Full text data of GSN
GSN
[Confidence: low (only semi-automatic identification from reviews)]
Gelsolin (AGEL; Actin-depolymerizing factor; ADF; Brevin; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Gelsolin (AGEL; Actin-depolymerizing factor; ADF; Brevin; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P06396
ID GELS_HUMAN Reviewed; 782 AA.
AC P06396; A2A418; A8MUD1; A8MYN7; B7Z373; Q5T0I2; Q8WVV7;
DT 01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JAN-1988, sequence version 1.
DT 22-JAN-2014, entry version 172.
DE RecName: Full=Gelsolin;
DE AltName: Full=AGEL;
DE AltName: Full=Actin-depolymerizing factor;
DE Short=ADF;
DE AltName: Full=Brevin;
DE Flags: Precursor;
GN Name=GSN;
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] (ISOFORMS 1 AND 2), AND ALTERNATIVE
RP INITIATION.
RX PubMed=3020431; DOI=10.1038/323455a0;
RA Kwiatkowski D.J., Stossel T.P., Orkin S.H., Mole J.E., Colten H.R.,
RA Yin H.L.;
RT "Plasma and cytoplasmic gelsolins are encoded by a single gene and
RT contain a duplicated actin-binding domain.";
RL Nature 323:455-458(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3).
RC TISSUE=Hippocampus, Testis, and Tongue;
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 GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Colon, and Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PROTEIN SEQUENCE OF 53-72 (ISOFORM 2).
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [7]
RP INTERACTION WITH FIBRONECTIN.
RX PubMed=6092370;
RA Lind S.E., Janmey P.A.;
RT "Human plasma gelsolin binds to fibronectin.";
RL J. Biol. Chem. 259:13262-13266(1984).
RN [8]
RP IDENTITY OF AMYL5 AMYLOID PROTEIN WITH GELSOLIN.
RX PubMed=2157434; DOI=10.1016/0006-291X(90)90612-Q;
RA Haltia M., Prelli F., Ghiso J., Kiuru S., Sommer H., Palo J.,
RA Frangione B.;
RT "Amyloid protein in familial amyloidosis (Finnish type) is homologous
RT to gelsolin, an actin-binding protein.";
RL Biochem. Biophys. Res. Commun. 167:927-932(1990).
RN [9]
RP IDENTITY OF AMYL5 AMYLOID PROTEIN WITH GELSOLIN.
RX PubMed=2153578; DOI=10.1016/0014-5793(90)80072-Q;
RA Maury C.P.J., Alli K., Baumann M.;
RT "Finnish hereditary amyloidosis. Amino acid sequence homology between
RT the amyloid fibril protein and human plasma gelsoline.";
RL FEBS Lett. 260:85-87(1990).
RN [10]
RP DISULFIDE BOND.
RX PubMed=8703941; DOI=10.1021/bi960920n;
RA Wen D., Corina K., Chow E.P., Miller S., Janmey P.A., Pepinsky R.B.;
RT "The plasma and cytoplasmic forms of human gelsolin differ in
RT disulfide structure.";
RL Biochemistry 35:9700-9709(1996).
RN [11]
RP DISULFIDE BOND.
RX PubMed=9003812; DOI=10.1016/S0014-5793(96)01439-1;
RA Allen P.G.;
RT "Functional consequences of disulfide bond formation in gelsolin.";
RL FEBS Lett. 401:89-94(1997).
RN [12]
RP PHOSPHORYLATION AT TYR-86; TYR-409; TYR-465; TYR-603 AND TYR-651.
RX PubMed=10210201;
RA De Corte V., Demol H., Goethals M., Van Damme J., Gettemans J.,
RA Vandekerckhove J.;
RT "Identification of Tyr438 as the major in vitro c-Src phosphorylation
RT site in human gelsolin: a mass spectrometric approach.";
RL Protein Sci. 8:234-241(1999).
RN [13]
RP FUNCTION.
RX PubMed=20393563; DOI=10.1038/nature08895;
RA Kim J., Lee J.E., Heynen-Genel S., Suyama E., Ono K., Lee K.,
RA Ideker T., Aza-Blanc P., Gleeson J.G.;
RT "Functional genomic screen for modulators of ciliogenesis and cilium
RT length.";
RL Nature 464:1048-1051(2010).
RN [14]
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 [15]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 28-503.
RX PubMed=8395021; DOI=10.1038/364685a0;
RA McLaughlin P.J., Gooch J.T., Mannherz H.-G., Weeds A.G.;
RT "Structure of gelsolin segment 1-actin complex and the mechanism of
RT filament severing.";
RL Nature 364:685-692(1993).
RN [16]
RP STRUCTURE BY NMR OF 177-196.
RX PubMed=8599675; DOI=10.1016/S0006-3495(95)80140-2;
RA Xian W., Vegners R., Janmey P.A., Braunlin W.H.;
RT "Spectroscopic studies of a phosphoinositide-binding peptide from
RT gelsolin: behavior in solutions of mixed solvent and anionic
RT micelles.";
RL Biophys. J. 69:2695-2702(1995).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) OF 439-782, AND CALCIUM-BINDING
RP SITES.
RX PubMed=16466744; DOI=10.1016/j.jmb.2006.01.026;
RA Chumnarnsilpa S., Loonchanta A., Xue B., Choe H., Urosev D., Wang H.,
RA Lindberg U., Burtnick L.D., Robinson R.C.;
RT "Calcium ion exchange in crystalline gelsolin.";
RL J. Mol. Biol. 357:773-782(2006).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 53-174 IN COMPLEX WITH ACTA1;
RP COBL AND TMSB4X, AND SUBUNIT.
RX PubMed=23009842; DOI=10.1016/j.bpj.2012.07.030;
RA Durer Z.A., Kudryashov D.S., Sawaya M.R., Altenbach C., Hubbell W.,
RA Reisler E.;
RT "Structural states and dynamics of the D-loop in actin.";
RL Biophys. J. 103:930-939(2012).
RN [19]
RP VARIANT AMYL5 ASN-214.
RX PubMed=2176481;
RA Ghiso J., Haltia M., Prelli F., Novello J., Frangione B.;
RT "Gelsolin variant (Asn-187) in familial amyloidosis, Finnish type.";
RL Biochem. J. 272:827-830(1990).
RN [20]
RP VARIANTS AMYL5 ASN-214 AND TYR-214.
RX PubMed=1338910; DOI=10.1038/ng1092-157;
RA de la Chapelle A., Tolvanen R., Boysen G., Santavy J.,
RA Bleeker-Wagemakers L., Maury C.P.J., Kere J.;
RT "Gelsolin-derived familial amyloidosis caused by asparagine or
RT tyrosine substitution for aspartic acid at residue 187.";
RL Nat. Genet. 2:157-160(1992).
RN [21]
RP VARIANTS [LARGE SCALE ANALYSIS] LEU-22; ILE-201 AND ASN-611.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Calcium-regulated, actin-modulating protein that binds
CC to the plus (or barbed) ends of actin monomers or filaments,
CC preventing monomer exchange (end-blocking or capping). It can
CC promote the assembly of monomers into filaments (nucleation) as
CC well as sever filaments already formed. Plays a role in
CC ciliogenesis.
CC -!- SUBUNIT: Binds to actin and to fibronectin. Identified in a
CC complex composed of ACTA1, COBL, GSN AND TMSB4X. Interacts with
CC the inactive form of EIF2AK2/PKR (By similarity).
CC -!- INTERACTION:
CC P49407:ARRB1; NbExp=3; IntAct=EBI-351506, EBI-743313;
CC P32121:ARRB2; NbExp=3; IntAct=EBI-351506, EBI-714559;
CC -!- SUBCELLULAR LOCATION: Isoform 2: Cytoplasm, cytoskeleton.
