Perlman et al. (1975) reported a sixth offspring
from the Jewish-Yemenite family with fetal gigantism, renal hamartomas,
and nephroblastomatosis, in whom Wilms tumor (194070) occurred. Perlman
(1986) published very instructive photographs of the 2 sibs that he and
his colleagues reported in 1973 and 1975. The remarkably similar and
distinctive facies consisted of round fullness, hypotonic appearance
with open mouth, a long upper lip with inverted V-shape, upsweep of
anterior scalp hair, and mild micrognathia.
Neri et al. (1984) reported an affected brother and sister with
unaffected, unrelated parents. The brother died suddenly at 8 months of
age after a seizure during an apneic episode. His sister, who underwent
surgery for Wilms tumor (194070) and removal of a recurrence at 4.5 and
5.5 years of age, respectively, with subsequent removal of a pulmonary
metastasis and hamartoma at 6.5 years of age, was alive at 12 years of
age. Hyperinsulinism is probably an important feature and may be a
preventable cause of death. The cases of Greenberg et al. (1984, 1985,
1986) were in 2 sibs with polyhydramnios, fetal ascites, abdominal
muscular hypoplasia, visceromegaly, and subsequent development of
bilateral Wilms tumor in one of them. This disorder should be considered
in the differential diagnosis of fetal ascites without hydrops.
Dao et al. (1987) studied chromosome 11p markers in a patient with this
syndrome and found the same loss of 11p DNA sequences that occurs in
Wilms tumor. Genetic differences between 2 tumors indicated that they
developed independently, the results of different genetic events.
Greenberg et al. (1988) reported an infant with manifestations of
Perlman syndrome, including polyhydramnios, macrosomia, bilateral
nephromegaly with nephroblastomatosis, visceromegaly, and
cryptorchidism. The patient also had diaphragmatic hernia and
interrupted aortic arch, suggesting that these may be findings of
Perlman syndrome.
Hamel et al. (1989) described additional features of volvulus and distal
ileal atresia as well as agenesis of the corpus callosum. From a study
of 11p markers, they found no evidence of rearrangements. Because of the
overlapping of clinical features with the Beckwith-Wiedemann syndrome,
the findings of a cytogenetic abnormality of chromosome 11 is of
interest.
Chernos et al. (1990) described a newborn with macroglossia and
bilateral hydronephrosis which had been diagnosed in utero. The infant
had prominent forehead, broad flat facies, hypertelorism, bilateral
epicanthic folds, deep-set eyes, a short upturned nose with wide
nostrils, and prominent upper lip. Cytogenetic studies demonstrated an
extra band on the tip of the short arm of one chromosome 11 which was
G-dark, Q-bright, and C-negative.
Henneveld et al. (1999) reported 4 patients from 3 Dutch families with
Perlman syndrome. All had typical manifestations, including macrosomia,
nephromegaly with renal dysplasia, hypotonia, and characteristic facies.
Additional features included dextroposition of the heart (1 patient),
hepatic fibrosis with porto-portal bridging (1 patient), volvulus and
intestinal atresia (1 patient), choroid plexus hemangiomas (2 patients),
agenesis of the corpus callosum (1 patient), and cleft palate (1
patient). All 4 died within the first year of life. Two patients were
brother and sister, supporting the hypothesis that this condition is
inherited in an autosomal recessive manner.
Schilke et al. (2000) described a neonate presenting with
polyhydramnios; macrosomia; macrocephaly; visceromegaly including
bilateral nephromegaly, hepatomegaly, and cardiomegaly; thymus
hyperplasia; cryptorchidism; generalized muscle hypotonia; and a
distinctive facial appearance. The clinical course was marked by severe
neurodevelopmental deficits combined with progressive respiratory
decompensation, leading to death at the age of 6 months. MRI disclosed a
generalized cerebral atrophy with a marked deficit of the white matter.
