Full text data of DDHD2
DDHD2
(KIAA0725, SAMWD1)
[Confidence: low (only semi-automatic identification from reviews)]
Phospholipase DDHD2; 3.1.1.- (DDHD domain-containing protein 2; KIAA0725p; SAM, WWE and DDHD domain-containing protein 1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Phospholipase DDHD2; 3.1.1.- (DDHD domain-containing protein 2; KIAA0725p; SAM, WWE and DDHD domain-containing protein 1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
O94830
ID DDHD2_HUMAN Reviewed; 711 AA.
AC O94830; B3KWV2; Q9H8X7;
DT 13-NOV-2007, integrated into UniProtKB/Swiss-Prot.
read moreDT 13-NOV-2007, sequence version 2.
DT 22-JAN-2014, entry version 92.
DE RecName: Full=Phospholipase DDHD2;
DE EC=3.1.1.-;
DE AltName: Full=DDHD domain-containing protein 2;
DE AltName: Full=KIAA0725p;
DE AltName: Full=SAM, WWE and DDHD domain-containing protein 1;
GN Name=DDHD2; Synonyms=KIAA0725, SAMWD1;
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], FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR
RP LOCATION, AND MUTAGENESIS OF SER-351.
RX PubMed=11788596; DOI=10.1074/jbc.M111092200;
RA Nakajima K., Sonoda H., Mizoguchi T., Aoki J., Arai H., Nagahama M.,
RA Tagaya M., Tani K.;
RT "A novel phospholipase A1 with sequence homology to a mammalian
RT Sec23p-interacting protein, p125.";
RL J. Biol. Chem. 277:11329-11335(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S.,
RA Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A.,
RA Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X.,
RA Allen N.R., Anderson S., Asakawa T., Blechschmidt K., Bloom T.,
RA Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K.,
RA DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G.,
RA Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B.,
RA Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C.,
RA O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K.,
RA Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R.,
RA Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K.,
RA Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q.,
RA Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N.,
RA Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 139-711, AND VARIANT
RP MET-186.
RC TISSUE=Brain;
RX PubMed=9872452; DOI=10.1093/dnares/5.5.277;
RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Miyajima N., Tanaka A.,
RA Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XI.
RT The complete sequences of 100 new cDNA clones from brain which code
RT for large proteins in vitro.";
RL DNA Res. 5:277-286(1998).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 220-711.
RC TISSUE=Placenta;
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 [7]
RP SUBCELLULAR LOCATION.
RX PubMed=15623529; DOI=10.1074/jbc.M409673200;
RA Shimoi W., Ezawa I., Nakamoto K., Uesaki S., Gabreski G., Aridor M.,
RA Yamamoto A., Nagahama M., Tagaya M., Tani K.;
RT "p125 is localized in endoplasmic reticulum exit sites and involved in
RT their organization.";
RL J. Biol. Chem. 280:10141-10148(2005).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF SER-351.
RX PubMed=20932832; DOI=10.1016/j.febslet.2010.09.047;
RA Sato S., Inoue H., Kogure T., Tagaya M., Tani K.;
RT "Golgi-localized KIAA0725p regulates membrane trafficking from the
RT Golgi apparatus to the plasma membrane in mammalian cells.";
RL FEBS Lett. 584:4389-4395(2010).
RN [9]
RP FUNCTION, PHOSPHOLIPID-BINDING, INTERACTION WITH DDHD1, HOMOOLIGOMER
RP FORMATION, AND MUTAGENESIS OF SER-351; ARG-434; LYS-435 AND LYS-436.
RX PubMed=22922100; DOI=10.1016/j.bbamcr.2012.02.002;
RA Inoue H., Baba T., Sato S., Ohtsuki R., Takemori A., Watanabe T.,
RA Tagaya M., Tani K.;
RT "Roles of SAM and DDHD domains in mammalian intracellular
RT phospholipase A1 KIAA0725p.";
RL Biochim. Biophys. Acta 1823:930-939(2012).
RN [10]
RP VARIANT SPG54 HIS-660.
RX PubMed=23176823; DOI=10.1016/j.ajhg.2012.10.017;
RA Schuurs-Hoeijmakers J.H., Geraghty M.T., Kamsteeg E.J., Ben-Salem S.,
RA de Bot S.T., Nijhof B., van de Vondervoort I.I., van der Graaf M.,
RA Nobau A.C., Otte-Holler I., Vermeer S., Smith A.C., Humphreys P.,
RA Schwartzentruber J., Ali B.R., Al-Yahyaee S.A., Tariq S.,
RA Pramathan T., Bayoumi R., Kremer H.P., van de Warrenburg B.P.,
RA van den Akker W.M., Gilissen C., Veltman J.A., Janssen I.M.,
RA Vulto-van Silfhout A.T., van der Velde-Visser S., Lefeber D.J.,
RA Diekstra A., Erasmus C.E., Willemsen M.A., Vissers L.E., Lammens M.,
RA van Bokhoven H., Brunner H.G., Wevers R.A., Schenck A., Al-Gazali L.,
RA de Vries B.B., de Brouwer A.P.;
RT "Mutations in DDHD2, encoding an intracellular phospholipase A(1),
RT cause a recessive form of complex hereditary spastic paraplegia.";
RL Am. J. Hum. Genet. 91:1073-1081(2012).
CC -!- FUNCTION: Phospholipase that hydrolyzes preferentially
CC phosphatidic acid, including 1,2-dioleoyl-sn-phosphatidic acid,
CC and phosphatidylethanolamine. Specifically binds to
CC phosphatidylinositol 3-phosphate (PI(3)P), phosphatidylinositol 4-
CC phosphate (PI(4)P), phosphatidylinositol 5-phosphate (PI(5)P) and
CC possibly phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). May be
CC involved in the maintenance of the endoplasmic reticulum and/or
CC Golgi structures. May regulate the transport between Golgi
CC apparatus and plasma membrane.
CC -!- SUBUNIT: Forms homooligomers and, to a much smaller extent,
CC heterooligomers with DDHD1.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol. Endoplasmic reticulum-
CC Golgi intermediate compartment. Golgi apparatus, cis-Golgi
CC network. Note=Cycles between the Golgi apparatus and the cytosol.
CC DDHD2 recruitment to the Golgi/endoplasmic reticulum-Golgi
CC intermediate compartment (ERGIC) is regulated by the levels of
CC phosphoinositides, including PI(4)P.
CC -!- TISSUE SPECIFICITY: Widely expressed (at protein level).
CC -!- DOMAIN: SAM and DDHD domains together are required for
CC phospholipid binding.
CC -!- DISEASE: Spastic paraplegia 54, autosomal recessive (SPG54)
CC [MIM:615033]: A form of spastic paraplegia, a neurodegenerative
CC disorder characterized by a slow, gradual, progressive weakness
CC and spasticity of the lower limbs. Rate of progression and the
CC severity of symptoms are quite variable. Initial symptoms may
CC include difficulty with balance, weakness and stiffness in the
CC legs, muscle spasms, and dragging the toes when walking.
CC Complicated forms are characterized by the addition of such
CC neurological features as spastic quadriparesis, seizures,
CC dementia, amyotrophy, extrapyramidal disturbance, cerebral or
CC cerebellar atrophy, optic atrophy, and peripheral neuropathy, as
CC well as by extra neurological manifestations such as dysmorphism,
CC albinism, retinitis pigmentosa, deafness, dementia, amyotrophy and
CC ichthyosis. SPG54 patients have delayed psychomotor development,
CC intellectual disability, and early-onset spasticity of the lower
CC limbs. Brain MRI shows a thin corpus callosum and periventricular
CC white matter lesions. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the PA-PLA1 family.
CC -!- SIMILARITY: Contains 1 DDHD domain.
CC -!- SIMILARITY: Contains 1 SAM (sterile alpha motif) domain.
CC -!- SIMILARITY: Contains 1 WWE domain.
CC -!- CAUTION: It is uncertain whether Met-1 or Met-31 is the initiator.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH10504.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=BAB14470.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
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DR EMBL; AK023218; BAB14470.1; ALT_INIT; mRNA.
DR EMBL; AK125904; BAG54264.1; -; mRNA.
DR EMBL; AC084024; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC087362; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AB018268; BAA34445.1; -; mRNA.
DR EMBL; CH471080; EAW63324.1; -; Genomic_DNA.
DR EMBL; BC010504; AAH10504.1; ALT_INIT; mRNA.
DR RefSeq; NP_001157704.1; NM_001164232.1.
DR RefSeq; NP_056029.2; NM_015214.2.
DR RefSeq; XP_005273511.1; XM_005273454.1.
DR RefSeq; XP_005273512.1; XM_005273455.1.
DR UniGene; Hs.434966; -.
DR ProteinModelPortal; O94830; -.
DR SMR; O94830; 386-453.
DR IntAct; O94830; 2.