CC -!- SUBCELLULAR LOCATION: Isoform 1: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing, Alternative initiation; Named isoforms=3;
CC Name=1; Synonyms=Secreted, Plasma;
CC IsoId=P06396-1; Sequence=Displayed;
CC Name=2; Synonyms=Cytoplasmic;
CC IsoId=P06396-2; Sequence=VSP_018959;
CC Note=Initiator Met-1 may be either removed, or N-acetylated;
CC Name=3;
CC IsoId=P06396-3; Sequence=VSP_042879;
CC -!- TISSUE SPECIFICITY: Phagocytic cells, platelets, fibroblasts,
CC nonmuscle cells, smooth and skeletal muscle cells.
CC -!- PTM: Phosphorylation on Tyr-86, Tyr-409, Tyr-465, Tyr-603 and Tyr-
CC 651 in vitro is induced in presence of phospholipids.
CC -!- DISEASE: Amyloidosis 5 (AMYL5) [MIM:105120]: A hereditary
CC generalized amyloidosis due to gelsolin amyloid deposition. It is
CC typically characterized by cranial neuropathy and lattice corneal
CC dystrophy. Most patients have modest involvement of internal
CC organs, but severe systemic disease can develop in some
CC individuals causing peripheral polyneuropathy, amyloid
CC cardiomyopathy, and nephrotic syndrome leading to renal failure.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the villin/gelsolin family.
CC -!- SIMILARITY: Contains 6 gelsolin-like repeats.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GSN";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Gelsolin entry;
CC URL="http://en.wikipedia.org/wiki/Gelsolin";
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DR EMBL; X04412; CAA28000.1; -; mRNA.
DR EMBL; AK096280; BAG53247.1; -; mRNA.
DR EMBL; AK125819; BAG54252.1; -; mRNA.
DR EMBL; AK295572; BAH12109.1; -; mRNA.
DR EMBL; AK315494; BAG37878.1; -; mRNA.
DR EMBL; AL137068; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL513122; CAI14413.1; -; Genomic_DNA.
DR EMBL; AL513122; CAM20459.1; -; Genomic_DNA.
DR EMBL; CH471090; EAW87489.1; -; Genomic_DNA.
DR EMBL; CH471090; EAW87490.1; -; Genomic_DNA.
DR EMBL; CH471090; EAW87491.1; -; Genomic_DNA.
DR EMBL; BC017491; AAH17491.1; -; mRNA.
DR EMBL; BC026033; AAH26033.1; -; mRNA.
DR PIR; A03011; FAHUP.
DR RefSeq; NP_000168.1; NM_000177.4.
DR RefSeq; NP_001121134.1; NM_001127662.1.
DR RefSeq; NP_001121135.2; NM_001127663.1.
DR RefSeq; NP_001121136.1; NM_001127664.1.
DR RefSeq; NP_001121137.1; NM_001127665.1.
DR RefSeq; NP_001121138.1; NM_001127666.1.
DR RefSeq; NP_001121139.1; NM_001127667.1.
DR RefSeq; NP_001244958.1; NM_001258029.1.
DR RefSeq; NP_001244959.1; NM_001258030.1.
DR RefSeq; NP_937895.1; NM_198252.2.
DR RefSeq; XP_005251998.1; XM_005251941.1.
DR RefSeq; XP_005251999.1; XM_005251942.1.
DR RefSeq; XP_005252000.1; XM_005251943.1.
DR RefSeq; XP_005252001.1; XM_005251944.1.
DR RefSeq; XP_005252002.1; XM_005251945.1.
DR UniGene; Hs.522373; -.
DR PDB; 1C0F; X-ray; 2.40 A; S=53-176.
DR PDB; 1C0G; X-ray; 2.00 A; S=53-176.
DR PDB; 1D4X; X-ray; 1.75 A; G=52-177.
DR PDB; 1DEJ; X-ray; 2.40 A; S=53-176.
DR PDB; 1EQY; X-ray; 2.30 A; S=52-176.
DR PDB; 1ESV; X-ray; 2.00 A; S=52-176.
DR PDB; 1H1V; X-ray; 3.00 A; G=439-769.
DR PDB; 1KCQ; X-ray; 1.65 A; A=185-288.
DR PDB; 1MDU; X-ray; 2.20 A; A/D=52-176.
DR PDB; 1NLV; X-ray; 1.80 A; G=52-176.
DR PDB; 1NM1; X-ray; 1.80 A; G=52-176.
DR PDB; 1NMD; X-ray; 1.90 A; G=52-176.
DR PDB; 1P8X; X-ray; 2.00 A; A/B/C=439-782.
DR PDB; 1P8Z; X-ray; 2.60 A; G=52-187.
DR PDB; 1SOL; NMR; -; A=177-196.
DR PDB; 1T44; X-ray; 2.00 A; G=55-179.
DR PDB; 1YAG; X-ray; 1.90 A; G=52-176.
DR PDB; 1YVN; X-ray; 2.10 A; G=52-176.
DR PDB; 2FF3; X-ray; 2.00 A; A=52-179.
DR PDB; 2FF6; X-ray; 2.05 A; G=51-179.
DR PDB; 2FH1; X-ray; 1.55 A; A/B/C=439-782.
DR PDB; 2FH2; X-ray; 2.50 A; A/B/C=439-782.
DR PDB; 2FH3; X-ray; 2.87 A; A/B/C=439-782.
DR PDB; 2FH4; X-ray; 3.00 A; A/B/C=439-782.
DR PDB; 3A5L; X-ray; 2.40 A; S=53-176.
DR PDB; 3A5M; X-ray; 2.40 A; S=53-176.
DR PDB; 3A5N; X-ray; 2.36 A; S=53-176.
DR PDB; 3A5O; X-ray; 2.40 A; S=53-176.
DR PDB; 3CI5; X-ray; 1.70 A; G=52-176.
DR PDB; 3CIP; X-ray; 1.60 A; G=52-176.
DR PDB; 3CJB; X-ray; 3.21 A; G=52-176.
DR PDB; 3CJC; X-ray; 3.90 A; G=52-176.
DR PDB; 3FFK; X-ray; 3.00 A; A/D=52-426.
DR PDB; 3FFN; X-ray; 3.00 A; A/B=1-782.
DR PDB; 3TU5; X-ray; 3.00 A; B=53-174.
DR PDBsum; 1C0F; -.
DR PDBsum; 1C0G; -.
DR PDBsum; 1D4X; -.
DR PDBsum; 1DEJ; -.
DR PDBsum; 1EQY; -.
DR PDBsum; 1ESV; -.
DR PDBsum; 1H1V; -.
DR PDBsum; 1KCQ; -.
DR PDBsum; 1MDU; -.
DR PDBsum; 1NLV; -.
DR PDBsum; 1NM1; -.
DR PDBsum; 1NMD; -.
DR PDBsum; 1P8X; -.
DR PDBsum; 1P8Z; -.
DR PDBsum; 1SOL; -.
DR PDBsum; 1T44; -.
DR PDBsum; 1YAG; -.
DR PDBsum; 1YVN; -.
DR PDBsum; 2FF3; -.
DR PDBsum; 2FF6; -.
DR PDBsum; 2FH1; -.
DR PDBsum; 2FH2; -.
DR PDBsum; 2FH3; -.
DR PDBsum; 2FH4; -.
DR PDBsum; 3A5L; -.
DR PDBsum; 3A5M; -.
DR PDBsum; 3A5N; -.
DR PDBsum; 3A5O; -.
DR PDBsum; 3CI5; -.
DR PDBsum; 3CIP; -.
DR PDBsum; 3CJB; -.
DR PDBsum; 3CJC; -.
DR PDBsum; 3FFK; -.
DR PDBsum; 3FFN; -.
DR PDBsum; 3TU5; -.
DR ProteinModelPortal; P06396; -.
DR SMR; P06396; 50-782.
DR DIP; DIP-2196N; -.
DR IntAct; P06396; 13.
DR MINT; MINT-5000481; -.
DR STRING; 9606.ENSP00000362924; -.