Renal ultrasound and MRI showed markedly enlarged kidneys with multiple
small cystic lesions, a pattern indistinguishable from polycystic kidney
disease. The postmortem kidney biopsy showed dysplastic changes,
microcysts, and a focal nephrogenic rest, characteristic features of the
Perlman syndrome. The parents were nonconsanguineous, healthy Albanians.
Piccione et al. (2005) reported the 9-year follow-up of a girl with
Perlman syndrome. She was born of nonconsanguineous parents by cesarean
section due to polyhydramnios and at birth was noted to have macrosomia,
macrocephaly, prominent forehead, full round face, deeply set eyes,
hypertelorism, epicanthic folds, broad flat nasal bridge, anteverted
upper lip, highly arched palate, dysplastic ears, and axial hypotonia,
but no organomegaly. At 6 months of age she was noted to have mild
hepatosplenomegaly and bilateral nephromegaly; Wilms tumor was diagnosed
at 20 months of age. When seen at age 9, she had macrocephaly, severe
right convex dorsal and left convex lumbar scoliosis, lumbar
hyperlordosis and asymmetry of the iliac crests, and prominent
xiphisternum. Psychomotor development was normal.
Alessandri et al. (2008) reported an infant with Perlman syndrome who
died at 2 days of age. Prenatal ultrasound showed enlarged kidneys and
marked ascites. After birth, she was found to have macrosomia, abdominal
distention, nephromegaly, hypoplastic thorax, characteristic face with
depressed nasal bridge, deep-set eyes, low-set dysplastic ears and
micrognathia. Renal biopsy showed bilateral nephroblastomatosis. A
previous pregnancy resulted in an infant who rapidly expired after birth
and probably had the same syndrome. Alessandri et al. (2008) reviewed 28
patients with typical Perlman syndrome and concluded that there is a
high neonatal mortality rate. Most affected infants developed
respiratory distress with refractory hypoxemia and/or renal failure and
died within the first hours or days of life.
MAPPING
In a consanguineous Pakistani kindred with Perlman syndrome, in which
mutation in the IGF2 (147470) and IGF2R (147280) candidate genes had
been excluded, Astuti et al. (2012) performed autozygosity mapping by
genomewide SNP genotyping and identified 8 regions of extended
homozygosity, including a 43-cM (28-Mb) region on chromosome 2q.
Analysis of 3 affected individuals from 2 potentially consanguineous
Dutch kindreds with Perlman syndrome, previously reported by Henneveld
et al. (1999), confirmed the autozygous region at 2q37 and narrowed it
to a 4.8-cM (2.1-Mb) interval between dbSNP rs1992188 and dbSNP
rs1104953.
MOLECULAR GENETICS
In a consanguineous Pakistani kindred and 2 Dutch kindreds with Perlman
syndrome mapping to chromosome 2q37, Astuti et al. (2012) analyzed 36
candidate genes and identified a failure to amplify exons 6 and 9,
respectively, of the DIS3L2 gene (614184). Further investigation
revealed that affected individuals in the Pakistani family were
homozygous for an 82.8-kb deletion in DIS3L2 (614184.0001), whereas
patients from the 2 Dutch families previously studied by Henneveld et
al. (1999), as well as an unrelated Dutch patient, were homozygous for
an approximately 22-kb deletion (614184.0002). Analysis of DIS3L2 in
cell lines from 2 additional unrelated children with Perlman syndrome, 1
of whom was the sister previously studied by Neri et al. (1984),
revealed compound heterozygous mutations (614184.0002-614184.0004).
*FIELD* RF
1. Alessandri, J.-L.; Cuillier, F.; Ramful, D.; Ernould, S.; Robin,
S.; de Napoli-Cocci, S.; Riviere, J.-P.; Rossignol, S.: Perlman syndrome:
report, prenatal findings and review. Am. J. Med. Genet. 146A: 2532-2537,
2008.
2. Astuti, D.; Morris, M. R.; Cooper, W. N.; Staals, R. H. J.; Wake,
N. C.; Fews, G. A.; Gill, H.; Gentle, D.; Shuib, S.; Ricketts, C.
J.; Cole, T.; van Essen, A. J.; and 9 others: Germline mutations
in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor
susceptibility. Nature Genet. 44: 277-284, 2012.