DR MINT; MINT-4649256; -.
DR STRING; 9606.ENSP00000380352; -.
DR PhosphoSite; O94830; -.
DR PaxDb; O94830; -.
DR PRIDE; O94830; -.
DR DNASU; 23259; -.
DR Ensembl; ENST00000397166; ENSP00000380352; ENSG00000085788.
DR Ensembl; ENST00000520272; ENSP00000429932; ENSG00000085788.
DR GeneID; 23259; -.
DR KEGG; hsa:23259; -.
DR UCSC; uc003xlb.3; human.
DR CTD; 23259; -.
DR GeneCards; GC08P038107; -.
DR HGNC; HGNC:29106; DDHD2.
DR HPA; CAB015202; -.
DR HPA; HPA023143; -.
DR HPA; HPA023147; -.
DR HPA; HPA023150; -.
DR MIM; 615003; gene.
DR MIM; 615033; phenotype.
DR neXtProt; NX_O94830; -.
DR Orphanet; 320380; Autosomal recessive spastic paraplegia type 54.
DR PharmGKB; PA128394618; -.
DR eggNOG; NOG285690; -.
DR HOGENOM; HOG000007725; -.
DR HOVERGEN; HBG057256; -.
DR InParanoid; O94830; -.
DR KO; K16545; -.
DR OMA; KDLQEMG; -.
DR OrthoDB; EOG7JDQWX; -.
DR GenomeRNAi; 23259; -.
DR NextBio; 44992; -.
DR PRO; PR:O94830; -.
DR ArrayExpress; O94830; -.
DR Bgee; O94830; -.
DR CleanEx; HS_DDHD2; -.
DR Genevestigator; O94830; -.
DR GO; GO:0005813; C:centrosome; IDA:HPA.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR GO; GO:0016787; F:hydrolase activity; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:InterPro.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0016042; P:lipid catabolic process; IEA:UniProtKB-KW.
DR Gene3D; 1.10.150.50; -; 1.
DR InterPro; IPR004177; DDHD.
DR InterPro; IPR001660; SAM.
DR InterPro; IPR013761; SAM/pointed.
DR InterPro; IPR021129; SAM_type1.
DR InterPro; IPR004170; WWE-dom.
DR Pfam; PF02862; DDHD; 1.
DR Pfam; PF00536; SAM_1; 1.
DR Pfam; PF02825; WWE; 1.
DR SMART; SM00454; SAM; 1.
DR SUPFAM; SSF47769; SSF47769; 1.
DR PROSITE; PS51043; DDHD; 1.
DR PROSITE; PS50105; SAM_DOMAIN; FALSE_NEG.
DR PROSITE; PS50918; WWE; 1.
PE 1: Evidence at protein level;
KW Complete proteome; Cytoplasm; Disease mutation; Golgi apparatus;
KW Hereditary spastic paraplegia; Hydrolase; Lipid degradation;
KW Lipid metabolism; Neurodegeneration; Polymorphism; Reference proteome.
FT CHAIN 1 711 Phospholipase DDHD2.
FT /FTId=PRO_0000309330.
FT DOMAIN 30 112 WWE.
FT DOMAIN 385 448 SAM.
FT DOMAIN 495 700 DDHD.
FT ACT_SITE 351 351 Probable.
FT VARIANT 186 186 T -> M (in dbSNP:rs2306899).
FT /FTId=VAR_036930.
FT VARIANT 660 660 D -> H (in SPG54).
FT /FTId=VAR_069574.
FT MUTAGEN 351 351 S->A: Abolishes phospholipase activity.
FT Loss of efficient targeting to the Golgi
FT apparatus. No effect on PI(3)P-, PI(4)P-,
FT PI(5)P-binding.
FT MUTAGEN 434 434 R->A: Loss of phospholipid binding and of
FT Golgi/ERGIC localization; when associated
FT with A-435 and A-436.
FT MUTAGEN 435 435 K->A: Loss of phospholipid binding and of
FT Golgi/ERGIC localization; when associated
FT with A-434 and A-436.
FT MUTAGEN 436 436 K->A: Loss of phospholipid binding and of
FT Golgi/ERGIC localization; when associated
FT with A-434 and A-435.
FT CONFLICT 292 292 S -> G (in Ref. 2; BAB14470).
FT CONFLICT 376 376 D -> G (in Ref. 5; BAA34445).
SQ SEQUENCE 711 AA; 81032 MW; 8C03CD9254B1DBFB CRC64;
MSSVQSQQEQ LSQSDPSPSP NSCSSFELID MDAGSLYEPV SPHWFYCKII DSKETWIPFN
SEDSQQLEEA YSSGKGCNGR VVPTDGGRYD VHLGERMRYA VYWDELASEV RRCTWFYKGD
KDNKYVPYSE SFSQVLEETY MLAVTLDEWK KKLESPNREI IILHNPKLMV HYQPVAGSDD
WGSTPTEQGR PRTVKRGVEN ISVDIHCGEP LQIDHLVFVV HGIGPACDLR FRSIVQCVND
FRSVSLNLLQ THFKKAQENQ QIGRVEFLPV NWHSPLHSTG VDVDLQRITL PSINRLRHFT
NDTILDVFFY NSPTYCQTIV DTVASEMNRI YTLFLQRNPD FKGGVSIAGH SLGSLILFDI
LTNQKDSLGD IDSEKDSLNI VMDQGDTPTL EEDLKKLQLS EFFDIFEKEK VDKEALALCT
DRDLQEIGIP LGPRKKILNY FSTRKNSMGI KRPAPQPASG ANIPKESEFC SSSNTRNGDY
LDVGIGQVSV KYPRLIYKPE IFFAFGSPIG MFLTVRGLKR IDPNYRFPTC KGFFNIYHPF
DPVAYRIEPM VVPGVEFEPM LIPHHKGRKR MHLELREGLT RMSMDLKNNL LGSLRMAWKS
FTRAPYPALQ ASETPEETEA EPESTSEKPS DVNTEETSVA VKEEVLPINV GMLNGGQRID
YVLQEKPIES FNEYLFALQS HLCYWESEDT VLLVLKEIYQ TQGIFLDQPL Q
//
ID DDHD2_HUMAN Reviewed; 711 AA.
AC O94830; B3KWV2; Q9H8X7;
DT 13-NOV-2007, integrated into UniProtKB/Swiss-Prot.
read moreDT 13-NOV-2007, sequence version 2.
DT 22-JAN-2014, entry version 92.
DE RecName: Full=Phospholipase DDHD2;
DE EC=3.1.1.-;
DE AltName: Full=DDHD domain-containing protein 2;
DE AltName: Full=KIAA0725p;
DE AltName: Full=SAM, WWE and DDHD domain-containing protein 1;
GN Name=DDHD2; Synonyms=KIAA0725, SAMWD1;
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], FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR
RP LOCATION, AND MUTAGENESIS OF SER-351.
RX PubMed=11788596; DOI=10.1074/jbc.M111092200;
RA Nakajima K., Sonoda H., Mizoguchi T., Aoki J., Arai H., Nagahama M.,
RA Tagaya M., Tani K.;
RT "A novel phospholipase A1 with sequence homology to a mammalian
RT Sec23p-interacting protein, p125.";
RL J. Biol. Chem. 277:11329-11335(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S.,
RA Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A.,
RA Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X.,
RA Allen N.R., Anderson S., Asakawa T., Blechschmidt K., Bloom T.,
RA Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K.,
RA DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G.,
RA Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B.,
RA Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C.,
RA O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K.,
RA Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R.,
RA Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K.,
RA Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q.,
RA Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N.,
RA Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 139-711, AND VARIANT
RP MET-186.
RC TISSUE=Brain;
RX PubMed=9872452; DOI=10.1093/dnares/5.5.277;
RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Miyajima N., Tanaka A.,
RA Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XI.
RT The complete sequences of 100 new cDNA clones from brain which code
RT for large proteins in vitro.";
RL DNA Res. 5:277-286(1998).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 220-711.
RC TISSUE=Placenta;
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 [7]
RP SUBCELLULAR LOCATION.
RX PubMed=15623529; DOI=10.1074/jbc.M409673200;
RA Shimoi W., Ezawa I., Nakamoto K., Uesaki S., Gabreski G., Aridor M.,
RA Yamamoto A., Nagahama M., Tagaya M., Tani K.;
RT "p125 is localized in endoplasmic reticulum exit sites and involved in
RT their organization.";
RL J. Biol. Chem. 280:10141-10148(2005).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF SER-351.
RX PubMed=20932832; DOI=10.1016/j.febslet.2010.09.047;
RA Sato S., Inoue H., Kogure T., Tagaya M., Tani K.;
RT "Golgi-localized KIAA0725p regulates membrane trafficking from the
RT Golgi apparatus to the plasma membrane in mammalian cells.";
RL FEBS Lett. 584:4389-4395(2010).