DR PhosphoSite; P06396; -.
DR DMDM; 121116; -.
DR OGP; P06396; -.
DR PaxDb; P06396; -.
DR PeptideAtlas; P06396; -.
DR PRIDE; P06396; -.
DR DNASU; 2934; -.
DR Ensembl; ENST00000341272; ENSP00000340888; ENSG00000148180.
DR Ensembl; ENST00000373808; ENSP00000362914; ENSG00000148180.
DR Ensembl; ENST00000373818; ENSP00000362924; ENSG00000148180.
DR Ensembl; ENST00000373823; ENSP00000362929; ENSG00000148180.
DR Ensembl; ENST00000394353; ENSP00000377882; ENSG00000148180.
DR Ensembl; ENST00000412819; ENSP00000416586; ENSG00000148180.
DR Ensembl; ENST00000436847; ENSP00000411293; ENSG00000148180.
DR Ensembl; ENST00000449733; ENSP00000409358; ENSG00000148180.
DR GeneID; 2934; -.
DR KEGG; hsa:2934; -.
DR UCSC; uc004bld.1; human.
DR CTD; 2934; -.
DR GeneCards; GC09P123971; -.
DR HGNC; HGNC:4620; GSN.
DR HPA; CAB010823; -.
DR HPA; CAB016728; -.
DR HPA; CAB036009; -.
DR MIM; 105120; phenotype.
DR MIM; 137350; gene.
DR neXtProt; NX_P06396; -.
DR Orphanet; 85448; Familial amyloidosis, Finnish type.
DR PharmGKB; PA29011; -.
DR eggNOG; NOG304849; -.
DR HOGENOM; HOG000233630; -.
DR HOVERGEN; HBG004183; -.
DR InParanoid; P06396; -.
DR KO; K05768; -.
DR OMA; MILDTWE; -.
DR OrthoDB; EOG7288RJ; -.
DR PhylomeDB; P06396; -.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_578; Apoptosis.
DR ChiTaRS; GSN; human.
DR EvolutionaryTrace; P06396; -.
DR GeneWiki; Gelsolin; -.
DR GenomeRNAi; 2934; -.
DR NextBio; 11625; -.
DR PMAP-CutDB; P06396; -.
DR PRO; PR:P06396; -.
DR ArrayExpress; P06396; -.
DR Bgee; P06396; -.
DR CleanEx; HS_GSN; -.
DR Genevestigator; P06396; -.
DR GO; GO:0015629; C:actin cytoskeleton; TAS:ProtInc.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0030027; C:lamellipodium; IEA:Ensembl.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0043234; C:protein complex; IEA:Ensembl.
DR GO; GO:0001726; C:ruffle; IEA:Ensembl.
DR GO; GO:0005509; F:calcium ion binding; TAS:ProtInc.
DR GO; GO:0030041; P:actin filament polymerization; IDA:UniProtKB.
DR GO; GO:0051014; P:actin filament severing; IDA:UniProtKB.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0051016; P:barbed-end actin filament capping; TAS:ProtInc.
DR GO; GO:0006921; P:cellular component disassembly involved in execution phase of apoptosis; TAS:Reactome.
DR GO; GO:0071276; P:cellular response to cadmium ion; IEA:Ensembl.
DR GO; GO:0060271; P:cilium morphogenesis; IMP:UniProtKB.
DR GO; GO:0014003; P:oligodendrocyte development; IEA:Ensembl.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; IEA:Ensembl.
DR GO; GO:0030155; P:regulation of cell adhesion; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0051593; P:response to folic acid; IEA:Ensembl.
DR GO; GO:0042246; P:tissue regeneration; IEA:Ensembl.
DR GO; GO:0016192; P:vesicle-mediated transport; IEA:Ensembl.
DR InterPro; IPR007123; Gelsolin_dom.
DR InterPro; IPR007122; Villin/Gelsolin.
DR PANTHER; PTHR11977; PTHR11977; 1.
DR Pfam; PF00626; Gelsolin; 6.
DR PRINTS; PR00597; GELSOLIN.
DR SMART; SM00262; GEL; 6.
PE 1: Evidence at protein level;
KW 3D-structure; Actin capping; Actin-binding; Alternative initiation;
KW Alternative splicing; Amyloid; Amyloidosis; Calcium;
KW Cilium biogenesis/degradation; Complete proteome; Corneal dystrophy;
KW Cytoplasm; Cytoskeleton; Direct protein sequencing; Disease mutation;
KW Disulfide bond; Metal-binding; Phosphoprotein; Polymorphism;
KW Reference proteome; Repeat; Secreted; Signal.
FT SIGNAL 1 27
FT CHAIN 28 782 Gelsolin.
FT /FTId=PRO_0000036385.
FT REPEAT 76 126 Gelsolin-like 1.
FT REPEAT 198 238 Gelsolin-like 2.
FT REPEAT 314 356 Gelsolin-like 3.
FT REPEAT 453 504 Gelsolin-like 4.
FT REPEAT 576 616 Gelsolin-like 5.
FT REPEAT 679 721 Gelsolin-like 6.
FT REGION 53 176 Actin-severing (Potential).
FT REGION 123 126 Actin-actin interfilament contact point.
FT REGION 162 169 Polyphosphoinositide binding (By
FT similarity).
FT REGION 188 196 Polyphosphoinositide binding (By
FT similarity).
FT REGION 434 782 Actin-binding, Ca-sensitive (Potential).
FT METAL 471 471 Calcium 1; via carbonyl oxygen.
FT METAL 472 472 Calcium 1.
FT METAL 502 502 Calcium 1.
FT METAL 551 551 Calcium 1; via carbonyl oxygen.
FT METAL 591 591 Calcium 2.
FT METAL 591 591 Calcium 2; via carbonyl oxygen.
FT METAL 592 592 Calcium 2.
FT METAL 614 614 Calcium 2.
FT METAL 696 696 Calcium 3; via carbonyl oxygen.
FT METAL 697 697 Calcium 3.
FT METAL 719 719 Calcium 3.
FT MOD_RES 86 86 Phosphotyrosine; by SRC; in vitro.
FT MOD_RES 409 409 Phosphotyrosine; by SRC; in vitro.
FT MOD_RES 465 465 Phosphotyrosine; by SRC.
FT MOD_RES 603 603 Phosphotyrosine; by SRC; in vitro.
FT MOD_RES 651 651 Phosphotyrosine; by SRC; in vitro.
FT DISULFID 215 228 In isoform 1.
FT VAR_SEQ 1 51 Missing (in isoform 2).
FT /FTId=VSP_018959.
FT VAR_SEQ 1 48 MAPHRPAPALLCALSLALCALSLPVRAATASRGASQAGAPQ
FT GRVPEAR -> MEKLFCCF (in isoform 3).
FT /FTId=VSP_042879.
FT VARIANT 22 22 S -> L (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036337.
FT VARIANT 129 129 A -> T (in dbSNP:rs2230287).
FT /FTId=VAR_024690.
FT VARIANT 201 201 T -> I (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036338.
FT VARIANT 214 214 D -> N (in AMYL5).
FT /FTId=VAR_007718.
FT VARIANT 214 214 D -> Y (in AMYL5).
FT /FTId=VAR_007719.
FT VARIANT 231 231 N -> D (in dbSNP:rs11550199).
FT /FTId=VAR_061982.
FT VARIANT 611 611 S -> N (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036339.
FT VARIANT 668 668 R -> L (in dbSNP:rs9696578).
FT /FTId=VAR_033958.
