RBCC Red Blood Cell Collection

LRSAM1 (TAL) [Confidence: low (only semi-automatic identification from reviews)]
E3 ubiquitin-protein ligase LRSAM1; 6.3.2.- (Leucine-rich repeat and sterile alpha motif-containing protein 1; Tsg101-associated ligase; hTAL)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q6UWE0
ID LRSM1_HUMAN Reviewed; 723 AA.
AC Q6UWE0; Q5VVV0; Q8NB40; Q96GT5; Q96MX5; Q96MZ7;
DT 01-FEB-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-JUL-2004, sequence version 1.
DT 22-JAN-2014, entry version 105.
DE RecName: Full=E3 ubiquitin-protein ligase LRSAM1;
DE EC=6.3.2.-;
DE AltName: Full=Leucine-rich repeat and sterile alpha motif-containing protein 1;
DE AltName: Full=Tsg101-associated ligase;
DE Short=hTAL;
GN Name=LRSAM1; Synonyms=TAL; ORFNames=UNQ6496/PRO21356;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S.,
RA Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J.,
RA Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J.,
RA Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A.,
RA Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H.,
RA Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D.,
RA Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale
RT effort to identify novel human secreted and transmembrane proteins: a
RT bioinformatics assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3).
RC TISSUE=Brain, and Teratocarcinoma;
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=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP ASP-318.
RC TISSUE=Skin;
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 [5]
RP FUNCTION, SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF CYS-675;
RP HIS-692 AND 649-PRO--PRO-664.
RX PubMed=15256501; DOI=10.1101/gad.294904;
RA Amit I., Yakir L., Katz M., Zwang Y., Marmor M.D., Citri A.,
RA Shtiegman K., Alroy I., Tuvia S., Reiss Y., Roubini E., Cohen M.,
RA Wides R., Bacharach E., Schubert U., Yarden Y.;
RT "Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor
RT endocytosis and retrovirus budding.";
RL Genes Dev. 18:1737-1752(2004).
RN [6]
RP INTERACTION WITH TSG101.
RX PubMed=17556548; DOI=10.1126/science.1143422;
RA Carlton J.G., Martin-Serrano J.;
RT "Parallels between cytokinesis and retroviral budding: a role for the
RT ESCRT machinery.";
RL Science 316:1908-1912(2007).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-234 AND SER-604, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [8]
RP INVOLVEMENT IN CMT2P.
RX PubMed=20865121; DOI=10.1371/journal.pgen.1001081;
RA Guernsey D.L., Jiang H., Bedard K., Evans S.C., Ferguson M.,
RA Matsuoka M., Macgillivray C., Nightingale M., Perry S., Rideout A.L.,
RA Orr A., Ludman M., Skidmore D.L., Benstead T., Samuels M.E.;
RT "Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients
RT with Charcot-Marie-Tooth disease.";
RL PLoS Genet. 6:1-7(2010).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-604, 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 TISSUE SPECIFICITY, AND INVOLVEMENT IN CMT2P.
RX PubMed=22012984; DOI=10.1093/hmg/ddr471;
RA Weterman M.A., Sorrentino V., Kasher P.R., Jakobs M.E.,
RA van Engelen B.G., Fluiter K., de Wissel M.B., Sizarov A., Nurnberg G.,
RA Nurnberg P., Zelcer N., Schelhaas H.J., Baas F.;
RT "A frameshift mutation in LRSAM1 is responsible for a dominant
RT hereditary polyneuropathy.";
RL Hum. Mol. Genet. 21:358-370(2012).
CC -!- FUNCTION: E3 ubiquitin-protein ligase that mediates
CC monoubiquitination of TSG101 at multiple sites, leading to
CC inactivate the ability of TSG101 to sort endocytic (EGF receptors)