3. Chernos, J. E.; Fowlow, S. B.; Cox, D. M.: A case of Perlman syndrome
associated with a cytogenetic abnormality of chromosome 11. (Abstract) Am.
J. Hum. Genet. 47 (suppl.): A28 only, 1990.
4. Dao, D. D.; Schroeder, W. T.; Chao, L.-Y.; Kikuchi, H.; Strong,
L. C.; Riccardi, V. M.; Pathak, S.; Nichols, W. W.; Lewis, W. H.;
Saunders, G. F.: Genetic mechanisms of tumor-specific loss of 11p
DNA sequences in Wilms tumor. Am. J. Hum. Genet. 41: 202-217, 1987.
5. Greenberg, F.; Copeland, K.; Gresik, M. V.: Expanding the spectrum
of the Perlman syndrome. Am. J. Med. Genet. 29: 773-776, 1988.
6. Greenberg, F.; Stein, F.; Gresik, M. V.; Finegold, M. J.; Carpenter,
R. J.; Riccardi, V. M.; Beaudet, A. L.: Perlman syndrome: familial
nephroblastomatosis, fetal ascites, polyhydramnios, macrosomia, and
Wilms' tumor--follow-up. (Abstract) Proc. Greenwood Genet. Center 4:
150 only, 1985.
7. Greenberg, F.; Stein, F.; Gresik, M. V.; Finegold, M. J.; Carpenter,
R. J.; Riccardi, V. M.; Beaudet, A. L.: The Perlman familial nephroblastomatosis
syndrome. Am. J. Med. Genet. 24: 101-110, 1986.
8. Greenberg, F.; Stein, F.; Gresik, M. V.; Finegold, M. J.; Carpenter,
R. J.; Riccardi, V. M.; Beaudet, A. L.: Fetal ascites, 'prune belly'
sequence, hepatomegaly, and nephromegaly associated with Wilms tumor.
(Abstract) Proc. Greenwood Genet. Center 3: 133 only, 1984.
9. Hamel, B. C. J.; Mannens, M.; Bokkerink, J. P. M.: Perlman syndrome:
report of a case and results of molecular studies. (Abstract) Am.
J. Hum. Genet. 45 (suppl.): A48 only, 1989.
10. Henneveld, H. T.; van Lingen, R. A.; Hamel, B. C. J.; Stolte-Dijkstra,
I.; van Essen, A. J.: Perlman syndrome: four additional cases and
review. Am. J. Med. Genet. 86: 439-446, 1999.
11. Liban, E.; Kozenitzky, I. L.: Metanephric hamartomas and nephroblastomatosis
in siblings. Cancer 25: 885-888, 1970.
12. Neri, G.; Martini-Neri, M. E.; Katz, B. E.; Opitz, B. E.: The
Perlman syndrome: familial renal dysplasia with Wilms tumor, fetal
gigantism and multiple congenital anomalies. Am. J. Med. Genet. 19:
195-207, 1984.
13. Perlman, M.: Perlman syndrome: familial renal dysplasia with
Wilms tumor, fetal gigantism, and multiple congenital anomalies. (Letter) Am.
J. Med. Genet. 25: 793-795, 1986.
14. Perlman, M.; Goldberg, G. M.; Bar-Ziv, J.; Danovitch, G.: Renal
hamartomas and nephroblastomatosis with fetal gigantism: a familial
syndrome. J. Pediat. 83: 414-418, 1973.
15. Perlman, M.; Levin, M.; Wittels, B.: Syndrome of fetal gigantism,
renal hamartomas and nephroblastomatosis with Wilms' tumour. Cancer 35:
1212-1217, 1975.
16. Piccione, M.; Cecconi, M.; Giuffre, M.; Lo Curto, M.; Malacarne,
M.; Piro, E.; Riccio, A.; Corsello, G.: Perlman syndrome: clinical
report and nine-year follow-up. Am. J. Med. Genet. 139A: 131-135,
2005.