FT STRAND 52 55
FT HELIX 57 61
FT STRAND 64 74
FT STRAND 77 80
FT HELIX 83 85
FT STRAND 88 90
FT STRAND 94 102
FT TURN 104 106
FT STRAND 108 116
FT HELIX 122 138
FT TURN 139 141
FT STRAND 143 149
FT HELIX 155 158
FT STRAND 166 169
FT HELIX 172 174
FT STRAND 179 181
FT STRAND 188 203
FT HELIX 207 209
FT STRAND 214 219
FT STRAND 221 228
FT HELIX 234 250
FT STRAND 256 262
FT TURN 263 265
FT HELIX 268 274
FT HELIX 288 294
FT STRAND 299 304
FT STRAND 306 309
FT STRAND 311 321
FT HELIX 323 325
FT STRAND 330 336
FT HELIX 337 339
FT STRAND 341 346
FT HELIX 352 368
FT STRAND 376 381
FT HELIX 387 390
FT STRAND 393 395
FT STRAND 402 406
FT HELIX 412 414
FT TURN 424 426
FT HELIX 427 429
FT HELIX 431 437
FT STRAND 445 453
FT STRAND 456 459
FT HELIX 462 464
FT STRAND 467 469
FT STRAND 472 482
FT STRAND 485 494
FT HELIX 500 516
FT TURN 517 519
FT STRAND 521 527
FT HELIX 533 536
FT HELIX 537 539
FT STRAND 544 548
FT TURN 553 555
FT STRAND 562 570
FT STRAND 576 581
FT HELIX 585 587
FT STRAND 592 597
FT STRAND 602 606
FT HELIX 612 624
FT STRAND 630 633
FT HELIX 639 644
FT STRAND 645 647
FT HELIX 655 658
FT HELIX 661 664
FT STRAND 668 673
FT TURN 675 677
FT STRAND 680 684
FT HELIX 690 692
FT STRAND 697 702
FT STRAND 707 711
FT HELIX 717 732
FT STRAND 744 748
FT HELIX 754 757
FT STRAND 760 762
FT STRAND 765 767
FT HELIX 772 778
SQ SEQUENCE 782 AA; 85698 MW; 8CEBC52257A160F7 CRC64;
MAPHRPAPAL LCALSLALCA LSLPVRAATA SRGASQAGAP QGRVPEARPN SMVVEHPEFL
KAGKEPGLQI WRVEKFDLVP VPTNLYGDFF TGDAYVILKT VQLRNGNLQY DLHYWLGNEC
SQDESGAAAI FTVQLDDYLN GRAVQHREVQ GFESATFLGY FKSGLKYKKG GVASGFKHVV
PNEVVVQRLF QVKGRRVVRA TEVPVSWESF NNGDCFILDL GNNIHQWCGS NSNRYERLKA
TQVSKGIRDN ERSGRARVHV SEEGTEPEAM LQVLGPKPAL PAGTEDTAKE DAANRKLAKL
YKVSNGAGTM SVSLVADENP FAQGALKSED CFILDHGKDG KIFVWKGKQA NTEERKAALK
TASDFITKMD YPKQTQVSVL PEGGETPLFK QFFKNWRDPD QTDGLGLSYL SSHIANVERV
PFDAATLHTS TAMAAQHGMD DDGTGQKQIW RIEGSNKVPV DPATYGQFYG GDSYIILYNY
RHGGRQGQII YNWQGAQSTQ DEVAASAILT AQLDEELGGT PVQSRVVQGK EPAHLMSLFG
GKPMIIYKGG TSREGGQTAP ASTRLFQVRA NSAGATRAVE VLPKAGALNS NDAFVLKTPS
AAYLWVGTGA SEAEKTGAQE LLRVLRAQPV QVAEGSEPDG FWEALGGKAA YRTSPRLKDK
KMDAHPPRLF ACSNKIGRFV IEEVPGELMQ EDLATDDVML LDTWDQVFVW VGKDSQEEEK
TEALTSAKRY IETDPANRDR RTPITVVKQG FEPPSFVGWF LGWDDDYWSV DPLDRAMAEL
AA
//
ID GELS_HUMAN Reviewed; 782 AA.
AC P06396; A2A418; A8MUD1; A8MYN7; B7Z373; Q5T0I2; Q8WVV7;
DT 01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JAN-1988, sequence version 1.
DT 22-JAN-2014, entry version 172.
DE RecName: Full=Gelsolin;
DE AltName: Full=AGEL;
DE AltName: Full=Actin-depolymerizing factor;
DE Short=ADF;
DE AltName: Full=Brevin;
DE Flags: Precursor;
GN Name=GSN;
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] (ISOFORMS 1 AND 2), AND ALTERNATIVE
RP INITIATION.
RX PubMed=3020431; DOI=10.1038/323455a0;
RA Kwiatkowski D.J., Stossel T.P., Orkin S.H., Mole J.E., Colten H.R.,
RA Yin H.L.;
RT "Plasma and cytoplasmic gelsolins are encoded by a single gene and
RT contain a duplicated actin-binding domain.";
RL Nature 323:455-458(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3).
RC TISSUE=Hippocampus, Testis, and Tongue;
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 GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Colon, and Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PROTEIN SEQUENCE OF 53-72 (ISOFORM 2).
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [7]
RP INTERACTION WITH FIBRONECTIN.
RX PubMed=6092370;
RA Lind S.E., Janmey P.A.;
RT "Human plasma gelsolin binds to fibronectin.";
RL J. Biol. Chem. 259:13262-13266(1984).
RN [8]
RP IDENTITY OF AMYL5 AMYLOID PROTEIN WITH GELSOLIN.
RX PubMed=2157434; DOI=10.1016/0006-291X(90)90612-Q;
RA Haltia M., Prelli F., Ghiso J., Kiuru S., Sommer H., Palo J.,
RA Frangione B.;
RT "Amyloid protein in familial amyloidosis (Finnish type) is homologous
RT to gelsolin, an actin-binding protein.";
RL Biochem. Biophys. Res. Commun. 167:927-932(1990).
RN [9]
RP IDENTITY OF AMYL5 AMYLOID PROTEIN WITH GELSOLIN.
RX PubMed=2153578; DOI=10.1016/0014-5793(90)80072-Q;
RA Maury C.P.J., Alli K., Baumann M.;
RT "Finnish hereditary amyloidosis. Amino acid sequence homology between
RT the amyloid fibril protein and human plasma gelsoline.";
RL FEBS Lett. 260:85-87(1990).
RN [10]
RP DISULFIDE BOND.
RX PubMed=8703941; DOI=10.1021/bi960920n;
RA Wen D., Corina K., Chow E.P., Miller S., Janmey P.A., Pepinsky R.B.;
RT "The plasma and cytoplasmic forms of human gelsolin differ in
RT disulfide structure.";
RL Biochemistry 35:9700-9709(1996).
RN [11]
RP DISULFIDE BOND.
RX PubMed=9003812; DOI=10.1016/S0014-5793(96)01439-1;
RA Allen P.G.;
RT "Functional consequences of disulfide bond formation in gelsolin.";
RL FEBS Lett. 401:89-94(1997).
RN [12]
RP PHOSPHORYLATION AT TYR-86; TYR-409; TYR-465; TYR-603 AND TYR-651.
RX PubMed=10210201;
RA De Corte V., Demol H., Goethals M., Van Damme J., Gettemans J.,
RA Vandekerckhove J.;
RT "Identification of Tyr438 as the major in vitro c-Src phosphorylation
RT site in human gelsolin: a mass spectrometric approach.";
RL Protein Sci. 8:234-241(1999).
RN [13]
RP FUNCTION.
RX PubMed=20393563; DOI=10.1038/nature08895;
RA Kim J., Lee J.E., Heynen-Genel S., Suyama E., Ono K., Lee K.,
RA Ideker T., Aza-Blanc P., Gleeson J.G.;
RT "Functional genomic screen for modulators of ciliogenesis and cilium
RT length.";
RL Nature 464:1048-1051(2010).
RN [14]
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 [15]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 28-503.
RX PubMed=8395021; DOI=10.1038/364685a0;
RA McLaughlin P.J., Gooch J.T., Mannherz H.-G., Weeds A.G.;
RT "Structure of gelsolin segment 1-actin complex and the mechanism of
RT filament severing.";
RL Nature 364:685-692(1993).