CC and exocytic (HIV-1 viral proteins) cargos.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts with TSG101.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Note=Displays a punctuate
CC distribution and localizes to a submembranal ring.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q6UWE0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6UWE0-2; Sequence=VSP_012661;
CC Name=3;
CC IsoId=Q6UWE0-3; Sequence=VSP_012660;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Highly expressed in adult spinal cord
CC motoneurons as well as in fetal spinal cord and muscle tissue.
CC -!- DOMAIN: The coiled coil domains interact with the SB domain of
CC TSG101.
CC -!- DOMAIN: The PTAP motifs mediate the binding to UEV domains.
CC -!- DISEASE: Charcot-Marie-Tooth disease 2P (CMT2P) [MIM:614436]: An
CC axonal form of Charcot-Marie-Tooth disease, a disorder of the
CC peripheral nervous system, characterized by progressive weakness
CC and atrophy, initially of the peroneal muscles and later of the
CC distal muscles of the arms. Charcot-Marie-Tooth disease is
CC classified in two main groups on the basis of electrophysiologic
CC properties and histopathology: primary peripheral demyelinating
CC neuropathies (designated CMT1 when they are dominantly inherited)
CC and primary peripheral axonal neuropathies (CMT2). Neuropathies of
CC the CMT2 group are characterized by signs of axonal degeneration
CC in the absence of obvious myelin alterations, normal or slightly
CC reduced nerve conduction velocities, and progressive distal muscle
CC weakness and atrophy. Nerve conduction velocities are normal or
CC slightly reduced. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 6 LRR (leucine-rich) repeats.
CC -!- SIMILARITY: Contains 1 RING-type zinc finger.
CC -!- SIMILARITY: Contains 1 SAM (sterile alpha motif) domain.
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DR EMBL; AY358830; AAQ89189.1; -; mRNA.
DR EMBL; AK056203; BAB71119.1; -; mRNA.
DR EMBL; AK056305; BAB71144.1; -; mRNA.
DR EMBL; AK091589; BAC03703.1; -; mRNA.
DR EMBL; AL445222; CAH72930.1; -; Genomic_DNA.
DR EMBL; AL445222; CAH72931.1; -; Genomic_DNA.
DR EMBL; BC009239; AAH09239.1; -; mRNA.
DR RefSeq; NP_001005373.1; NM_001005373.3.
DR RefSeq; NP_001005374.1; NM_001005374.3.
DR RefSeq; NP_001177652.1; NM_001190723.2.
DR RefSeq; NP_612370.3; NM_138361.5.
DR UniGene; Hs.495188; -.
DR ProteinModelPortal; Q6UWE0; -.
DR SMR; Q6UWE0; 40-221, 675-720.
DR IntAct; Q6UWE0; 33.
DR MINT; MINT-1377718; -.
DR STRING; 9606.ENSP00000300417; -.
DR PhosphoSite; Q6UWE0; -.
DR DMDM; 62511890; -.
DR PaxDb; Q6UWE0; -.
DR PRIDE; Q6UWE0; -.
DR Ensembl; ENST00000300417; ENSP00000300417; ENSG00000148356.
DR Ensembl; ENST00000323301; ENSP00000322937; ENSG00000148356.
DR Ensembl; ENST00000373322; ENSP00000362419; ENSG00000148356.
DR Ensembl; ENST00000373324; ENSP00000362421; ENSG00000148356.
DR GeneID; 90678; -.
DR KEGG; hsa:90678; -.
DR UCSC; uc004brb.2; human.
DR CTD; 90678; -.
DR GeneCards; GC09P130215; -.
DR HGNC; HGNC:25135; LRSAM1.
DR HPA; HPA021403; -.
DR HPA; HPA021844; -.
DR MIM; 610933; gene.
DR MIM; 614436; phenotype.
DR neXtProt; NX_Q6UWE0; -.
DR Orphanet; 300319; Autosomal dominant Charcot-Marie-Tooth disease type 2P.
DR PharmGKB; PA134890010; -.
DR eggNOG; COG4886; -.
DR HOGENOM; HOG000231972; -.
DR HOVERGEN; HBG052363; -.
DR InParanoid; Q6UWE0; -.
DR KO; K10641; -.
DR OMA; IFLNCGH; -.
DR OrthoDB; EOG77T149; -.
DR PhylomeDB; Q6UWE0; -.
DR Reactome; REACT_6900; Immune System.
DR UniPathway; UPA00143; -.