17. Schilke, K.; Schaefer, F.; Waldherr, R.; Rohrschneider, W.; John,
C.; Himbert, U.; Mayatepek, E.; Tariverdian, G.: A case of Perlman
syndrome: fetal gigantism, renal dysplasia, and severe neurological
deficits. Am. J. Med. Genet. 91: 29-33, 2000.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Large birth size;
Macrosomia
HEAD AND NECK:
[Face];
Unusual facies;
Round facial fullness;
Micrognathia;
[Ears];
Low-set ears;
[Nose];
Depressed nasal bridge;
Broad nasal bridge;
[Mouth];
Anteverted upper lip;
Open mouth;
Long upper lip;
Inverted V-shaped upper lip
CARDIOVASCULAR:
[Vascular];
Interrupted aortic arch
CHEST:
[Diaphragm];
Diaphragmatic hernia
ABDOMEN:
[External features];
Abdominal muscular hypoplasia;
Visceromegaly;
[Pancreas];
Islets of Langerhans hypertrophy;
[Gastrointestinal];
Volvulus;
Distal ileal atresia
GENITOURINARY:
[External genitalia, male];
Cryptorchidism;
[Kidneys];
Bilateral renal hamartomas;
Nephroblastomatosis;
Wilms tumor
SKIN, NAILS, HAIR:
[Hair];
Upsweep of anterior scalp hair
NEUROLOGIC:
[Central nervous system];
Corpus callosum agenesis;
Developmental delay
ENDOCRINE FEATURES:
Hyperinsulinism
PRENATAL MANIFESTATIONS:
Fetal ascites without hydrops;
[Amniotic fluid];
Polyhydramnios
MISCELLANEOUS:
Fatal in the neonatal period (in some patients)
MOLECULAR BASIS:
Caused by mutation in the Dis3 mitotic control, S. cerevisiae, homolog-like
2 gene (DIS3L2, 614184.0001)
*FIELD* CN
Marla J. F. O'Neill - revised: 3/16/2012
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 11/30/2012
joanna: 3/16/2012
*FIELD* CN
Marla J. F. O'Neill - updated: 3/16/2012
Cassandra L. Kniffin - updated: 4/15/2009
Marla J. F. O'Neill - updated: 1/12/2006
Victor A. McKusick - updated: 3/15/2000
Sonja A. Rasmussen - updated: 12/2/1999
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 03/16/2012
terry: 3/16/2012
wwang: 5/7/2009
ckniffin: 4/15/2009
wwang: 1/19/2006
terry: 1/12/2006
mgross: 3/17/2004
joanna: 8/15/2001
mcapotos: 3/28/2000
terry: 3/15/2000
mgross: 12/2/1999
davew: 6/7/1994
mimadm: 3/12/1994
carol: 2/24/1993
supermim: 3/17/1992
carol: 3/2/1992
supermim: 3/20/1990
MIM
614184
*RECORD*
*FIELD* NO
614184
*FIELD* TI
*614184 DIS3 MITOTIC CONTROL, S. CEREVISIAE, HOMOLOG-LIKE 2; DIS3L2
*FIELD* TX
DESCRIPTION
read more
The RNA exosome is an approximately 400-kD multimeric ribonucleolytic
complex that participates in both endonucleolytic and 3-prime/5-prime
exonucleolytic activity in RNA processing and in the degradation of a
variety of RNA substrates. DIS3L2 shares high sequence similarity with
catalytic exosome subunits that have 3-prime/5-prime exonucleolytic
activity (summary by Tomecki et al., 2010).
CLONING
By searching the human genomic database for sequences similar to DIS3L
(614183), Staals et al. (2010) identified 5 potential splice variants of
DIS3L2. The longest deduced protein contains 885 amino acids and has a
calculated molecular mass of 99.2 kD. It has a poorly conserved
N-terminal PIN domain, followed by a cold-shock domain, a putative RNB
exonuclease catalytic domain, and a possible C-terminal S1 RNA-binding
domain.