RN [16]
RP STRUCTURE BY NMR OF 177-196.
RX PubMed=8599675; DOI=10.1016/S0006-3495(95)80140-2;
RA Xian W., Vegners R., Janmey P.A., Braunlin W.H.;
RT "Spectroscopic studies of a phosphoinositide-binding peptide from
RT gelsolin: behavior in solutions of mixed solvent and anionic
RT micelles.";
RL Biophys. J. 69:2695-2702(1995).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) OF 439-782, AND CALCIUM-BINDING
RP SITES.
RX PubMed=16466744; DOI=10.1016/j.jmb.2006.01.026;
RA Chumnarnsilpa S., Loonchanta A., Xue B., Choe H., Urosev D., Wang H.,
RA Lindberg U., Burtnick L.D., Robinson R.C.;
RT "Calcium ion exchange in crystalline gelsolin.";
RL J. Mol. Biol. 357:773-782(2006).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 53-174 IN COMPLEX WITH ACTA1;
RP COBL AND TMSB4X, AND SUBUNIT.
RX PubMed=23009842; DOI=10.1016/j.bpj.2012.07.030;
RA Durer Z.A., Kudryashov D.S., Sawaya M.R., Altenbach C., Hubbell W.,
RA Reisler E.;
RT "Structural states and dynamics of the D-loop in actin.";
RL Biophys. J. 103:930-939(2012).
RN [19]
RP VARIANT AMYL5 ASN-214.
RX PubMed=2176481;
RA Ghiso J., Haltia M., Prelli F., Novello J., Frangione B.;
RT "Gelsolin variant (Asn-187) in familial amyloidosis, Finnish type.";
RL Biochem. J. 272:827-830(1990).
RN [20]
RP VARIANTS AMYL5 ASN-214 AND TYR-214.
RX PubMed=1338910; DOI=10.1038/ng1092-157;
RA de la Chapelle A., Tolvanen R., Boysen G., Santavy J.,
RA Bleeker-Wagemakers L., Maury C.P.J., Kere J.;
RT "Gelsolin-derived familial amyloidosis caused by asparagine or
RT tyrosine substitution for aspartic acid at residue 187.";
RL Nat. Genet. 2:157-160(1992).
RN [21]
RP VARIANTS [LARGE SCALE ANALYSIS] LEU-22; ILE-201 AND ASN-611.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Calcium-regulated, actin-modulating protein that binds
CC to the plus (or barbed) ends of actin monomers or filaments,
CC preventing monomer exchange (end-blocking or capping). It can
CC promote the assembly of monomers into filaments (nucleation) as
CC well as sever filaments already formed. Plays a role in
CC ciliogenesis.
CC -!- SUBUNIT: Binds to actin and to fibronectin. Identified in a
CC complex composed of ACTA1, COBL, GSN AND TMSB4X. Interacts with
CC the inactive form of EIF2AK2/PKR (By similarity).
CC -!- INTERACTION:
CC P49407:ARRB1; NbExp=3; IntAct=EBI-351506, EBI-743313;
CC P32121:ARRB2; NbExp=3; IntAct=EBI-351506, EBI-714559;
CC -!- SUBCELLULAR LOCATION: Isoform 2: Cytoplasm, cytoskeleton.
CC -!- SUBCELLULAR LOCATION: Isoform 1: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing, Alternative initiation; Named isoforms=3;
CC Name=1; Synonyms=Secreted, Plasma;
CC IsoId=P06396-1; Sequence=Displayed;
CC Name=2; Synonyms=Cytoplasmic;
CC IsoId=P06396-2; Sequence=VSP_018959;
CC Note=Initiator Met-1 may be either removed, or N-acetylated;
CC Name=3;
CC IsoId=P06396-3; Sequence=VSP_042879;
CC -!- TISSUE SPECIFICITY: Phagocytic cells, platelets, fibroblasts,
CC nonmuscle cells, smooth and skeletal muscle cells.
CC -!- PTM: Phosphorylation on Tyr-86, Tyr-409, Tyr-465, Tyr-603 and Tyr-
CC 651 in vitro is induced in presence of phospholipids.
CC -!- DISEASE: Amyloidosis 5 (AMYL5) [MIM:105120]: A hereditary
CC generalized amyloidosis due to gelsolin amyloid deposition. It is
CC typically characterized by cranial neuropathy and lattice corneal
CC dystrophy. Most patients have modest involvement of internal
CC organs, but severe systemic disease can develop in some
CC individuals causing peripheral polyneuropathy, amyloid
CC cardiomyopathy, and nephrotic syndrome leading to renal failure.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the villin/gelsolin family.
CC -!- SIMILARITY: Contains 6 gelsolin-like repeats.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GSN";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Gelsolin entry;
CC URL="http://en.wikipedia.org/wiki/Gelsolin";
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DR EMBL; X04412; CAA28000.1; -; mRNA.
DR EMBL; AK096280; BAG53247.1; -; mRNA.
DR EMBL; AK125819; BAG54252.1; -; mRNA.
DR EMBL; AK295572; BAH12109.1; -; mRNA.
DR EMBL; AK315494; BAG37878.1; -; mRNA.
DR EMBL; AL137068; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL513122; CAI14413.1; -; Genomic_DNA.
DR EMBL; AL513122; CAM20459.1; -; Genomic_DNA.
DR EMBL; CH471090; EAW87489.1; -; Genomic_DNA.
DR EMBL; CH471090; EAW87490.1; -; Genomic_DNA.
DR EMBL; CH471090; EAW87491.1; -; Genomic_DNA.
DR EMBL; BC017491; AAH17491.1; -; mRNA.
DR EMBL; BC026033; AAH26033.1; -; mRNA.
DR PIR; A03011; FAHUP.
DR RefSeq; NP_000168.1; NM_000177.4.
DR RefSeq; NP_001121134.1; NM_001127662.1.
DR RefSeq; NP_001121135.2; NM_001127663.1.
DR RefSeq; NP_001121136.1; NM_001127664.1.
DR RefSeq; NP_001121137.1; NM_001127665.1.
DR RefSeq; NP_001121138.1; NM_001127666.1.
DR RefSeq; NP_001121139.1; NM_001127667.1.
DR RefSeq; NP_001244958.1; NM_001258029.1.
DR RefSeq; NP_001244959.1; NM_001258030.1.
DR RefSeq; NP_937895.1; NM_198252.2.
DR RefSeq; XP_005251998.1; XM_005251941.1.
DR RefSeq; XP_005251999.1; XM_005251942.1.
DR RefSeq; XP_005252000.1; XM_005251943.1.
DR RefSeq; XP_005252001.1; XM_005251944.1.
DR RefSeq; XP_005252002.1; XM_005251945.1.
DR UniGene; Hs.522373; -.
DR PDB; 1C0F; X-ray; 2.40 A; S=53-176.
DR PDB; 1C0G; X-ray; 2.00 A; S=53-176.
DR PDB; 1D4X; X-ray; 1.75 A; G=52-177.
DR PDB; 1DEJ; X-ray; 2.40 A; S=53-176.
DR PDB; 1EQY; X-ray; 2.30 A; S=52-176.
DR PDB; 1ESV; X-ray; 2.00 A; S=52-176.
DR PDB; 1H1V; X-ray; 3.00 A; G=439-769.
DR PDB; 1KCQ; X-ray; 1.65 A; A=185-288.
DR PDB; 1MDU; X-ray; 2.20 A; A/D=52-176.
DR PDB; 1NLV; X-ray; 1.80 A; G=52-176.
DR PDB; 1NM1; X-ray; 1.80 A; G=52-176.
DR PDB; 1NMD; X-ray; 1.90 A; G=52-176.
DR PDB; 1P8X; X-ray; 2.00 A; A/B/C=439-782.