DR ChiTaRS; LRSAM1; human.
DR GeneWiki; LRSAM1; -.
DR GenomeRNAi; 90678; -.
DR NextBio; 76927; -.
DR PRO; PR:Q6UWE0; -.
DR Bgee; Q6UWE0; -.
DR CleanEx; HS_LRSAM1; -.
DR Genevestigator; Q6UWE0; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; IEA:InterPro.
DR GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR GO; GO:0004842; F:ubiquitin-protein ligase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0045806; P:negative regulation of endocytosis; IMP:UniProtKB.
DR GO; GO:0051865; P:protein autoubiquitination; IDA:UniProtKB.
DR GO; GO:0030163; P:protein catabolic process; IMP:UniProtKB.
DR GO; GO:0000209; P:protein polyubiquitination; IDA:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0070086; P:ubiquitin-dependent endocytosis; IDA:UniProtKB.
DR GO; GO:0046755; P:viral budding; IMP:UniProtKB.
DR Gene3D; 1.10.150.50; -; 1.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR016179; Insulin-like.
DR InterPro; IPR001611; Leu-rich_rpt.
DR InterPro; IPR025875; Leu-rich_rpt_4.
DR InterPro; IPR001660; SAM.
DR InterPro; IPR013761; SAM/pointed.
DR InterPro; IPR011510; SAM_2.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR Pfam; PF12799; LRR_4; 2.
DR Pfam; PF07647; SAM_2; 1.
DR SMART; SM00078; IlGF; 1.
DR SMART; SM00184; RING; 1.
DR SMART; SM00454; SAM; 1.
DR SUPFAM; SSF47769; SSF47769; 1.
DR PROSITE; PS51450; LRR; 4.
DR PROSITE; PS50105; SAM_DOMAIN; 1.
DR PROSITE; PS00518; ZF_RING_1; FALSE_NEG.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Charcot-Marie-Tooth disease; Coiled coil;
KW Complete proteome; Cytoplasm; Leucine-rich repeat; Ligase;
KW Metal-binding; Neuropathy; Phosphoprotein; Polymorphism;
KW Protein transport; Reference proteome; Repeat; Transport;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1 723 E3 ubiquitin-protein ligase LRSAM1.
FT /FTId=PRO_0000055923.
FT REPEAT 30 51 LRR 1.
FT REPEAT 56 77 LRR 2.
FT REPEAT 82 103 LRR 3.
FT REPEAT 105 127 LRR 4.
FT REPEAT 128 149 LRR 5.
FT REPEAT 151 172 LRR 6.
FT DOMAIN 569 632 SAM.
FT ZN_FING 675 710 RING-type.
FT COILED 254 380 Potential.
FT COILED 510 562 Potential.
FT MOTIF 649 652 PTAP motif 1.
FT MOTIF 661 664 PTAP motif 2.
FT MOD_RES 234 234 Phosphoserine.
FT MOD_RES 604 604 Phosphoserine.
FT VAR_SEQ 1 420 Missing (in isoform 3).
FT /FTId=VSP_012660.
FT VAR_SEQ 474 500 Missing (in isoform 2).
FT /FTId=VSP_012661.
FT VARIANT 318 318 N -> D (in dbSNP:rs1539567).
FT /FTId=VAR_021051.
FT MUTAGEN 649 664 Missing: Abolishes interaction with
FT TSG101.
FT MUTAGEN 675 675 C->A: Abolishes ubiquitination of TSG101.
FT MUTAGEN 692 692 H->A: Abolishes ubiquitination of TSG101.
FT CONFLICT 385 385 V -> F (in Ref. 2; BAB71119).
FT CONFLICT 402 402 I -> V (in Ref. 2; BAC03703).
SQ SEQUENCE 723 AA; 83594 MW; 4A59461C92467BB1 CRC64;
MPLFFRKRKP SEEARKRLEY QMCLAKEAGA DDILDISKCE LSEIPFGAFA TCKVLQKKVL
IVHTNHLTSL LPKSCSLLSL ATIKVLDLHD NQLTALPDDL GQLTALQVLN VERNQLMQLP
RSIGNLTQLQ TLNVKDNKLK ELPDTVGELR SLRTLNISGN EIQRLPQMLA HVRTLEMLSL
DASAMVYPPR EVCGAGTAAI LQFLCKESGL EYYPPSQYLL PILEQDGIEN SRDSPDGPTD
RFSREELEWQ NRFSDYEKRK EQKMLEKLEF ERRLELGQRE HTQLLQQSSS QKDEILQTVK
EEQSRLEQGL SEHQRHLNAE RQRLQEQLKQ TEQNISSRIQ KLLQDNQRQK KSSEILKSLE
NERIRMEQLM SITQEETESL RRRDVASAMQ QMLTESCKNR LIQMAYESQR QNLVQQACSS
MAEMDERFQQ ILSWQQMDQN KAISQILQES AMQKAAFEAL QVKKDLMHRQ IRSQIKLIET
ELLQLTQLEL KRKSLDTESL QEMISEQRWA LSSLLQQLLK EKQQREEELR EILTELEAKS
ETRQENYWLI QYQRLLNQKP LSLKLQEEGM ERQLVALLEE LSAEHYLPIF AHHRLSLDLL
SQMSPGDLAK VGVSEAGLQH EILRRVQELL DAARIQPELK PPMGEVVTPT APQEPPESVR
PSAPPAELEV QASECVVCLE REAQMIFLNC GHVCCCQQCC QPLRTCPLCR QDIAQRLRIY
HSS
//