MAPPING
Hartz (2011) mapped the DIS3L2 gene to chromosome 2q37.2 based on an
alignment of the DIS3L2 sequence (GenBank GENBANK BC030113) with the
genomic sequence (GRCh37).
GENE FUNCTION
In transfected COS-7 and HeLa cells, Astuti et al. (2012) observed that
DIS3L2 was localized predominantly in the cytoplasm. RNA degradation
assays using transfected HEK293 cells demonstrated that DIS3L2 has
exonuclease activity. Knockdown studies in HeLa cells showed that DIS3L2
inactivation was associated with mitotic abnormalities and altered
expression of mitotic checkpoint proteins, with lowered expression of
TTK (604092), aurora B (AURKB; 604970), and phosphorylated CDC25C
(157680), but upregulation of cyclin B1 (CCNB1; 123836), RAD21 (606462),
and securin (PTTG1; 604147). DIS3L2 overexpression suppressed the growth
of human cancer cell lines, and knockdown enhanced the growth of those
cells. Astuti et al. (2012) concluded that DIS3L2 has a critical role in
RNA metabolism and is essential for the regulation of cell growth and
division.
The pluripotency factor LIN28 (611043) blocks the expression of LET7
(605386) microRNAs in undifferentiated cells during development by
binding to pre-LET7 RNAs and recruiting RNA uridyltransferases ZCCHC11
(613692) and ZCCHC6 to uridylate pre-LET7. The identity of the RNase
that degrades uridylated pre-LET7 was unknown. Chang et al. (2013)
identified Dis3l2 as the 3-prime-5-prime exonuclease responsible for the
decay of uridylated pre-let7 in mouse embryonic stem cells. Biochemical
reconstitution assays showed that 3-prime oligouridylation stimulates
Dis3l2 activity in vitro, and knockdown of Dis3l2 in mouse embryonic
stem cells leads to the stabilization of pre-let7. Chang et al. (2013)
concluded that their study established 3-prime oligouridylation as an
RNA decay signal for DIS3L2 and identified the first physiologic RNA
substrate of this exonuclease.
MOLECULAR GENETICS
In 8 affected individuals from 6 families with Perlman syndrome (PRLMNS;
267000), Astuti et al. (2012) identified homozygosity or compound
heterozygosity for mutations in the DIS3L2 gene
(614184.0001-614184.0004).
*FIELD* AV
.0001
PERLMAN SYNDROME
DIS3L2, 82.8-KB DEL, EX6DEL
In a brother and sister from a consanguineous Pakistani family with
Perlman syndrome (267000), Astuti et al. (2012) identified homozygosity
for an 82.8-kb deletion (367-41553_602+40962del) between exons 5 and 7
of the DIS3L2 gene, resulting in a truncated protein of 258 amino acids.
Functional studies in HEK293 cells demonstrated that mutant DIS3L2
lacking exon 6 had substantially reduced ribonuclease activity. The
mutation segregated with disease in the family and was not found in at
least 300 ancestrally matched samples. The brother died at 3.5 years of
age and the sister at 2 months of age.
.0002
PERLMAN SYNDROME
DIS3L2, 22-KB DEL, EX9DEL
In 3 patients from 2 Dutch families with Perlman syndrome (267000),
previously reported by Henneveld et al. (1999), as well as an unrelated
Dutch infant with this syndrome, Astuti et al. (2012) identified
homozygosity for an approximately 22-kb deletion (951-?_1124+?del)
between exons 8 and 10 of the DIS3L2 gene, resulting in loss of the RNB
domain (gln318_arg375del). Functional studies in HEK293 cells
demonstrated that mutant DIS3L2 lacking exon 9 had substantially reduced
ribonuclease activity. The mutation segregated with disease in both
families and was not found in at least 300 ancestrally matched samples.