DR PDB; 1P8Z; X-ray; 2.60 A; G=52-187.
DR PDB; 1SOL; NMR; -; A=177-196.
DR PDB; 1T44; X-ray; 2.00 A; G=55-179.
DR PDB; 1YAG; X-ray; 1.90 A; G=52-176.
DR PDB; 1YVN; X-ray; 2.10 A; G=52-176.
DR PDB; 2FF3; X-ray; 2.00 A; A=52-179.
DR PDB; 2FF6; X-ray; 2.05 A; G=51-179.
DR PDB; 2FH1; X-ray; 1.55 A; A/B/C=439-782.
DR PDB; 2FH2; X-ray; 2.50 A; A/B/C=439-782.
DR PDB; 2FH3; X-ray; 2.87 A; A/B/C=439-782.
DR PDB; 2FH4; X-ray; 3.00 A; A/B/C=439-782.
DR PDB; 3A5L; X-ray; 2.40 A; S=53-176.
DR PDB; 3A5M; X-ray; 2.40 A; S=53-176.
DR PDB; 3A5N; X-ray; 2.36 A; S=53-176.
DR PDB; 3A5O; X-ray; 2.40 A; S=53-176.
DR PDB; 3CI5; X-ray; 1.70 A; G=52-176.
DR PDB; 3CIP; X-ray; 1.60 A; G=52-176.
DR PDB; 3CJB; X-ray; 3.21 A; G=52-176.
DR PDB; 3CJC; X-ray; 3.90 A; G=52-176.
DR PDB; 3FFK; X-ray; 3.00 A; A/D=52-426.
DR PDB; 3FFN; X-ray; 3.00 A; A/B=1-782.
DR PDB; 3TU5; X-ray; 3.00 A; B=53-174.
DR PDBsum; 1C0F; -.
DR PDBsum; 1C0G; -.
DR PDBsum; 1D4X; -.
DR PDBsum; 1DEJ; -.
DR PDBsum; 1EQY; -.
DR PDBsum; 1ESV; -.
DR PDBsum; 1H1V; -.
DR PDBsum; 1KCQ; -.
DR PDBsum; 1MDU; -.
DR PDBsum; 1NLV; -.
DR PDBsum; 1NM1; -.
DR PDBsum; 1NMD; -.
DR PDBsum; 1P8X; -.
DR PDBsum; 1P8Z; -.
DR PDBsum; 1SOL; -.
DR PDBsum; 1T44; -.
DR PDBsum; 1YAG; -.
DR PDBsum; 1YVN; -.
DR PDBsum; 2FF3; -.
DR PDBsum; 2FF6; -.
DR PDBsum; 2FH1; -.
DR PDBsum; 2FH2; -.
DR PDBsum; 2FH3; -.
DR PDBsum; 2FH4; -.
DR PDBsum; 3A5L; -.
DR PDBsum; 3A5M; -.
DR PDBsum; 3A5N; -.
DR PDBsum; 3A5O; -.
DR PDBsum; 3CI5; -.
DR PDBsum; 3CIP; -.
DR PDBsum; 3CJB; -.
DR PDBsum; 3CJC; -.
DR PDBsum; 3FFK; -.
DR PDBsum; 3FFN; -.
DR PDBsum; 3TU5; -.
DR ProteinModelPortal; P06396; -.
DR SMR; P06396; 50-782.
DR DIP; DIP-2196N; -.
DR IntAct; P06396; 13.
DR MINT; MINT-5000481; -.
DR STRING; 9606.ENSP00000362924; -.
DR PhosphoSite; P06396; -.
DR DMDM; 121116; -.
DR OGP; P06396; -.
DR PaxDb; P06396; -.
DR PeptideAtlas; P06396; -.
DR PRIDE; P06396; -.
DR DNASU; 2934; -.
DR Ensembl; ENST00000341272; ENSP00000340888; ENSG00000148180.
DR Ensembl; ENST00000373808; ENSP00000362914; ENSG00000148180.
DR Ensembl; ENST00000373818; ENSP00000362924; ENSG00000148180.
DR Ensembl; ENST00000373823; ENSP00000362929; ENSG00000148180.
DR Ensembl; ENST00000394353; ENSP00000377882; ENSG00000148180.
DR Ensembl; ENST00000412819; ENSP00000416586; ENSG00000148180.
DR Ensembl; ENST00000436847; ENSP00000411293; ENSG00000148180.
DR Ensembl; ENST00000449733; ENSP00000409358; ENSG00000148180.
DR GeneID; 2934; -.
DR KEGG; hsa:2934; -.
DR UCSC; uc004bld.1; human.
DR CTD; 2934; -.
DR GeneCards; GC09P123971; -.
DR HGNC; HGNC:4620; GSN.
DR HPA; CAB010823; -.
DR HPA; CAB016728; -.
DR HPA; CAB036009; -.
DR MIM; 105120; phenotype.
DR MIM; 137350; gene.
DR neXtProt; NX_P06396; -.
DR Orphanet; 85448; Familial amyloidosis, Finnish type.
DR PharmGKB; PA29011; -.
DR eggNOG; NOG304849; -.
DR HOGENOM; HOG000233630; -.
DR HOVERGEN; HBG004183; -.
DR InParanoid; P06396; -.
DR KO; K05768; -.
DR OMA; MILDTWE; -.
DR OrthoDB; EOG7288RJ; -.
DR PhylomeDB; P06396; -.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_578; Apoptosis.
DR ChiTaRS; GSN; human.
DR EvolutionaryTrace; P06396; -.
DR GeneWiki; Gelsolin; -.
DR GenomeRNAi; 2934; -.
DR NextBio; 11625; -.
DR PMAP-CutDB; P06396; -.
DR PRO; PR:P06396; -.
DR ArrayExpress; P06396; -.
DR Bgee; P06396; -.
DR CleanEx; HS_GSN; -.
DR Genevestigator; P06396; -.
DR GO; GO:0015629; C:actin cytoskeleton; TAS:ProtInc.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0030027; C:lamellipodium; IEA:Ensembl.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0043234; C:protein complex; IEA:Ensembl.
DR GO; GO:0001726; C:ruffle; IEA:Ensembl.
DR GO; GO:0005509; F:calcium ion binding; TAS:ProtInc.
DR GO; GO:0030041; P:actin filament polymerization; IDA:UniProtKB.
DR GO; GO:0051014; P:actin filament severing; IDA:UniProtKB.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0051016; P:barbed-end actin filament capping; TAS:ProtInc.
DR GO; GO:0006921; P:cellular component disassembly involved in execution phase of apoptosis; TAS:Reactome.
DR GO; GO:0071276; P:cellular response to cadmium ion; IEA:Ensembl.
DR GO; GO:0060271; P:cilium morphogenesis; IMP:UniProtKB.
DR GO; GO:0014003; P:oligodendrocyte development; IEA:Ensembl.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; IEA:Ensembl.
DR GO; GO:0030155; P:regulation of cell adhesion; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0051593; P:response to folic acid; IEA:Ensembl.
DR GO; GO:0042246; P:tissue regeneration; IEA:Ensembl.
DR GO; GO:0016192; P:vesicle-mediated transport; IEA:Ensembl.
DR InterPro; IPR007123; Gelsolin_dom.
DR InterPro; IPR007122; Villin/Gelsolin.
DR PANTHER; PTHR11977; PTHR11977; 1.
DR Pfam; PF00626; Gelsolin; 6.
DR PRINTS; PR00597; GELSOLIN.
DR SMART; SM00262; GEL; 6.
PE 1: Evidence at protein level;
KW 3D-structure; Actin capping; Actin-binding; Alternative initiation;
KW Alternative splicing; Amyloid; Amyloidosis; Calcium;
KW Cilium biogenesis/degradation; Complete proteome; Corneal dystrophy;
KW Cytoplasm; Cytoskeleton; Direct protein sequencing; Disease mutation;
KW Disulfide bond; Metal-binding; Phosphoprotein; Polymorphism;
KW Reference proteome; Repeat; Secreted; Signal.