MIM 610933
*RECORD*
*FIELD* NO
610933
*FIELD* TI
*610933 LEUCINE-RICH REPEAT- AND STERILE ALPHA MOTIF-CONTAINING 1; LRSAM1
;;TSG101-ASSOCIATED LIGASE; TAL;;
read moreRING ZINC FINGER AND LEUCINE-RICH REPEAT-CONTAINING PROTEIN; RIFLE
*FIELD* TX

DESCRIPTION

LRSAM1 is a multifunctional RING finger protein that selectively
regulates cell adhesion molecules, has ubiquitin ligase activity, and
plays a role in receptor endocytosis and viral budding (Li et al., 2003;
Amit et al., 2004).

CLONING

By database analysis with the ring zinc finger region of NAIP (BIRC1;
600355) as probe, followed by screening a human brain cDNA library, Li
et al. (2003) cloned LRSAM1, which they called RIFLE. The deduced
702-amino acid protein has a predicted molecular mass of 80 kD and
contains a leucine-rich repeat (LRR) motif, nuclear localization signal,
leucine zipper domain, and a ring zinc finger domain. Northern blot
analysis detected a 3.14-kb transcript in human heart, skeletal muscle,
kidney, liver, and in all brain regions examined. Western analysis
localized RIFLE to the cytosol and nuclear fractions when expressed in
PC12 cells.

By yeast 2-hybrid analysis using TSG101 (601387) as bait to screen a
human brain cDNA library, Amit et al. (2004) independently cloned
LRSAM1, which they called TAL. The deduced 723-amino acid protein
contains an LRR, ezrin-radixin-moesin (ERM) domain, a coiled-coil
region, a SAM domain, 2 PTAP motifs, and a C-terminal RING finger
domain. Northern blot analysis detected a 3.5-kb transcript in all human
tissues examined. Immunofluorescence studies showed a punctate
distribution and localization to a submembrane ring. TAL also showed
partial colocalization with TSG101.