All 4 Dutch patients died in infancy. In addition, in a cell line from a
30-week amniotic fluid sample from a male patient with Perlman syndrome,
the exon 9 deletion was found in compound heterozygosity with a 1466G-A
transition in the DIS3L2 gene, resulting in a cys489-to-tyr (C489Y;
614184.0003) substitution at a highly conserved residue.
.0003
PERLMAN SYNDROME
DIS3L2, CYS489TYR
See 614184.0002 and Astuti et al. (2012).
.0004
PERLMAN SYNDROME
DIS3L2, IVS19, G-A, +5
In a cell line taken from a 14-year-old girl with Perlman syndrome
(267000), previously reported by Neri et al. (1984), Astuti et al.
(2012) identified a heterozygous G-to-A transition in exon 19
(2394+5G-A) of the DIS3L2 gene, predicted to cause skipping or deletion
of exon 19. The mutation segregated with disease in the family and was
not found in at least 300 ancestrally matched control samples. Although
a second mutation was not detected, only the transcript lacking exon 19
was found, suggesting the presence of another mutation that might
abolish transcription or cause mRNA instability.
*FIELD* RF
1. Astuti, D.; Morris, M. R.; Cooper, W. N.; Staals, R. H. J.; Wake,
N. C.; Fews, G. A.; Gill, H.; Gentle, D.; Shuib, S.; Ricketts, C.
J.; Cole, T.; van Essen, A. J.; and 9 others: Germline mutations
in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor
susceptibility. Nature Genet. 44: 277-284, 2012.
2. Chang, H.-M.; Triboulet, R.; Thornton, J. E.; Gregory, R. I.:
A role for the Perlman syndrome exonuclease Dis3l2 in the Lin28-let-7
pathway. Nature 497: 244-248, 2013.
3. Hartz, P. A.: Personal Communication. Baltimore, Md. 7/13/2011.
4. Henneveld, H. T.; van Lingen, R. A.; Hamel, B. C. J.; Stolte-Dijkstra,
I.; van Essen, A. J.: Perlman syndrome: four additional cases and
review. Am. J. Med. Genet. 86: 439-446, 1999.
5. Neri, G.; Martini-Neri, M. E.; Katz, B. E.; Opitz, B. E.: The
Perlman syndrome: familial renal dysplasia with Wilms tumor, fetal
gigantism and multiple congenital anomalies. Am. J. Med. Genet. 19:
195-207, 1984.
6. Staals, R. H. J.; Bronkhorst, A. W.; Schilders, G.; Slomovic, S.;
Schuster, G.; Heck, A. J. R.; Raijmakers, R.; Pruijn, G. J. M.: Dis3-like
1: a novel exoribonuclease associated with the human exosome. EMBO
J. 29: 2358-2367, 2010.
7. Tomecki, R.; Kristiansen, M. S.; Lykke-Andersen, S.; Chlebowski,
A.; Larsen, K. M.; Szczesny, R. J.; Drazkowska, K.; Pastula, A.; Andersen,
J. S.; Stepien, P. P.; Dziembowski, A.; Jensen, T. H.: The human
core exosome interacts with differentially localized processive RNases:
hDIS3 and hDIS3L. EMBO J. 29: 2342-2357, 2010.
*FIELD* CN
Ada Hamosh - updated: 05/24/2013
Marla J. F. O'Neill - updated: 3/16/2012
*FIELD* CD
Patricia A. Hartz: 8/22/2011
*FIELD* ED
alopez: 05/24/2013
carol: 3/16/2012
terry: 3/16/2012
wwang: 8/22/2011
*RECORD*
*FIELD* NO
614184
*FIELD* TI
*614184 DIS3 MITOTIC CONTROL, S. CEREVISIAE, HOMOLOG-LIKE 2; DIS3L2
*FIELD* TX
DESCRIPTION
read more
The RNA exosome is an approximately 400-kD multimeric ribonucleolytic
complex that participates in both endonucleolytic and 3-prime/5-prime
exonucleolytic activity in RNA processing and in the degradation of a
variety of RNA substrates. DIS3L2 shares high sequence similarity with
catalytic exosome subunits that have 3-prime/5-prime exonucleolytic
activity (summary by Tomecki et al., 2010).