RN [9]
RP FUNCTION, PHOSPHOLIPID-BINDING, INTERACTION WITH DDHD1, HOMOOLIGOMER
RP FORMATION, AND MUTAGENESIS OF SER-351; ARG-434; LYS-435 AND LYS-436.
RX PubMed=22922100; DOI=10.1016/j.bbamcr.2012.02.002;
RA Inoue H., Baba T., Sato S., Ohtsuki R., Takemori A., Watanabe T.,
RA Tagaya M., Tani K.;
RT "Roles of SAM and DDHD domains in mammalian intracellular
RT phospholipase A1 KIAA0725p.";
RL Biochim. Biophys. Acta 1823:930-939(2012).
RN [10]
RP VARIANT SPG54 HIS-660.
RX PubMed=23176823; DOI=10.1016/j.ajhg.2012.10.017;
RA Schuurs-Hoeijmakers J.H., Geraghty M.T., Kamsteeg E.J., Ben-Salem S.,
RA de Bot S.T., Nijhof B., van de Vondervoort I.I., van der Graaf M.,
RA Nobau A.C., Otte-Holler I., Vermeer S., Smith A.C., Humphreys P.,
RA Schwartzentruber J., Ali B.R., Al-Yahyaee S.A., Tariq S.,
RA Pramathan T., Bayoumi R., Kremer H.P., van de Warrenburg B.P.,
RA van den Akker W.M., Gilissen C., Veltman J.A., Janssen I.M.,
RA Vulto-van Silfhout A.T., van der Velde-Visser S., Lefeber D.J.,
RA Diekstra A., Erasmus C.E., Willemsen M.A., Vissers L.E., Lammens M.,
RA van Bokhoven H., Brunner H.G., Wevers R.A., Schenck A., Al-Gazali L.,
RA de Vries B.B., de Brouwer A.P.;
RT "Mutations in DDHD2, encoding an intracellular phospholipase A(1),
RT cause a recessive form of complex hereditary spastic paraplegia.";
RL Am. J. Hum. Genet. 91:1073-1081(2012).
CC -!- FUNCTION: Phospholipase that hydrolyzes preferentially
CC phosphatidic acid, including 1,2-dioleoyl-sn-phosphatidic acid,
CC and phosphatidylethanolamine. Specifically binds to
CC phosphatidylinositol 3-phosphate (PI(3)P), phosphatidylinositol 4-
CC phosphate (PI(4)P), phosphatidylinositol 5-phosphate (PI(5)P) and
CC possibly phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). May be
CC involved in the maintenance of the endoplasmic reticulum and/or
CC Golgi structures. May regulate the transport between Golgi
CC apparatus and plasma membrane.
CC -!- SUBUNIT: Forms homooligomers and, to a much smaller extent,
CC heterooligomers with DDHD1.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol. Endoplasmic reticulum-
CC Golgi intermediate compartment. Golgi apparatus, cis-Golgi
CC network. Note=Cycles between the Golgi apparatus and the cytosol.
CC DDHD2 recruitment to the Golgi/endoplasmic reticulum-Golgi
CC intermediate compartment (ERGIC) is regulated by the levels of
CC phosphoinositides, including PI(4)P.
CC -!- TISSUE SPECIFICITY: Widely expressed (at protein level).
CC -!- DOMAIN: SAM and DDHD domains together are required for
CC phospholipid binding.
CC -!- DISEASE: Spastic paraplegia 54, autosomal recessive (SPG54)
CC [MIM:615033]: A form of spastic paraplegia, a neurodegenerative
CC disorder characterized by a slow, gradual, progressive weakness
CC and spasticity of the lower limbs. Rate of progression and the
CC severity of symptoms are quite variable. Initial symptoms may
CC include difficulty with balance, weakness and stiffness in the
CC legs, muscle spasms, and dragging the toes when walking.
CC Complicated forms are characterized by the addition of such
CC neurological features as spastic quadriparesis, seizures,
CC dementia, amyotrophy, extrapyramidal disturbance, cerebral or
CC cerebellar atrophy, optic atrophy, and peripheral neuropathy, as
CC well as by extra neurological manifestations such as dysmorphism,
CC albinism, retinitis pigmentosa, deafness, dementia, amyotrophy and
CC ichthyosis. SPG54 patients have delayed psychomotor development,
CC intellectual disability, and early-onset spasticity of the lower
CC limbs. Brain MRI shows a thin corpus callosum and periventricular
CC white matter lesions. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the PA-PLA1 family.
CC -!- SIMILARITY: Contains 1 DDHD domain.
CC -!- SIMILARITY: Contains 1 SAM (sterile alpha motif) domain.
CC -!- SIMILARITY: Contains 1 WWE domain.
CC -!- CAUTION: It is uncertain whether Met-1 or Met-31 is the initiator.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH10504.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=BAB14470.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC -----------------------------------------------------------------------
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DR EMBL; AK023218; BAB14470.1; ALT_INIT; mRNA.
DR EMBL; AK125904; BAG54264.1; -; mRNA.
DR EMBL; AC084024; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC087362; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AB018268; BAA34445.1; -; mRNA.
DR EMBL; CH471080; EAW63324.1; -; Genomic_DNA.
DR EMBL; BC010504; AAH10504.1; ALT_INIT; mRNA.
DR RefSeq; NP_001157704.1; NM_001164232.1.
DR RefSeq; NP_056029.2; NM_015214.2.
DR RefSeq; XP_005273511.1; XM_005273454.1.
DR RefSeq; XP_005273512.1; XM_005273455.1.
DR UniGene; Hs.434966; -.
DR ProteinModelPortal; O94830; -.
DR SMR; O94830; 386-453.
DR IntAct; O94830; 2.
DR MINT; MINT-4649256; -.
DR STRING; 9606.ENSP00000380352; -.
DR PhosphoSite; O94830; -.
DR PaxDb; O94830; -.
DR PRIDE; O94830; -.
DR DNASU; 23259; -.
DR Ensembl; ENST00000397166; ENSP00000380352; ENSG00000085788.
DR Ensembl; ENST00000520272; ENSP00000429932; ENSG00000085788.
DR GeneID; 23259; -.
DR KEGG; hsa:23259; -.
DR UCSC; uc003xlb.3; human.
DR CTD; 23259; -.
DR GeneCards; GC08P038107; -.
DR HGNC; HGNC:29106; DDHD2.
DR HPA; CAB015202; -.
DR HPA; HPA023143; -.
DR HPA; HPA023147; -.
DR HPA; HPA023150; -.
DR MIM; 615003; gene.
DR MIM; 615033; phenotype.
DR neXtProt; NX_O94830; -.
DR Orphanet; 320380; Autosomal recessive spastic paraplegia type 54.
DR PharmGKB; PA128394618; -.
DR eggNOG; NOG285690; -.
DR HOGENOM; HOG000007725; -.
DR HOVERGEN; HBG057256; -.
DR InParanoid; O94830; -.
DR KO; K16545; -.
DR OMA; KDLQEMG; -.
DR OrthoDB; EOG7JDQWX; -.
DR GenomeRNAi; 23259; -.
DR NextBio; 44992; -.
DR PRO; PR:O94830; -.
DR ArrayExpress; O94830; -.
DR Bgee; O94830; -.
DR CleanEx; HS_DDHD2; -.
DR Genevestigator; O94830; -.
DR GO; GO:0005813; C:centrosome; IDA:HPA.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR GO; GO:0016787; F:hydrolase activity; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:InterPro.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0016042; P:lipid catabolic process; IEA:UniProtKB-KW.
DR Gene3D; 1.10.150.50; -; 1.
DR InterPro; IPR004177; DDHD.
DR InterPro; IPR001660; SAM.
DR InterPro; IPR013761; SAM/pointed.
DR InterPro; IPR021129; SAM_type1.
DR InterPro; IPR004170; WWE-dom.
DR Pfam; PF02862; DDHD; 1.
DR Pfam; PF00536; SAM_1; 1.
DR Pfam; PF02825; WWE; 1.
DR SMART; SM00454; SAM; 1.
DR SUPFAM; SSF47769; SSF47769; 1.
DR PROSITE; PS51043; DDHD; 1.
DR PROSITE; PS50105; SAM_DOMAIN; FALSE_NEG.
DR PROSITE; PS50918; WWE; 1.
PE 1: Evidence at protein level;
KW Complete proteome; Cytoplasm; Disease mutation; Golgi apparatus;
KW Hereditary spastic paraplegia; Hydrolase; Lipid degradation;
KW Lipid metabolism; Neurodegeneration; Polymorphism; Reference proteome.
FT CHAIN 1 711 Phospholipase DDHD2.
FT /FTId=PRO_0000309330.
FT DOMAIN 30 112 WWE.
FT DOMAIN 385 448 SAM.