GENE FUNCTION

By Western blot analysis, Li et al. (2003) showed that RIFLE expression
selectively increased beta-catenin (CTNNB1; 116806) and E-cadherin
(CDH1; 192090) protein accumulation in PC12 cells but did not change the
expression of other cell adhesion molecules. RIFLE expression induced
serine phosphorylation of both GSK3A (606784) and GSK3B (605004) in PC12
cells, resulting in significantly inhibited GSK3 kinase activity and
increased beta-catenin levels. PC12 cells expressing RIFLE showed
increased calcium-dependent cell-cell adhesion, forming clusters that
were blocked in the presence of an E-cadherin blocking antibody. In
addition, RIFLE enhanced cell-matrix adhesion to extracellular matrix
molecules collagen IV (see 120070) and fibronectin (FN1; 135600). Li et
al. (2003) suggested that RIFLE mediates components of the WNT signaling
pathway and cell adhesion.

Using yeast 2-hybrid analysis and immunoprecipitation studies, Amit et
al. (2004) showed that the TAL PTAP motifs and TSG101 SB (steadiness
box) and ubiquitin E2 variant (UEV) regions mediate TAL-TSG101 binding.
TAL ubiquitylates TSG101 both in HEK293T cells and in vitro, through its
RING finger domain, CC domain, PTAP motifs, and TSG101 UEV elements. The
RING finger domain of TAL mediates self-ubiquitylation. The authors
showed that TAL carries out multiple monomeric ubiquitylation of TSG101,
resulting in inactivation of TSG101 sorting function. Studies of
receptor endocytosis and virus budding suggested that TAL enables
recycling of TSG101-containing sorting complexes and cargo reloading.

Using RNA in situ hybridization, Weterman et al. (2012) demonstrated
that LRSAM1 is highly expressed in adult human spinal cord motoneurons
as well as in fetal spinal cord and muscle tissue.

Following a categorization of 375 human leucine-rich repeat
(LRR)-containing proteins, including those having transmembrane domains
and others with F-box domains, Ng et al. (2011) identified a subset of
LRR proteins exhibiting strong conservation in fungi and an enrichment
for nucleic acid-binding function. Expression analysis identified a
subset of pathogen-responsive genes in human primary macrophages
infected with pathogenic bacteria. Protein interaction network analysis
followed by functional RNA interference (RNAi) identified LRSAM1 as a
component of the antibacterial autophagic response.

MOLECULAR GENETICS

Guernsey et al. (2010) described a 6-generation family from rural
eastern Canada with a mild axonal distal neuropathy (CMT2P; 614436)
inherited in an autosomal recessive pattern. Affected family members
were homozygous for a splice acceptor mutation in LRSAM1 (610933.0001).

Weterman et al. (2012) described a large 3-generation family with an
autosomal dominant axonal neuropathy whose phenotype was linked to a
5-Mb region on 9q33-q34 (lod = 5.12). Sequencing of the region
identified a 2-bp insertion in the last exon of LRSAM1 (610933.0002)
that was absent in 676 ethnicity-matched control chromosomes. Given the
earlier report by Guernsey et al. (2010), Weterman et al. (2012)
hypothesized that LRSAM1 mutations may cause both dominant and recessive
forms of CMT.

In affected members of a large Sardinian family with autosomal dominant
axonal CMT, Nicolaou et al. (2013) identified a heterozygous truncating
mutation in the LRSAM1 gene (610933.0003).

ANIMAL MODEL

Weterman et al. (2012) injected zebrafish embryos with morpholino
oligonucleotides directed against the ATG or last splice site of
zebrafish Lrsam1. The embryos showed disturbed neurodevelopment, with a
less organized neural structure and affected tail formation and
movement.

*FIELD* AV
.0001
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2P
LRSAM1, G-A

Guernsey et al. (2010) described a large consanguineous family from
rural eastern Canada with a mild axonal distal neuropathy inherited in
an autosomal recessive pattern (CMT2P; 614436). Affected individuals had
onset of symptoms in early adulthood, with both sensory and motor
dysfunction evident by electrophysiologic studies. Homozygosity mapping
narrowed the candidate region to 7 Mb on chromosome 9q33. Sequencing
revealed homozygosity for a G-to-A mutation in the splice acceptor site
of exon 25 (isoform 3) of the LRSAM1 gene in affected individuals. The
mutation resulted in obligatory frameshift leading to an altered open
reading frame and premature termination of the protein in all 3 spliced
isoforms.