CLONING
By searching the human genomic database for sequences similar to DIS3L
(614183), Staals et al. (2010) identified 5 potential splice variants of
DIS3L2. The longest deduced protein contains 885 amino acids and has a
calculated molecular mass of 99.2 kD. It has a poorly conserved
N-terminal PIN domain, followed by a cold-shock domain, a putative RNB
exonuclease catalytic domain, and a possible C-terminal S1 RNA-binding
domain.
MAPPING
Hartz (2011) mapped the DIS3L2 gene to chromosome 2q37.2 based on an
alignment of the DIS3L2 sequence (GenBank GENBANK BC030113) with the
genomic sequence (GRCh37).
GENE FUNCTION
In transfected COS-7 and HeLa cells, Astuti et al. (2012) observed that
DIS3L2 was localized predominantly in the cytoplasm. RNA degradation
assays using transfected HEK293 cells demonstrated that DIS3L2 has
exonuclease activity. Knockdown studies in HeLa cells showed that DIS3L2
inactivation was associated with mitotic abnormalities and altered
expression of mitotic checkpoint proteins, with lowered expression of
TTK (604092), aurora B (AURKB; 604970), and phosphorylated CDC25C
(157680), but upregulation of cyclin B1 (CCNB1; 123836), RAD21 (606462),
and securin (PTTG1; 604147). DIS3L2 overexpression suppressed the growth
of human cancer cell lines, and knockdown enhanced the growth of those
cells. Astuti et al. (2012) concluded that DIS3L2 has a critical role in
RNA metabolism and is essential for the regulation of cell growth and
division.
The pluripotency factor LIN28 (611043) blocks the expression of LET7
(605386) microRNAs in undifferentiated cells during development by
binding to pre-LET7 RNAs and recruiting RNA uridyltransferases ZCCHC11
(613692) and ZCCHC6 to uridylate pre-LET7. The identity of the RNase
that degrades uridylated pre-LET7 was unknown. Chang et al. (2013)
identified Dis3l2 as the 3-prime-5-prime exonuclease responsible for the
decay of uridylated pre-let7 in mouse embryonic stem cells. Biochemical
reconstitution assays showed that 3-prime oligouridylation stimulates
Dis3l2 activity in vitro, and knockdown of Dis3l2 in mouse embryonic
stem cells leads to the stabilization of pre-let7. Chang et al. (2013)
concluded that their study established 3-prime oligouridylation as an
RNA decay signal for DIS3L2 and identified the first physiologic RNA
substrate of this exonuclease.
MOLECULAR GENETICS
In 8 affected individuals from 6 families with Perlman syndrome (PRLMNS;
267000), Astuti et al. (2012) identified homozygosity or compound
heterozygosity for mutations in the DIS3L2 gene
(614184.0001-614184.0004).
*FIELD* AV
.0001
PERLMAN SYNDROME
DIS3L2, 82.8-KB DEL, EX6DEL
In a brother and sister from a consanguineous Pakistani family with
Perlman syndrome (267000), Astuti et al. (2012) identified homozygosity
for an 82.8-kb deletion (367-41553_602+40962del) between exons 5 and 7
of the DIS3L2 gene, resulting in a truncated protein of 258 amino acids.
Functional studies in HEK293 cells demonstrated that mutant DIS3L2
lacking exon 6 had substantially reduced ribonuclease activity. The
mutation segregated with disease in the family and was not found in at
least 300 ancestrally matched samples. The brother died at 3.5 years of
age and the sister at 2 months of age.