FT DOMAIN 495 700 DDHD.
FT ACT_SITE 351 351 Probable.
FT VARIANT 186 186 T -> M (in dbSNP:rs2306899).
FT /FTId=VAR_036930.
FT VARIANT 660 660 D -> H (in SPG54).
FT /FTId=VAR_069574.
FT MUTAGEN 351 351 S->A: Abolishes phospholipase activity.
FT Loss of efficient targeting to the Golgi
FT apparatus. No effect on PI(3)P-, PI(4)P-,
FT PI(5)P-binding.
FT MUTAGEN 434 434 R->A: Loss of phospholipid binding and of
FT Golgi/ERGIC localization; when associated
FT with A-435 and A-436.
FT MUTAGEN 435 435 K->A: Loss of phospholipid binding and of
FT Golgi/ERGIC localization; when associated
FT with A-434 and A-436.
FT MUTAGEN 436 436 K->A: Loss of phospholipid binding and of
FT Golgi/ERGIC localization; when associated
FT with A-434 and A-435.
FT CONFLICT 292 292 S -> G (in Ref. 2; BAB14470).
FT CONFLICT 376 376 D -> G (in Ref. 5; BAA34445).
SQ SEQUENCE 711 AA; 81032 MW; 8C03CD9254B1DBFB CRC64;
MSSVQSQQEQ LSQSDPSPSP NSCSSFELID MDAGSLYEPV SPHWFYCKII DSKETWIPFN
SEDSQQLEEA YSSGKGCNGR VVPTDGGRYD VHLGERMRYA VYWDELASEV RRCTWFYKGD
KDNKYVPYSE SFSQVLEETY MLAVTLDEWK KKLESPNREI IILHNPKLMV HYQPVAGSDD
WGSTPTEQGR PRTVKRGVEN ISVDIHCGEP LQIDHLVFVV HGIGPACDLR FRSIVQCVND
FRSVSLNLLQ THFKKAQENQ QIGRVEFLPV NWHSPLHSTG VDVDLQRITL PSINRLRHFT
NDTILDVFFY NSPTYCQTIV DTVASEMNRI YTLFLQRNPD FKGGVSIAGH SLGSLILFDI
LTNQKDSLGD IDSEKDSLNI VMDQGDTPTL EEDLKKLQLS EFFDIFEKEK VDKEALALCT
DRDLQEIGIP LGPRKKILNY FSTRKNSMGI KRPAPQPASG ANIPKESEFC SSSNTRNGDY
LDVGIGQVSV KYPRLIYKPE IFFAFGSPIG MFLTVRGLKR IDPNYRFPTC KGFFNIYHPF
DPVAYRIEPM VVPGVEFEPM LIPHHKGRKR MHLELREGLT RMSMDLKNNL LGSLRMAWKS
FTRAPYPALQ ASETPEETEA EPESTSEKPS DVNTEETSVA VKEEVLPINV GMLNGGQRID
YVLQEKPIES FNEYLFALQS HLCYWESEDT VLLVLKEIYQ TQGIFLDQPL Q
//
MIM
615003
*RECORD*
*FIELD* NO
615003
*FIELD* TI
*615003 DDHD DOMAIN-CONTAINING PROTEIN 2; DDHD2
;;KIAA0725
*FIELD* TX
DESCRIPTION
read more
The DDHD2 gene encodes a phospholipase that hydrolyzes sn-1 ester bonds
of phospholipids, producing 2-acyl-lysophospholipids and fatty acids.
DDHD2 prefers phosphatidic acid as substrate and has a role in efficient
membrane trafficking from the Golgi apparatus to the plasma membrane
(summary by Sato et al., 2010).
CLONING
By sequencing clones obtained from a size-fractionated human brain cDNA
library, Nagase et al. (1998) obtained a partial DDHD2 clone, which they
designated KIAA0725. RT-PCR ELISA detected variable DDHD2 expression in
all human tissues examined, with highest expression in brain, followed
by heart, lung, ovary, and testis, much lower expression in kidney,
liver, skeletal muscle, and pancreas, and little to none in spleen.
Using 5-prime RACE of a placenta cDNA library to extend KIAA0725,
Nakajima et al. (2002) obtained a full-length KIAA0725 clone. The
deduced 711-amino acid has a central consensus lipase signature motif,
Gly-X-Ser-X-Gly, and a calculated molecular mass of 81 kD. Northern blot
analysis detected a major transcript of 5.4 kb and a minor transcript of
2.8 kb in all human tissues examined, with highest expression in heart,
brain, skeletal muscle, and testis. Epitope-tagged KIAA0725 was
expressed in punctate structures and large aggregates that partly
overlapped with endoplasmic reticulum (ER) and Golgi markers.
Using immunofluorescence microscopy and photobleaching experiments, Sato
et al. (2010) showed that HeLa cell KIAA0725 rapidly cycled between the
perinuclear cis-Golgi and cytosol.
Inoue et al. (2012) described the domain structure of the full-length
711-amino acid KIAA0725. It has an N-terminal WWE domain predicted to
mediate protein-protein interaction, followed by a PI-PLC-X domain, a
lipase motif, a SAM domain, and a C-terminal DDHD domain. KIAA0725
localized to the ER-Golgi intermediate compartment (ERGIC) and ER exit
sites.
Schuurs-Hoeijmakers et al. (2012) found high expression of the DDHD2
gene in multiple human brain regions, including the cerebellum, cortex,
hippocampus, and thalamus. Expression in the brain was about 10-fold
higher than in other human tissues.
GENE FUNCTION
Nakajima et al. (2002) showed that soluble cytosolic KIAA0725 expressed
in mammalian cells cleaved the ester linkage at the sn-1 position of
phosphatidic acid in the presence or absence of Triton X-100. It also
hydrolyzed phosphatidylethanolamine, but only in the absence of Triton
X-100. KIAA0725 showed no activity against other phospholipids tested.
Overexpression of KIAA0725 altered the distribution of ER-Golgi
proteins. Mutation analysis revealed that catalytic ser351 was required
for lipase activity and for some, but not all, effects of KIAA0725
expression on ER-Golgi protein disorganization.
Using small interfering RNAs, Sato et al. (2010) showed that knockdown
of KIAA0725 in HeLa cells retarded the transport of vesicular stomatitis
virus-encoded glycoprotein (VSVG) from the Golgi apparatus to the plasma
membrane.
Using a lipid overlay and liposome sedimentation assays, Inoue et al.
(2012) showed that recombinant human KIAA0725 bound phosphatidylinositol
3-phosphate, i.e., PI(3)P, PI(4)P, and PI(5)P. Mutation analysis
revealed that the arg434-lys435-lys436 motif within its SAM domain, but
not its catalytic ser351, was required for binding of KIAA0725 to
phospholipids, and for KIAA0725 Golgi/ERGIC membrane association.
KIAA0725 formed oligomers via several interaction sites, including the
DDHD domain, which was also required for phospholipid binding. Nearly
the entire molecule was required for phospholipase activity.
MAPPING
By radiation hybrid analysis, Nagase et al. (1998) mapped the DDHD2 gene
to chromosome 8.
Hartz (2012) mapped the DDHD2 gene to chromosome 8p11.23 based on an
alignment of the DDHD2 sequence (GenBank GENBANK AB018268) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
By exome sequencing of 2 unrelated families with a complex form of
autosomal recessive spastic paraplegia (SPG54; 615033),
Schuurs-Hoeijmakers et al. (2012) identified biallelic mutations in the
DDHD2 gene (615003.0001-615003.0004). The mutations segregated with the
phenotype in both families. Affected individuals from a large Omani
family with a similar disorder, originally reported as family A by
Al-Yahyaee et al. (2006), were found to be homozygous for another
mutation (615003.0005). An unrelated Iranian patient was homozygous for
yet another DDHD2 mutation (615003.0006). Five of the 6 mutations were
predicted to introduce a premature termination codon into the mRNA. The
phenotype was characterized by delayed psychomotor development,
intellectual disability, and early-onset spasticity of the lower limbs.
Brain MRI showed a thin corpus callosum and periventricular white matter
lesions, whereas brain magnetic resonance spectroscopy showed an
abnormal lipid peak. Patient fibroblasts did not show any gross
abnormalities in lipid metabolism or organelle morphology. Knockdown of
the Drosophila Ddhd ortholog in 2 cell lines did not change the overall
synaptic terminals in the neuromuscular junction, although 1 cell line
showed smaller synaptic terminals. Knockdown in all 3 cell lines caused
a decrease in active-zone number per synaptic terminal; the active zones
represent the presynaptic sites of neurotransmitter release. However,
mutant flies showed no obvious motor abnormalities. Overall, the
findings suggested that DDHD2 may play a role in synaptic organization
and plasticity.
In affected members of 2 unrelated families with SPG54, Gonzalez et al.