.0002
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2P
LRSAM1, 2-BP INS, 2121GC

Weterman et al. (2012) described a large 3-generation family with an
autosomal dominant axonal neuropathy (CMT2P; 614436) whose phenotype was
linked to a 5-Mb region on 9q33-q34 (lod = 5.12). Sequencing of the
region identified heterozygosity for a 2-bp insertion at cDNA position
2121 in exon 26 of the LRSAM1 gene (Chr9: 129304950 bp, NCBI36) in
affected individuals. The mutation was absent in 676 ethnicity-matched
control chromosomes. The resulting frameshift (leu708argfx28) was
located in the C-terminal RING finger motif of the encoded protein.
Ubiquitin ligase activity in transfected cells with constructs carrying
the mutation was affected, as measured by a higher level of abundance of
TSG101 (601387), the only reported target of LRSAM1.

.0003
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2P
LRSAM1, IVS24AS, G-A, -1

In affected members of a large Sardinian family with adult-onset axonal
CMT2P (614436), Nicolaou et al. (2013) identified a heterozygous G-to-A
transition at a highly conserved nucleotide in intron 24 of the LRSAM1
gene (2047-1G-A), resulting in a frameshift and premature termination
(Ala683ProfsTer3). The resultant protein would lack a conserved
C-terminal RING finger motif important for ubiquitin ligase activity.
The mutation was found by genomewide linkage analysis and candidate gene
sequencing. The disorder was slowly progressive.

*FIELD* RF
1. Amit, I.; Yakir, L.; Katz, M.; Zwang, Y.; Marmor, M. D.; Citri,
A.; Shtiegman, K.; Alroy, I.; Tuvia, S.; Reiss, Y.; Roubini, E.; Cohen,
M.; Wides, R.; Bacharach, E.; Schubert, U.; Yarden, Y.: Tal, a Tsg101-specific
E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus
budding. Genes Dev. 18: 1737-1752, 2004.

2. Guernsey, D. L.; Jiang, H.; Bedard, K.; Evans, S. C.; Ferguson,
M.; Matsuoka, M.; Macgillivray, C.; Nightingale, M.; Perry, S.; Rideout,
A. L.; Orr, A.; Ludman, M.; Skidmore, D. L.; Benstead, T.; Samuels,
M. E.: Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients
with Charcot-Marie-Tooth disease. PLOS Genet. 6: e1001081, 2010.
Note: Electronic Article.

3. Li, B.; Su, Y.; Ryder, J.; Yan, L.; Na, S.; Ni, B.: RIFLE: a novel
ring zinc finger-leucine-rich repeat containing protein, regulates
select cell adhesion molecules in PC12 cells. J. Cell. Biochem. 90:
1224-1241, 2003.

4. Ng, A. C. Y.; Eisenberg, J. M.; Heath, R. J. W.; Huett, A.; Robinson,
C. M.; Nau, G. J.; Xavier, R. J.: Human leucine-rich repeat proteins:
a genome-wide bioinformatic categorization and functional analysis
in innate immunity. Proc. Nat. Acad. Sci. 108: 4631-4638, 2011.

5. Nicolaou, P.; Cianchetti, C.; Minaidou, A.; Marrosu, G.; Zamba-Papanicolaou,
E.; Middleton, L.; Christodoulou, K.: A novel LRSAM1 mutation is
associated with autosomal dominant axonal Charcot-Marie-Tooth disease. Europ.
J. Hum. Genet. 21: 190-194, 2013.