FT SIGNAL 1 27
FT CHAIN 28 782 Gelsolin.
FT /FTId=PRO_0000036385.
FT REPEAT 76 126 Gelsolin-like 1.
FT REPEAT 198 238 Gelsolin-like 2.
FT REPEAT 314 356 Gelsolin-like 3.
FT REPEAT 453 504 Gelsolin-like 4.
FT REPEAT 576 616 Gelsolin-like 5.
FT REPEAT 679 721 Gelsolin-like 6.
FT REGION 53 176 Actin-severing (Potential).
FT REGION 123 126 Actin-actin interfilament contact point.
FT REGION 162 169 Polyphosphoinositide binding (By
FT similarity).
FT REGION 188 196 Polyphosphoinositide binding (By
FT similarity).
FT REGION 434 782 Actin-binding, Ca-sensitive (Potential).
FT METAL 471 471 Calcium 1; via carbonyl oxygen.
FT METAL 472 472 Calcium 1.
FT METAL 502 502 Calcium 1.
FT METAL 551 551 Calcium 1; via carbonyl oxygen.
FT METAL 591 591 Calcium 2.
FT METAL 591 591 Calcium 2; via carbonyl oxygen.
FT METAL 592 592 Calcium 2.
FT METAL 614 614 Calcium 2.
FT METAL 696 696 Calcium 3; via carbonyl oxygen.
FT METAL 697 697 Calcium 3.
FT METAL 719 719 Calcium 3.
FT MOD_RES 86 86 Phosphotyrosine; by SRC; in vitro.
FT MOD_RES 409 409 Phosphotyrosine; by SRC; in vitro.
FT MOD_RES 465 465 Phosphotyrosine; by SRC.
FT MOD_RES 603 603 Phosphotyrosine; by SRC; in vitro.
FT MOD_RES 651 651 Phosphotyrosine; by SRC; in vitro.
FT DISULFID 215 228 In isoform 1.
FT VAR_SEQ 1 51 Missing (in isoform 2).
FT /FTId=VSP_018959.
FT VAR_SEQ 1 48 MAPHRPAPALLCALSLALCALSLPVRAATASRGASQAGAPQ
FT GRVPEAR -> MEKLFCCF (in isoform 3).
FT /FTId=VSP_042879.
FT VARIANT 22 22 S -> L (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036337.
FT VARIANT 129 129 A -> T (in dbSNP:rs2230287).
FT /FTId=VAR_024690.
FT VARIANT 201 201 T -> I (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036338.
FT VARIANT 214 214 D -> N (in AMYL5).
FT /FTId=VAR_007718.
FT VARIANT 214 214 D -> Y (in AMYL5).
FT /FTId=VAR_007719.
FT VARIANT 231 231 N -> D (in dbSNP:rs11550199).
FT /FTId=VAR_061982.
FT VARIANT 611 611 S -> N (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036339.
FT VARIANT 668 668 R -> L (in dbSNP:rs9696578).
FT /FTId=VAR_033958.
FT STRAND 52 55
FT HELIX 57 61
FT STRAND 64 74
FT STRAND 77 80
FT HELIX 83 85
FT STRAND 88 90
FT STRAND 94 102
FT TURN 104 106
FT STRAND 108 116
FT HELIX 122 138
FT TURN 139 141
FT STRAND 143 149
FT HELIX 155 158
FT STRAND 166 169
FT HELIX 172 174
FT STRAND 179 181
FT STRAND 188 203
FT HELIX 207 209
FT STRAND 214 219
FT STRAND 221 228
FT HELIX 234 250
FT STRAND 256 262
FT TURN 263 265
FT HELIX 268 274
FT HELIX 288 294
FT STRAND 299 304
FT STRAND 306 309
FT STRAND 311 321
FT HELIX 323 325
FT STRAND 330 336
FT HELIX 337 339
FT STRAND 341 346
FT HELIX 352 368
FT STRAND 376 381
FT HELIX 387 390
FT STRAND 393 395
FT STRAND 402 406
FT HELIX 412 414
FT TURN 424 426
FT HELIX 427 429
FT HELIX 431 437
FT STRAND 445 453
FT STRAND 456 459
FT HELIX 462 464
FT STRAND 467 469
FT STRAND 472 482
FT STRAND 485 494
FT HELIX 500 516
FT TURN 517 519
FT STRAND 521 527
FT HELIX 533 536
FT HELIX 537 539
FT STRAND 544 548
FT TURN 553 555
FT STRAND 562 570
FT STRAND 576 581
FT HELIX 585 587
FT STRAND 592 597
FT STRAND 602 606
FT HELIX 612 624
FT STRAND 630 633
FT HELIX 639 644
FT STRAND 645 647
FT HELIX 655 658
FT HELIX 661 664
FT STRAND 668 673
FT TURN 675 677
FT STRAND 680 684
FT HELIX 690 692
FT STRAND 697 702
FT STRAND 707 711
FT HELIX 717 732
FT STRAND 744 748
FT HELIX 754 757
FT STRAND 760 762
FT STRAND 765 767
FT HELIX 772 778
SQ SEQUENCE 782 AA; 85698 MW; 8CEBC52257A160F7 CRC64;
MAPHRPAPAL LCALSLALCA LSLPVRAATA SRGASQAGAP QGRVPEARPN SMVVEHPEFL
KAGKEPGLQI WRVEKFDLVP VPTNLYGDFF TGDAYVILKT VQLRNGNLQY DLHYWLGNEC
SQDESGAAAI FTVQLDDYLN GRAVQHREVQ GFESATFLGY FKSGLKYKKG GVASGFKHVV
PNEVVVQRLF QVKGRRVVRA TEVPVSWESF NNGDCFILDL GNNIHQWCGS NSNRYERLKA
TQVSKGIRDN ERSGRARVHV SEEGTEPEAM LQVLGPKPAL PAGTEDTAKE DAANRKLAKL
YKVSNGAGTM SVSLVADENP FAQGALKSED CFILDHGKDG KIFVWKGKQA NTEERKAALK
TASDFITKMD YPKQTQVSVL PEGGETPLFK QFFKNWRDPD QTDGLGLSYL SSHIANVERV
PFDAATLHTS TAMAAQHGMD DDGTGQKQIW RIEGSNKVPV DPATYGQFYG GDSYIILYNY
RHGGRQGQII YNWQGAQSTQ DEVAASAILT AQLDEELGGT PVQSRVVQGK EPAHLMSLFG
GKPMIIYKGG TSREGGQTAP ASTRLFQVRA NSAGATRAVE VLPKAGALNS NDAFVLKTPS
AAYLWVGTGA SEAEKTGAQE LLRVLRAQPV QVAEGSEPDG FWEALGGKAA YRTSPRLKDK
KMDAHPPRLF ACSNKIGRFV IEEVPGELMQ EDLATDDVML LDTWDQVFVW VGKDSQEEEK
TEALTSAKRY IETDPANRDR RTPITVVKQG FEPPSFVGWF LGWDDDYWSV DPLDRAMAEL
AA
//
MIM
105120
*RECORD*
*FIELD* NO
105120
*FIELD* TI
#105120 AMYLOIDOSIS, FINNISH TYPE
;;AMYLOIDOSIS V;;
AMYLOIDOSIS, MERETOJA TYPE;;
AMYLOID CRANIAL NEUROPATHY WITH LATTICE CORNEAL DYSTROPHY;;
read moreAMYLOIDOSIS DUE TO MUTANT GELSOLIN
CEREBRAL AMYLOID ANGIOPATHY, GSN-RELATED, INCLUDED;;
CORNEAL DYSTROPHY, LATTICE TYPE II, INCLUDED; LCD2, INCLUDED;;
LATTICE CORNEAL DYSTROPHY, TYPE II, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because the Finnish type of
amyloidosis is caused by mutation in the gelsolin gene (GSN; 137350).