(2013) identified homozygous truncating mutations in the DDHD2 gene
(615003.0006 and 615003.0007). The 2 families were identified from a
larger cohort of 79 probands with autosomal recessive SPG who underwent
exome sequencing. The phenotype, which included early onset of spastic
paraplegia, mental retardation, and thin corpus callosum, was similar to
that reported by Schuurs-Hoeijmakers et al. (2012).
*FIELD* AV
.0001
SPASTIC PARAPLEGIA 54, AUTOSOMAL RECESSIVE
DDHD2, 1-BP INS, 1804T
In 2 sibs of Dutch Filipino descent with autosomal recessive spastic
paraplegia-54 (SPG54; 615033), Schuurs-Hoeijmakers et al. (2012)
identified compound heterozygosity for 2 mutations in the DDHD2 gene: a
1-bp insertion (1804insT), resulting in a frameshift and premature
termination (Thr602IlefsTer18), and a 1-bp deletion (2057delA;
615003.0002), resulting in a frameshift and premature termination
(Glu686GlyfsTer35). RT-PCR analysis suggested that 1 of the alleles,
probably 1804delT, resulted in nonsense-mediated mRNA decay. The
mutations were found by exome sequencing and confirmed by Sanger
sequencing. Each unaffected parent was heterozygous for 1 of the
mutations, which were not found in several large exome databases.
.0002
SPASTIC PARAPLEGIA 54, AUTOSOMAL RECESSIVE
DDHD2, 1-BP DEL, 2057A
See 615003.0001 and Schuurs-Hoeijmakers et al. (2012).
.0003
SPASTIC PARAPLEGIA 54, AUTOSOMAL RECESSIVE
DDHD2, 1-BP DUP, 138C
In 2 Canadian sibs with SPG54 (615033), Schuurs-Hoeijmakers et al.
(2012) identified compound heterozygosity for 2 mutations in the DDHD2
gene: a 1-bp duplication (138dupC), resulting in a frameshift and
premature termination (Ile463HisfsTer6), and a 1978G-C transversion,
resulting in an asp660-to-his (D660H; 615003.0004) substitution at a
conserved residue in the RIDYXL motif. The mutations were found by exome
sequencing and confirmed by Sanger sequencing. The 1-bp duplication was
not found in several large exome databases. The D660H mutation was found
in 1 of 13,006 control alleles, but not in a local SNP database of 2,302
alleles. Each unaffected parent was heterozygous for 1 of the mutations.
.0004
SPASTIC PARAPLEGIA 54, AUTOSOMAL RECESSIVE
DDHD2, ASP660HIS
See 615003.0003 and Schuurs-Hoeijmakers et al. (2012).
.0005
SPASTIC PARAPLEGIA 54, AUTOSOMAL RECESSIVE
DDHD2, ARG516TER
In affected members of a large consanguineous Omani family with SPG54
(615033), Schuurs-Hoeijmakers et al. (2012) identified a homozygous
1546C-T transition in the DDHD2 gene, resulting in an arg516-to-ter
(R516X) substitution. This family had previously been reported by
Al-Yahyaee et al. (2006) as family A, showing linkage to chromosome 8p.
RT-PCR analysis suggested that the mutation resulted in
nonsense-mediated mRNA decay.
.0006
SPASTIC PARAPLEGIA 54, AUTOSOMAL RECESSIVE
DDHD2, ARG287TER
In an Iranian man, born of consanguineous parents, with SPG54 (615033),
Schuurs-Hoeijmakers et al. (2012) identified a homozygous 859C-T
transition in exon 9 of the DDHD2 gene, resulting in an arg287-to-ter
(R287X) substitution. RT-PCR analysis suggested that the mutation
resulted in nonsense-mediated mRNA decay.
Gonzalez et al. (2013) identified a homozygous R287X mutation in 2
Iranian sibs, born of consanguineous parents, with SPG54. The mutation
was found by exome sequencing and segregated with the disorder in the
family.
.0007
SPASTIC PARAPLEGIA 54, AUTOSOMAL RECESSIVE
DDHD2, 2-BP DEL, 1982AT
In 2 Indian brothers with SPG54 (615033), Gonzalez et al. (2013)
identified a homozygous 2-bp deletion (c.1982_1983delAT) in the DDHD2
gene, resulting in a frameshift and premature termination
(Tyr661CysfsTer8). The mutation was found by exome sequencing.
*FIELD* RF
1. Al-Yahyaee, S.; Al-Gazali, L. I.; De Jonghe, P.; Al-Barwany, H.;
Al-Kindi, M.; De Vriendt, E.; Chand, P.; Koul, R.; Jacob, P. C.; Gururaj,
A.; Sztriha, L.; Parrado, A.; Van Broeckhoven, C.; Bayoumi, R. A.
: A novel locus for hereditary spastic paraplegia with thin corpus
callosum and epilepsy. Neurology 66: 1230-1234, 2006.
2. Gonzalez, M.; Nampoothiri, S.; Kornblum, C.; Oteyza, A. C.; Walter,
J.; Konidari, I.; Hulme, W.; Speziani, F.; Schols, L.; Zuchner, S.;
Schule, R.: Mutations in phospholipase DDHD2 cause autosomal recessive
hereditary spastic paraplegia (SPG54). Europ. J. Hum. Genet. 21:
1214-1218, 2013.
3. Hartz, P. A.: Personal Communication. Baltimore, Md. 12/21/2012.
4. Inoue, H.; Baba, T.; Sato, S.; Ohtsuki, R.; Takemori, A.; Watanabe,
T.; Tagaya, M.; Tani, K.: Roles of SAM and DDHD domains in mammalian
intracellular phospholipase A1 KIAA0725p. Biochim. Biophys. Acta 1823:
930-939, 2012.
5. Nagase, T.; Ishikawa, K.; Suyama, M.; Kikuno, R.; Miyajima, N.;
Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O.: Prediction of the
coding sequences of unidentified human genes. XI. The complete sequences
of 100 new cDNA clones from brain which code for large proteins in
vitro. DNA Res. 5: 277-286, 1998.
6. Nakajima, K.; Sonoda, H.; Mizoguchi, T.; Aoki, J.; Arai, H.; Nagahama,
M.; Tagaya, M.; Tani, K.: A novel phospholipase A1 with sequence
homology to a mammalian Sec23p-interacting protein, p125. J. Biol.
Chem. 277: 11329-11335, 2002.
7. Sato, S.; Inoue, H.; Kogure, T.; Tagaya, M.; Tani, K.: Golgi-localized
KIAA0725p regulates membrane trafficking from the Golgi apparatus
to the plasma membrane in mammalian cell. FEBS Lett. 584: 4389-4395,
2010.
8. Schuurs-Hoeijmakers, J. H. M.; Geraghty, M. T.; Kamsteeg, E.-J.;
Ben-Salem, S.; de Bot, S. T.; Nijhof, B.; van de Vondervoort, I. I.
G. M.; van der Graaf, M.; Nobau, A. C.; Otte-Holler, I.; Vermeer,
S.; Smith, A. C.; and 29 others: Mutations in DDHD2, encoding an
intracellular phospholipase A(1), cause a recessive form of complex
hereditary spastic paraplegia. Am. J. Hum. Genet. 91: 1073-1081,
2012.
*FIELD* CN
Cassandra L. Kniffin - updated: 12/4/2013
Cassandra L. Kniffin - updated: 1/24/2013
*FIELD* CD
Patricia A. Hartz: 12/21/2012
*FIELD* ED
carol: 12/16/2013
ckniffin: 12/4/2013
carol: 8/28/2013
carol: 1/25/2013
ckniffin: 1/24/2013
alopez: 12/21/2012
*RECORD*
*FIELD* NO
615003
*FIELD* TI
*615003 DDHD DOMAIN-CONTAINING PROTEIN 2; DDHD2
;;KIAA0725
*FIELD* TX
DESCRIPTION
read more
The DDHD2 gene encodes a phospholipase that hydrolyzes sn-1 ester bonds
of phospholipids, producing 2-acyl-lysophospholipids and fatty acids.
DDHD2 prefers phosphatidic acid as substrate and has a role in efficient
membrane trafficking from the Golgi apparatus to the plasma membrane
(summary by Sato et al., 2010).
CLONING
By sequencing clones obtained from a size-fractionated human brain cDNA
library, Nagase et al. (1998) obtained a partial DDHD2 clone, which they
designated KIAA0725. RT-PCR ELISA detected variable DDHD2 expression in
all human tissues examined, with highest expression in brain, followed
by heart, lung, ovary, and testis, much lower expression in kidney,
liver, skeletal muscle, and pancreas, and little to none in spleen.