6. Weterman, M. A. J.; Sorrentino, V.; Kasher, P. R.; Jakobs, M. E.;
van Engelen, B. G. M.; Fluiter, K.; de Wissel, M. B.; Sizarov, A.;
Nurnberg, G.; Nurnberg, P.; Zelcer, N.; Schelhaas, H. J.; Baas, F.
: A frameshift mutation in LRSAM1 is responsible for a dominant hereditary
polyneuropathy. Hum. Molec. Genet. 21: 358-370, 2012.

*FIELD* CN
Cassandra L. Kniffin - updated: 3/20/2013
Paul J. Converse - updated: 5/29/2012
George E. Tiller - updated: 1/19/2012

*FIELD* CD
Dorothy S. Reilly: 4/16/2007

*FIELD* ED
carol: 09/24/2013
carol: 3/27/2013
ckniffin: 3/20/2013
alopez: 5/31/2012
terry: 5/29/2012
alopez: 1/19/2012
wwang: 4/16/2007

MIM 614436
*RECORD*
*FIELD* NO
614436
*FIELD* TI
#614436 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2P; CMT2P
;;CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2P
read more*FIELD* TX
A number sign (#) is used with this entry because axonal
Charcot-Marie-Tooth disease type 2P (CMT2P) can be caused by homozygous
or heterozygous mutation in the LRSAM1 gene (610933) on chromosome 9q33.

For a phenotypic description and a discussion of genetic heterogeneity
of axonal CMT, see CMT2A1 (118210).

CLINICAL FEATURES

Guernsey et al. (2010) identified an extended multiply consanguineous
family derived from a rural eastern Canadian isolate with 7 members
affected with axonal CMT. Three further individuals were suspected to be
affected. The index patient noted gradual onset of weakness around age
20, particularly affecting his distal lower extremities but also present
in the hands. He noted episodic muscle cramping of extremity and trunk
muscles. At the time of the examination he demonstrated bilateral pes
cavus with marked wasting of distal lower extremity muscles and mild
wasting of hand intrinsic muscles. Fasciculations were present in upper
and lower extremity muscles. There was no gait ataxia. Upper and lower
tendon reflexes were absent. He had mild loss of sensation on fingertips
and severe loss of sensation in feet and legs, most markedly to
vibration but also involving proprioception and pain perception. Other
affected family members exhibited sensory and motor dysfunction with pes
cavus. Autonomic symptoms were not consistently reported. Weakness and
wasting were moderate and predominantly in distal lower extremity
muscles. Onset was usually in the early adult years.

Weterman et al. (2012) reported a large 3-generation family with
autosomal dominant inheritance of an axonal peripheral neuropathy
consistent with CMT. Affected individuals presented in the second or
third decade of life with progressive distal muscle weakness and mild
sensory disturbances in the feet. Electrophysiologic studies in affected
individuals revealed a severe axonal neuropathy. Sural nerve biopsy in
one affected individual demonstrated severe axonal degeneration.

Nicolaou et al. (2013) reported a large 4-generation family from
Sardinia with autosomal dominant axonal CMT. The proband developed
distal weakness in the left lower limb and foot drop at about 34 years
of age. At age 43, he showed moderate foot drop, could not stand on his
heels, and had difficulty standing on his toes. There was atrophy in the
lower legs and feet, as well as distal sensory loss. The upper limbs
were not affected. He reported occasional cramps in the calf muscles and
erectile dysfunction. Nerve conduction studies were consistent with an
axonal form of CMT. Other affected family members had a similar
phenotype, with onset between ages 15 and 50 years of slowly progressive
distal weakness, atrophy, and multimodal hypesthesia in the lower limbs,
diffusing to the upper limbs in later years. All except 1 patient
remained ambulatory.

INHERITANCE

The transmission pattern of axonal CMT in the family described by
Guernsey et al. (2010) was consistent with autosomal recessive
inheritance. The transmission pattern in the family reported by Weterman
et al. (2012) was consistent with autosomal dominant inheritance.

MAPPING

By genomewide linkage analysis of a Sardinian family with autosomal
dominant axonal CMT, Nicolaou et al. (2013) found linkage to chromosome
9q33-q34 (maximum 2-point lod score of 8.06 at D9S63).