.0002
PERLMAN SYNDROME
DIS3L2, 22-KB DEL, EX9DEL
In 3 patients from 2 Dutch families with Perlman syndrome (267000),
previously reported by Henneveld et al. (1999), as well as an unrelated
Dutch infant with this syndrome, Astuti et al. (2012) identified
homozygosity for an approximately 22-kb deletion (951-?_1124+?del)
between exons 8 and 10 of the DIS3L2 gene, resulting in loss of the RNB
domain (gln318_arg375del). Functional studies in HEK293 cells
demonstrated that mutant DIS3L2 lacking exon 9 had substantially reduced
ribonuclease activity. The mutation segregated with disease in both
families and was not found in at least 300 ancestrally matched samples.
All 4 Dutch patients died in infancy. In addition, in a cell line from a
30-week amniotic fluid sample from a male patient with Perlman syndrome,
the exon 9 deletion was found in compound heterozygosity with a 1466G-A
transition in the DIS3L2 gene, resulting in a cys489-to-tyr (C489Y;
614184.0003) substitution at a highly conserved residue.
.0003
PERLMAN SYNDROME
DIS3L2, CYS489TYR
See 614184.0002 and Astuti et al. (2012).
.0004
PERLMAN SYNDROME
DIS3L2, IVS19, G-A, +5
In a cell line taken from a 14-year-old girl with Perlman syndrome
(267000), previously reported by Neri et al. (1984), Astuti et al.
(2012) identified a heterozygous G-to-A transition in exon 19
(2394+5G-A) of the DIS3L2 gene, predicted to cause skipping or deletion
of exon 19. The mutation segregated with disease in the family and was
not found in at least 300 ancestrally matched control samples. Although
a second mutation was not detected, only the transcript lacking exon 19
was found, suggesting the presence of another mutation that might
abolish transcription or cause mRNA instability.
*FIELD* RF
1. Astuti, D.; Morris, M. R.; Cooper, W. N.; Staals, R. H. J.; Wake,
N. C.; Fews, G. A.; Gill, H.; Gentle, D.; Shuib, S.; Ricketts, C.
J.; Cole, T.; van Essen, A. J.; and 9 others: Germline mutations
in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor
susceptibility. Nature Genet. 44: 277-284, 2012.
2. Chang, H.-M.; Triboulet, R.; Thornton, J. E.; Gregory, R. I.:
A role for the Perlman syndrome exonuclease Dis3l2 in the Lin28-let-7
pathway. Nature 497: 244-248, 2013.
3. Hartz, P. A.: Personal Communication. Baltimore, Md. 7/13/2011.
4. Henneveld, H. T.; van Lingen, R. A.; Hamel, B. C. J.; Stolte-Dijkstra,
I.; van Essen, A. J.: Perlman syndrome: four additional cases and
review. Am. J. Med. Genet. 86: 439-446, 1999.
5. Neri, G.; Martini-Neri, M. E.; Katz, B. E.; Opitz, B. E.: The
Perlman syndrome: familial renal dysplasia with Wilms tumor, fetal
gigantism and multiple congenital anomalies. Am. J. Med. Genet. 19:
195-207, 1984.
6. Staals, R. H. J.; Bronkhorst, A. W.; Schilders, G.; Slomovic, S.;
Schuster, G.; Heck, A. J. R.; Raijmakers, R.; Pruijn, G. J. M.: Dis3-like
1: a novel exoribonuclease associated with the human exosome. EMBO
J. 29: 2358-2367, 2010.
7. Tomecki, R.; Kristiansen, M. S.; Lykke-Andersen, S.; Chlebowski,
A.; Larsen, K. M.; Szczesny, R. J.; Drazkowska, K.; Pastula, A.; Andersen,
J. S.; Stepien, P. P.; Dziembowski, A.; Jensen, T. H.: The human
core exosome interacts with differentially localized processive RNases:
hDIS3 and hDIS3L. EMBO J. 29: 2342-2357, 2010.
*FIELD* CN
Ada Hamosh - updated: 05/24/2013
Marla J. F. O'Neill - updated: 3/16/2012
*FIELD* CD
Patricia A. Hartz: 8/22/2011
*FIELD* ED
alopez: 05/24/2013
carol: 3/16/2012
terry: 3/16/2012
wwang: 8/22/2011