Using 5-prime RACE of a placenta cDNA library to extend KIAA0725,
Nakajima et al. (2002) obtained a full-length KIAA0725 clone. The
deduced 711-amino acid has a central consensus lipase signature motif,
Gly-X-Ser-X-Gly, and a calculated molecular mass of 81 kD. Northern blot
analysis detected a major transcript of 5.4 kb and a minor transcript of
2.8 kb in all human tissues examined, with highest expression in heart,
brain, skeletal muscle, and testis. Epitope-tagged KIAA0725 was
expressed in punctate structures and large aggregates that partly
overlapped with endoplasmic reticulum (ER) and Golgi markers.
Using immunofluorescence microscopy and photobleaching experiments, Sato
et al. (2010) showed that HeLa cell KIAA0725 rapidly cycled between the
perinuclear cis-Golgi and cytosol.
Inoue et al. (2012) described the domain structure of the full-length
711-amino acid KIAA0725. It has an N-terminal WWE domain predicted to
mediate protein-protein interaction, followed by a PI-PLC-X domain, a
lipase motif, a SAM domain, and a C-terminal DDHD domain. KIAA0725
localized to the ER-Golgi intermediate compartment (ERGIC) and ER exit
sites.
Schuurs-Hoeijmakers et al. (2012) found high expression of the DDHD2
gene in multiple human brain regions, including the cerebellum, cortex,
hippocampus, and thalamus. Expression in the brain was about 10-fold
higher than in other human tissues.
GENE FUNCTION
Nakajima et al. (2002) showed that soluble cytosolic KIAA0725 expressed
in mammalian cells cleaved the ester linkage at the sn-1 position of
phosphatidic acid in the presence or absence of Triton X-100. It also
hydrolyzed phosphatidylethanolamine, but only in the absence of Triton
X-100. KIAA0725 showed no activity against other phospholipids tested.
Overexpression of KIAA0725 altered the distribution of ER-Golgi
proteins. Mutation analysis revealed that catalytic ser351 was required
for lipase activity and for some, but not all, effects of KIAA0725
expression on ER-Golgi protein disorganization.
Using small interfering RNAs, Sato et al. (2010) showed that knockdown
of KIAA0725 in HeLa cells retarded the transport of vesicular stomatitis
virus-encoded glycoprotein (VSVG) from the Golgi apparatus to the plasma
membrane.
Using a lipid overlay and liposome sedimentation assays, Inoue et al.
(2012) showed that recombinant human KIAA0725 bound phosphatidylinositol
3-phosphate, i.e., PI(3)P, PI(4)P, and PI(5)P. Mutation analysis
revealed that the arg434-lys435-lys436 motif within its SAM domain, but
not its catalytic ser351, was required for binding of KIAA0725 to
phospholipids, and for KIAA0725 Golgi/ERGIC membrane association.
KIAA0725 formed oligomers via several interaction sites, including the
DDHD domain, which was also required for phospholipid binding. Nearly
the entire molecule was required for phospholipase activity.
MAPPING
By radiation hybrid analysis, Nagase et al. (1998) mapped the DDHD2 gene
to chromosome 8.
Hartz (2012) mapped the DDHD2 gene to chromosome 8p11.23 based on an
alignment of the DDHD2 sequence (GenBank GENBANK AB018268) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
By exome sequencing of 2 unrelated families with a complex form of
autosomal recessive spastic paraplegia (SPG54; 615033),
Schuurs-Hoeijmakers et al. (2012) identified biallelic mutations in the
DDHD2 gene (615003.0001-615003.0004). The mutations segregated with the
phenotype in both families. Affected individuals from a large Omani
family with a similar disorder, originally reported as family A by
Al-Yahyaee et al. (2006), were found to be homozygous for another
mutation (615003.0005). An unrelated Iranian patient was homozygous for
yet another DDHD2 mutation (615003.0006). Five of the 6 mutations were
predicted to introduce a premature termination codon into the mRNA. The
phenotype was characterized by delayed psychomotor development,
intellectual disability, and early-onset spasticity of the lower limbs.
Brain MRI showed a thin corpus callosum and periventricular white matter
lesions, whereas brain magnetic resonance spectroscopy showed an
abnormal lipid peak. Patient fibroblasts did not show any gross
abnormalities in lipid metabolism or organelle morphology. Knockdown of
the Drosophila Ddhd ortholog in 2 cell lines did not change the overall
synaptic terminals in the neuromuscular junction, although 1 cell line
showed smaller synaptic terminals. Knockdown in all 3 cell lines caused
a decrease in active-zone number per synaptic terminal; the active zones
represent the presynaptic sites of neurotransmitter release. However,
mutant flies showed no obvious motor abnormalities. Overall, the
findings suggested that DDHD2 may play a role in synaptic organization
and plasticity.
In affected members of 2 unrelated families with SPG54, Gonzalez et al.
(2013) identified homozygous truncating mutations in the DDHD2 gene
(615003.0006 and 615003.0007). The 2 families were identified from a
larger cohort of 79 probands with autosomal recessive SPG who underwent
exome sequencing. The phenotype, which included early onset of spastic
paraplegia, mental retardation, and thin corpus callosum, was similar to
that reported by Schuurs-Hoeijmakers et al. (2012).
*FIELD* AV
.0001
SPASTIC PARAPLEGIA 54, AUTOSOMAL RECESSIVE
DDHD2, 1-BP INS, 1804T
In 2 sibs of Dutch Filipino descent with autosomal recessive spastic
paraplegia-54 (SPG54; 615033), Schuurs-Hoeijmakers et al. (2012)
identified compound heterozygosity for 2 mutations in the DDHD2 gene: a
1-bp insertion (1804insT), resulting in a frameshift and premature
termination (Thr602IlefsTer18), and a 1-bp deletion (2057delA;
615003.0002), resulting in a frameshift and premature termination
(Glu686GlyfsTer35). RT-PCR analysis suggested that 1 of the alleles,
probably 1804delT, resulted in nonsense-mediated mRNA decay. The
mutations were found by exome sequencing and confirmed by Sanger
sequencing. Each unaffected parent was heterozygous for 1 of the
mutations, which were not found in several large exome databases.
.0002
SPASTIC PARAPLEGIA 54, AUTOSOMAL RECESSIVE
DDHD2, 1-BP DEL, 2057A
See 615003.0001 and Schuurs-Hoeijmakers et al. (2012).
.0003
SPASTIC PARAPLEGIA 54, AUTOSOMAL RECESSIVE
DDHD2, 1-BP DUP, 138C
In 2 Canadian sibs with SPG54 (615033), Schuurs-Hoeijmakers et al.
(2012) identified compound heterozygosity for 2 mutations in the DDHD2
gene: a 1-bp duplication (138dupC), resulting in a frameshift and
premature termination (Ile463HisfsTer6), and a 1978G-C transversion,
resulting in an asp660-to-his (D660H; 615003.0004) substitution at a
conserved residue in the RIDYXL motif. The mutations were found by exome
sequencing and confirmed by Sanger sequencing. The 1-bp duplication was
not found in several large exome databases. The D660H mutation was found
in 1 of 13,006 control alleles, but not in a local SNP database of 2,302
alleles. Each unaffected parent was heterozygous for 1 of the mutations.
.0004
SPASTIC PARAPLEGIA 54, AUTOSOMAL RECESSIVE
DDHD2, ASP660HIS
See 615003.0003 and Schuurs-Hoeijmakers et al. (2012).
.0005
SPASTIC PARAPLEGIA 54, AUTOSOMAL RECESSIVE
DDHD2, ARG516TER
In affected members of a large consanguineous Omani family with SPG54
(615033), Schuurs-Hoeijmakers et al. (2012) identified a homozygous
1546C-T transition in the DDHD2 gene, resulting in an arg516-to-ter
(R516X) substitution. This family had previously been reported by
Al-Yahyaee et al. (2006) as family A, showing linkage to chromosome 8p.
RT-PCR analysis suggested that the mutation resulted in
nonsense-mediated mRNA decay.
.0006
SPASTIC PARAPLEGIA 54, AUTOSOMAL RECESSIVE
DDHD2, ARG287TER
In an Iranian man, born of consanguineous parents, with SPG54 (615033),
Schuurs-Hoeijmakers et al. (2012) identified a homozygous 859C-T
transition in exon 9 of the DDHD2 gene, resulting in an arg287-to-ter
(R287X) substitution. RT-PCR analysis suggested that the mutation
resulted in nonsense-mediated mRNA decay.
Gonzalez et al. (2013) identified a homozygous R287X mutation in 2
Iranian sibs, born of consanguineous parents, with SPG54. The mutation
was found by exome sequencing and segregated with the disorder in the
family.
.0007
SPASTIC PARAPLEGIA 54, AUTOSOMAL RECESSIVE
DDHD2, 2-BP DEL, 1982AT
In 2 Indian brothers with SPG54 (615033), Gonzalez et al. (2013)
identified a homozygous 2-bp deletion (c.1982_1983delAT) in the DDHD2
gene, resulting in a frameshift and premature termination
(Tyr661CysfsTer8). The mutation was found by exome sequencing.