MOLECULAR GENETICS

In affected members of a large consanguineous family with CMT2, Guernsey
et al. (2010) found homozygosity for a splice site mutation in the
LRSAM1 gene (610933.0001). Heterozygous mutation carriers were
unaffected.

In affected members of a large 3-generation family with autosomal
dominant axonal CMT2P, Weterman et al. (2012) identified a heterozygous
frameshift mutation in the LRSAM1 gene (610933.0002). The mutation was
identified by next-generation sequencing in the region of interest as
determined by linkage analysis. Weterman et al. (2012) noted that
zebrafish models had disturbed neurodevelopment and affected tail
formation and movement.

In affected members of a large Sardinian family with autosomal dominant
axonal CMT, Nicolaou et al. (2013) identified a heterozygous truncating
mutation in the LRSAM1 gene (610933.0003).

*FIELD* RF
1. Guernsey, D. L.; Jiang, H.; Bedard, K.; Evans, S. C.; Ferguson,
M.; Matsuoka, M.; Macgillivray, C.; Nightingale, M.; Perry, S.; Rideout,
A. L.; Orr, A.; Ludman, M.; Skidmore, D. L.; Benstread, T.; Samuels,
M. E.: Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients
with Charcot-Marie-Tooth disease. PLOS Genet. 6: e1001081, 2010.
Note: Electronic Article.

2. Nicolaou, P.; Cianchetti, C.; Minaidou, A.; Marrosu, G.; Zamba-Papanicolaou,
E.; Middleton, L.; Christodoulou, K.: A novel LRSAM1 mutation is
associated with autosomal dominant axonal Charcot-Marie-Tooth disease. Europ.
J. Hum. Genet. 21: 190-194, 2013.

3. Weterman, M. A.; Sorrentino, V.; Kasher, P. R.; Jakobs, M. E.;
van Engelen, B. G. M.; Fluiter, K.; de Wissel, M. B.; Sizarov, A.;
Nurnberg, G.; Nurnberg, P.; Zelcer, N.; Schelhaas, H. J.; Baas, F.
: A frameshift mutation in LRSAM1 is responsible for a dominant hereditary
polyneuropathy. Hum. Molec. Genet. 21: 358-370, 2012.

*FIELD* CS
INHERITANCE:
Autosomal dominant;
Autosomal recessive

SKELETAL:
Pes cavus (in some patients);
Hammertoes (in some patients)

MUSCLE, SOFT TISSUE:
Distal limb muscle weakness due to peripheral neuropathy (lower limbs
are more affected than upper limbs);
Distal limb muscle atrophy due to peripheral neuropathy (lower limbs
are more affected than upper limbs);
Muscle cramping

NEUROLOGIC:
[Peripheral nervous system];
Loss of ability to run due to lower limb weakness;
Difficulty in heel-to-toe walking;
Foot drop;
Fasciculations;
Hyporeflexia;
Areflexia;
Distal sensory loss;
Sensorimotor axonal neuropathy;
Sural nerve biopsy shows axonal degeneration;
Nerve conduction velocities only slightly decreased

MISCELLANEOUS:
Onset usually in adulthood;
Slowly progressive disorder;
Some patients may become wheelchair-bound;
Both homozygous and heterozygous mutations in LRSAM1 have been reported

MOLECULAR BASIS:
Caused by mutation in the leucine-rich repeat- and sterile alpha motif-containing
1 gene (LRSAM1, 610933.0001)

*FIELD* CD
Cassandra L. Kniffin: 3/20/2013

*FIELD* ED
joanna: 03/27/2013
ckniffin: 3/20/2013

*FIELD* CN
Cassandra L. Kniffin - updated: 3/20/2013

*FIELD* CD
George E. Tiller: 1/18/2012

*FIELD* ED
carol: 03/27/2013
ckniffin: 3/20/2013
carol: 1/26/2012
alopez: 1/19/2012