*FIELD* RF
1. Al-Yahyaee, S.; Al-Gazali, L. I.; De Jonghe, P.; Al-Barwany, H.;
Al-Kindi, M.; De Vriendt, E.; Chand, P.; Koul, R.; Jacob, P. C.; Gururaj,
A.; Sztriha, L.; Parrado, A.; Van Broeckhoven, C.; Bayoumi, R. A.
: A novel locus for hereditary spastic paraplegia with thin corpus
callosum and epilepsy. Neurology 66: 1230-1234, 2006.
2. Gonzalez, M.; Nampoothiri, S.; Kornblum, C.; Oteyza, A. C.; Walter,
J.; Konidari, I.; Hulme, W.; Speziani, F.; Schols, L.; Zuchner, S.;
Schule, R.: Mutations in phospholipase DDHD2 cause autosomal recessive
hereditary spastic paraplegia (SPG54). Europ. J. Hum. Genet. 21:
1214-1218, 2013.
3. Hartz, P. A.: Personal Communication. Baltimore, Md. 12/21/2012.
4. Inoue, H.; Baba, T.; Sato, S.; Ohtsuki, R.; Takemori, A.; Watanabe,
T.; Tagaya, M.; Tani, K.: Roles of SAM and DDHD domains in mammalian
intracellular phospholipase A1 KIAA0725p. Biochim. Biophys. Acta 1823:
930-939, 2012.
5. Nagase, T.; Ishikawa, K.; Suyama, M.; Kikuno, R.; Miyajima, N.;
Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O.: Prediction of the
coding sequences of unidentified human genes. XI. The complete sequences
of 100 new cDNA clones from brain which code for large proteins in
vitro. DNA Res. 5: 277-286, 1998.
6. Nakajima, K.; Sonoda, H.; Mizoguchi, T.; Aoki, J.; Arai, H.; Nagahama,
M.; Tagaya, M.; Tani, K.: A novel phospholipase A1 with sequence
homology to a mammalian Sec23p-interacting protein, p125. J. Biol.
Chem. 277: 11329-11335, 2002.
7. Sato, S.; Inoue, H.; Kogure, T.; Tagaya, M.; Tani, K.: Golgi-localized
KIAA0725p regulates membrane trafficking from the Golgi apparatus
to the plasma membrane in mammalian cell. FEBS Lett. 584: 4389-4395,
2010.
8. Schuurs-Hoeijmakers, J. H. M.; Geraghty, M. T.; Kamsteeg, E.-J.;
Ben-Salem, S.; de Bot, S. T.; Nijhof, B.; van de Vondervoort, I. I.
G. M.; van der Graaf, M.; Nobau, A. C.; Otte-Holler, I.; Vermeer,
S.; Smith, A. C.; and 29 others: Mutations in DDHD2, encoding an
intracellular phospholipase A(1), cause a recessive form of complex
hereditary spastic paraplegia. Am. J. Hum. Genet. 91: 1073-1081,
2012.
*FIELD* CN
Cassandra L. Kniffin - updated: 12/4/2013
Cassandra L. Kniffin - updated: 1/24/2013
*FIELD* CD
Patricia A. Hartz: 12/21/2012
*FIELD* ED
carol: 12/16/2013
ckniffin: 12/4/2013
carol: 8/28/2013
carol: 1/25/2013
ckniffin: 1/24/2013
alopez: 12/21/2012
MIM
615033
*RECORD*
*FIELD* NO
615033
*FIELD* TI
#615033 SPASTIC PARAPLEGIA 54, AUTOSOMAL RECESSIVE; SPG54
*FIELD* TX
A number sign (#) is used with this entry because autosomal recessive
read morespastic paraplegia-54 (SPG54) is caused by homozygous or compound
heterozygous mutation in the DDHD2 gene (615003) on chromosome 8p11.
DESCRIPTION
Spastic paraplegia-54 is a complicated form of spastic paraplegia, a
neurodegenerative disorder affecting fibers of the corticospinal tract.
Affected individuals have delayed psychomotor development, intellectual
disability, and early-onset spasticity of the lower limbs. Brain MRI
shows a thin corpus callosum and periventricular white matter lesions.
Brain magnetic resonance spectroscopy shows an abnormal lipid peak
(summary by Schuurs-Hoeijmakers et al., 2012).
For a general phenotypic description and a discussion of genetic
heterogeneity of autosomal recessive spastic paraplegia, see 270800.
CLINICAL FEATURES
Schuurs-Hoeijmakers et al. (2012) reported 2 unrelated families in which
2 sibs in each family had early-onset spastic paraplegia and
intellectual disability. Subsequently, a large Omani family and an
unrelated Iranian patient with a similar disorder were ascertained. The
phenotype among all 4 families was relatively homogeneous. Affected
individuals showed delayed psychomotor development that evolved into
mental retardation, and early onset of progressive spasticity before age
2 years. Other features included foot contractures, dysarthria,
dysphagia, and strabismus. Three of 5 patients examined had optic
hypoplasia. Brain imaging showed thin corpus callosum and subtle
periventricular white matter hyperintensities. Five individuals from 3
families showed an abnormal lipid peak on magnetic resonance
spectroscopy (MRS) of cerebral tissue, with the highest intensity around
the basal ganglia and thalamus. This peak was similar to that observed
in Sjogren-Larssen syndrome (SLS; 270200) and is indicative of abnormal
brain lipid accumulation. Two unrelated males had a syrinx on spinal
MRI.
Gonzalez et al. (2013) identified 2 unrelated families with SPG54 among
a cohort of 79 probands with autosomal recessive SPG who underwent exome
sequencing. The first family contained 2 affected sibs, born of
consanguineous Iranian parents. Both sibs developed a spastic gait
disorder in early childhood, but were still able to walk unsupported at
ages 19 and 25 years. Both had mental retardation requiring special
schooling, as well as short stature, high-arched palate, and dysgenesis
of the corpus callosum on brain imaging. The second family was of Indian
origin with no known consanguinity, but the parents originated from the
same village and were part of the Muslim community. These brothers
developed spasticity of the lower limbs in the first year of life. They
also had mental retardation, short stature, and thin corpus callosum.
One had dysmorphic features, with telecanthus and slanted palpebral
fissures. The phenotype in these patients was similar to that reported
by Schuurs-Hoeijmakers et al. (2012).
INHERITANCE
The transmission pattern in the families with SPG54 reported by
Schuurs-Hoeijmakers et al. (2012) was consistent with autosomal
recessive inheritance.
MOLECULAR GENETICS
By exome sequencing of 2 unrelated families with a complex form of
autosomal recessive spastic paraplegia, Schuurs-Hoeijmakers et al.
(2012) identified biallelic mutations in the DDHD2 gene
(615003.0001-615003.0004). The mutations segregated with the phenotype
in both families. Different homozygous mutations in the DDHD2 gene were
found in affected individuals from a large Omani family with a similar
disorder, originally reported as family A by Al-Yahyaee et al. (2006),
an in an unrelated Iranian patient (see 615003.0005 and 615003.0006).
Knockdown of the Drosophila ortholog resulted in a reduction of the
number of active zones at the synaptic terminal, suggesting that the
DDHD2 gene plays a role in synaptic function. The DDHD2 gene was found
to be highly expressed in various human brain regions.
In affected members of 2 unrelated families with SPG54, Gonzalez et al.
(2013) identified homozygous truncating mutations in the DDHD2 gene
(615003.0006 and 615003.0007). The 2 families were identified from a
larger cohort of 79 probands with autosomal recessive SPG who underwent
exome sequencing.
*FIELD* RF
1. Al-Yahyaee, S.; Al-Gazali, L. I.; De Jonghe, P.; Al-Barwany, H.;
Al-Kindi, M.; De Vriendt, E.; Chand, P.; Koul, R.; Jacob, P. C.; Gururaj,
A.; Sztriha, L.; Parrado, A.; Van Broeckhoven, C.; Bayoumi, R. A.
: A novel locus for hereditary spastic paraplegia with thin corpus
callosum and epilepsy. Neurology 66: 1230-1234, 2006.
2. Gonzalez, M.; Nampoothiri, S.; Kornblum, C.; Oteyza, A. C.; Walter,
J.; Konidari, I.; Hulme, W.; Speziani, F.; Schols, L.; Zuchner, S.;
Schule, R.: Mutations in phospholipase DDHD2 cause autosomal recessive
hereditary spastic paraplegia (SPG54). Europ. J. Hum. Genet. 21:
1214-1218, 2013.
3. Schuurs-Hoeijmakers, J. H. M.; Geraghty, M. T.; Kamsteeg, E.-J.;
Ben-Salem, S.; de Bot, S. T.; Nijhof, B.; van de Vondervoort, I. I.
G. M.; van der Graaf, M.; Nobau, A. C.; Otte-Holler, I.; Vermeer,
S.; Smith, A. C.; and 29 others: Mutations in DDHD2, encoding an
intracellular phospholipase A(1), cause a recessive form of complex
hereditary spastic paraplegia. Am. J. Hum. Genet. 91: 1073-1081,
2012.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Strabismus;
Optic nerve hypoplasia (in some patients)
ABDOMEN:
[Gastrointestinal];
Dysphagia;
Constipation (in some patients);
Fecal incontinence (rare)
GENITOURINARY:
[Bladder];
Urinary incontinence (rare)
SKELETAL:
[Feet];
Foot contractures
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation;
Spastic paraplegia;
Hyperreflexia;
Extensor plantar responses;
Lower limb weakness;
Dysarthria;
Thin corpus callosum;
Periventricular white matter abnormalities;
Abnormal lipid peak on brain MRS;
Spinal cord syrinx (in 2 patients)
MISCELLANEOUS:
Onset of spasticity by age 2 years;
Progressive disorder
MOLECULAR BASIS:
Caused by mutation in the DDHD domain-containing protein 2 gene (DDHD2,
615003.0001)
*FIELD* CD
Cassandra L. Kniffin: 1/24/2013
*FIELD* ED
joanna: 06/04/2013
ckniffin: 1/24/2013
*FIELD* CN
Cassandra L. Kniffin - updated: 12/4/2013
*FIELD* CD
Cassandra L. Kniffin: 1/23/2013
*FIELD* ED
carol: 12/16/2013
ckniffin: 12/4/2013
carol: 1/28/2013
carol: 1/25/2013
ckniffin: 1/24/2013
*RECORD*
*FIELD* NO
615033
*FIELD* TI
#615033 SPASTIC PARAPLEGIA 54, AUTOSOMAL RECESSIVE; SPG54
*FIELD* TX
A number sign (#) is used with this entry because autosomal recessive
read morespastic paraplegia-54 (SPG54) is caused by homozygous or compound
heterozygous mutation in the DDHD2 gene (615003) on chromosome 8p11.
DESCRIPTION
Spastic paraplegia-54 is a complicated form of spastic paraplegia, a
neurodegenerative disorder affecting fibers of the corticospinal tract.
Affected individuals have delayed psychomotor development, intellectual
disability, and early-onset spasticity of the lower limbs. Brain MRI
shows a thin corpus callosum and periventricular white matter lesions.
Brain magnetic resonance spectroscopy shows an abnormal lipid peak
(summary by Schuurs-Hoeijmakers et al., 2012).
For a general phenotypic description and a discussion of genetic
heterogeneity of autosomal recessive spastic paraplegia, see 270800.
CLINICAL FEATURES
Schuurs-Hoeijmakers et al. (2012) reported 2 unrelated families in which
2 sibs in each family had early-onset spastic paraplegia and
intellectual disability. Subsequently, a large Omani family and an
unrelated Iranian patient with a similar disorder were ascertained. The
phenotype among all 4 families was relatively homogeneous. Affected
individuals showed delayed psychomotor development that evolved into
mental retardation, and early onset of progressive spasticity before age
2 years. Other features included foot contractures, dysarthria,
dysphagia, and strabismus. Three of 5 patients examined had optic
hypoplasia. Brain imaging showed thin corpus callosum and subtle
periventricular white matter hyperintensities. Five individuals from 3
families showed an abnormal lipid peak on magnetic resonance
spectroscopy (MRS) of cerebral tissue, with the highest intensity around
the basal ganglia and thalamus. This peak was similar to that observed
in Sjogren-Larssen syndrome (SLS; 270200) and is indicative of abnormal
brain lipid accumulation. Two unrelated males had a syrinx on spinal
MRI.
Gonzalez et al. (2013) identified 2 unrelated families with SPG54 among
a cohort of 79 probands with autosomal recessive SPG who underwent exome
sequencing. The first family contained 2 affected sibs, born of
consanguineous Iranian parents. Both sibs developed a spastic gait
disorder in early childhood, but were still able to walk unsupported at
ages 19 and 25 years. Both had mental retardation requiring special
schooling, as well as short stature, high-arched palate, and dysgenesis
of the corpus callosum on brain imaging. The second family was of Indian
origin with no known consanguinity, but the parents originated from the
same village and were part of the Muslim community. These brothers
developed spasticity of the lower limbs in the first year of life. They
also had mental retardation, short stature, and thin corpus callosum.
One had dysmorphic features, with telecanthus and slanted palpebral
fissures. The phenotype in these patients was similar to that reported
by Schuurs-Hoeijmakers et al. (2012).
INHERITANCE
The transmission pattern in the families with SPG54 reported by
Schuurs-Hoeijmakers et al. (2012) was consistent with autosomal
recessive inheritance.
MOLECULAR GENETICS
By exome sequencing of 2 unrelated families with a complex form of
autosomal recessive spastic paraplegia, Schuurs-Hoeijmakers et al.
(2012) identified biallelic mutations in the DDHD2 gene
(615003.0001-615003.0004). The mutations segregated with the phenotype
in both families. Different homozygous mutations in the DDHD2 gene were
found in affected individuals from a large Omani family with a similar
disorder, originally reported as family A by Al-Yahyaee et al. (2006),
an in an unrelated Iranian patient (see 615003.0005 and 615003.0006).
Knockdown of the Drosophila ortholog resulted in a reduction of the
number of active zones at the synaptic terminal, suggesting that the
DDHD2 gene plays a role in synaptic function. The DDHD2 gene was found
to be highly expressed in various human brain regions.
In affected members of 2 unrelated families with SPG54, Gonzalez et al.
(2013) identified homozygous truncating mutations in the DDHD2 gene
(615003.0006 and 615003.0007). The 2 families were identified from a
larger cohort of 79 probands with autosomal recessive SPG who underwent
exome sequencing.
*FIELD* RF
1. Al-Yahyaee, S.; Al-Gazali, L. I.; De Jonghe, P.; Al-Barwany, H.;
Al-Kindi, M.; De Vriendt, E.; Chand, P.; Koul, R.; Jacob, P. C.; Gururaj,
A.; Sztriha, L.; Parrado, A.; Van Broeckhoven, C.; Bayoumi, R. A.
: A novel locus for hereditary spastic paraplegia with thin corpus
callosum and epilepsy. Neurology 66: 1230-1234, 2006.
2. Gonzalez, M.; Nampoothiri, S.; Kornblum, C.; Oteyza, A. C.; Walter,
J.; Konidari, I.; Hulme, W.; Speziani, F.; Schols, L.; Zuchner, S.;
Schule, R.: Mutations in phospholipase DDHD2 cause autosomal recessive
hereditary spastic paraplegia (SPG54). Europ. J. Hum. Genet. 21:
1214-1218, 2013.
3. Schuurs-Hoeijmakers, J. H. M.; Geraghty, M. T.; Kamsteeg, E.-J.;
Ben-Salem, S.; de Bot, S. T.; Nijhof, B.; van de Vondervoort, I. I.
G. M.; van der Graaf, M.; Nobau, A. C.; Otte-Holler, I.; Vermeer,
S.; Smith, A. C.; and 29 others: Mutations in DDHD2, encoding an
intracellular phospholipase A(1), cause a recessive form of complex
hereditary spastic paraplegia. Am. J. Hum. Genet. 91: 1073-1081,
2012.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Strabismus;
Optic nerve hypoplasia (in some patients)
ABDOMEN:
[Gastrointestinal];
Dysphagia;
Constipation (in some patients);
Fecal incontinence (rare)
GENITOURINARY:
[Bladder];
Urinary incontinence (rare)
SKELETAL:
[Feet];
Foot contractures
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation;
Spastic paraplegia;
Hyperreflexia;
Extensor plantar responses;
Lower limb weakness;
Dysarthria;
Thin corpus callosum;
Periventricular white matter abnormalities;
Abnormal lipid peak on brain MRS;
Spinal cord syrinx (in 2 patients)
MISCELLANEOUS:
Onset of spasticity by age 2 years;
Progressive disorder
MOLECULAR BASIS:
Caused by mutation in the DDHD domain-containing protein 2 gene (DDHD2,
615003.0001)
*FIELD* CD
Cassandra L. Kniffin: 1/24/2013
*FIELD* ED
joanna: 06/04/2013
ckniffin: 1/24/2013
*FIELD* CN
Cassandra L. Kniffin - updated: 12/4/2013
*FIELD* CD
Cassandra L. Kniffin: 1/23/2013
*FIELD* ED
carol: 12/16/2013
ckniffin: 12/4/2013
carol: 1/28/2013
carol: 1/25/2013
ckniffin: 1/24/2013