See also corneal lattice dystrophy due to local amyloid deposition
(122200), which occurs as an isolated dominant.
DESCRIPTION
The Finnish type of systemic amyloidosis is characterized clinically by
a unique constellation of features including corneal lattice dystrophy,
and cranial neuropathy, bulbar signs, and skin changes. Some patients
may develop peripheral neuropathy and renal failure. The disorder is
usually inherited in an autosomal dominant pattern; however, homozygotes
with a more severe phenotype have also been reported (Meretoja, 1973).
CLINICAL FEATURES
In a massive investigation in Finland, Meretoja (1973) identified 207
affected persons. Two patients, whose parents were affected and who were
more severely affected than the others, were thought to represent
homozygosity. A few of the patients developed nephrotic syndrome and
renal failure and some had cardiac involvement. Amyloid involvement was
rather widespread at autopsy. Meretoja et al. (1978) collected 307
patients in Finland.
Three Czechoslovakian sisters with bulbar palsy, 'cutis hyperelastica,'
and lattice dystrophy of the cornea, reported by Klaus et al. (1959),
may have had this disorder. Cases were reported from the United States
by Sack et al. (1981), Purcell et al. (1983), Darras et al. (1986), and
Starck et al. (1991); from Holland by Winkelman et al. (1971); and from
Denmark by Boysen et al. (1979).
One of the patients reported by Sack et al. (1981) had onset of facial
paralysis, which began as inability to control a drooping lower lip, at
the age of about 56; the lip became strikingly protuberant and everted
with exposure of the lower gingival mucosa. Five years after onset he
could not wrinkle his forehead and there was an intermittent twitch of
the right side of the lower lip. The extraocular muscles were affected
only minimally and there was no ptosis. A striking feature was laxity of
the skin, which raised the question of cutis laxa. Slit-lamp examination
showed a lattice type of corneal opacity bilaterally. The mother had the
identical disorder beginning at about the same stage of life. The
proband had bulbar manifestations.
Kiuru (1992) reported the clinical findings of 30 patients. Signs of
cranial neuropathy especially affecting the facial nerve were found in
all, and peripheral polyneuropathy mainly affecting vibration and touch
senses was demonstrated in 26 patients. Kiuru et al. (1994) studied the
autonomic nervous system and heart in 30 patients. Minor autonomic
nervous system dysfunction was found in most patients, but clinically
significant autonomic dysfunction or cardiopathy was not characteristic.
MOLECULAR GENETICS
Maury et al. (1990) studied amyloid fibrils isolated from the kidney of
a patient with the Finnish form. The amino acid sequence determined for
part of the protein was identical to that deduced for plasma gelsolin in
the region of amino acids 235-269. Using PCR and allele-specific
oligonucleotide hybridization analysis of genomic DNA in patients with
this disorder, Maury et al. (1990) identified a 654G-A transition in the
GSN gene, resulting in an asp187-to-asn substitution (137350.0001), in
all 5 unrelated patients studied, but not in 45 unrelated control
subjects.
Haltia et al. (1990) likewise showed that the amyloid in this disorder
is antigenically and structurally related to gelsolin. The same mutation
in gelsolin (asp187-to-asn) has been found in all Finnish families
studied to date (Maury et al., 1990; Paunio et al., 1992; de la Chapelle
et al., 1992; Haltia et al., 1992; Sipila and Aula (2002)); furthermore,
it was found also in the affected son of the proband of the
Scottish-American family reported by Sack et al. (1981); see de la
Chapelle et al., (1992).
Maury (1993) reported the findings in 2 sisters who were homozygous for
the asp187-to-asn mutation in gelsolin. In both, the disease was
unusually severe, manifesting with nephrotic syndrome and end-stage
renal failure. Immunohistochemical studies of the kidneys demonstrated
heavy glomerular deposits of gelsolin-derived amyloid. Immunostaining
also demonstrated gelsolin in the tubular epithelium, where it was
Congo-red negative.
Akiya et al. (1996) reported a Japanese brother and half-sister with
lattice corneal dystrophy as part of the Finnish type amyloidosis. They
referred to the Finnish-type as FAP type IV. The patients were 70 and 68
years old, respectively.
*FIELD* SA
Meretoja (1973)
*FIELD* RF
1. Akiya, S.; Nishio, Y.; Ibi, K.; Uozumi, H.; Takahashi, H.; Hamada,
T.; Onishi, A.; Ishiguchi, H.; Hoshii, Y.; Nakazato, M.: Lattice
corneal dystrophy type II associated with familial amyloid polyneuropathy
type IV. Ophthalmology 103: 1106-1110, 1996.
2. Boysen, G.; Galassi, G.; Kamieniecka, Z.; Schlaeger, J.; Trojaborg,
W.: Familial amyloidosis with cranial neuropathy and corneal lattice
dystrophy. J. Neurol. Neurosurg. Psychiat. 42: 1020-1030, 1979.
3. Darras, B. T.; Adelman, L. S.; Mora, J. S.; Rodziner, R. A.; Munsat,
T. L.: Familial amyloidosis with cranial neuropathy and corneal lattice
dystrophy. Neurology 36: 432-435, 1986.
4. de la Chapelle, A.; Kere, J.; Sack, G. H., Jr.; Tolvanen, R.; Maury,
C. P. J.: Familial amyloidosis, Finnish type: G654-to-A mutation
of the gelsolin gene in Finnish families and an unrelated American
family. Genomics 13: 898-901, 1992.
5. Haltia, M.; Ghiso, J.; Prelli, F.; Gallo, G.; Kiuru, S.; Somer,
H.; Palo, J.; Frangione, G.: Amyloid in familial amyloidosis, Finnish
type, is antigenically and structurally related to gelsolin. Am.
J. Path. 136: 1223-1228, 1990.
6. Haltia, M.; Levy, E.; Meretoja, J.; Fernandez-Madrid, I.; Koivunen,
O.; Frangione, B.: Gelsolin gene mutation--at codon 187--in familial
amyloidosis, Finnish: DNA-diagnostic assay. Am. J. Med. Genet. 42:
357-359, 1992.
7. Kiuru, S.: Familial amyloidosis of the Finnish type (FAF): a clinical
study of 30 patients. Acta Neurol. Scand. 86: 346-353, 1992.
8. Kiuru, S.; Matikainen, E.; Kupari, M.; Haltia, M.; Palo, J.: Autonomic
nervous system and cardiac involvement in familial amyloidosis, Finnish
type (FAF). J. Neurol. Sci. 126: 40-48, 1994.
9. Klaus, E.; Freyberger, E.; Kavka, G.; Vodicka, F.: Familial occurrence
of a bulbar paralytic form of amyotrophic lateral sclerosis with reticular
corneal dystrophy and cutis hyperelastica in 3 sisters. Psychiat.
Neurol. 138: 79-97, 1959.
10. Maury, C. P. J.: Homozygous familial amyloidosis, Finnish type:
demonstration of glomerular gelsolin-derived amyloid and non-amyloid
tubular gelsolin. Clin. Nephrol. 40: 53-56, 1993.
11. Maury, C. P. J.; Alli, K.; Baumann, M.: Finnish hereditary amyloidosis:
amino acid sequence homology between the amyloid fibril protein and
human plasma gelsoline. FEBS Lett. 260: 85-87, 1990.
12. Maury, C. P. J.; Kere, J.; Tolvanen, R.; de la Chapelle, A.:
Finnish hereditary amyloidosis is caused by a single nucleotide substitution
in the gelsolin gene. FEBS Lett. 276: 75-77, 1990.
13. Meretoja, J.: Inherited Systemic Amyloidosis with Lattice Corneal
Dystrophy. Acad. Dissertation: Helsinki (pub.) 1973.
14. Meretoja, J.: Genetic aspects of familial amyloidosis with corneal
lattice dystrophy and cranial neuropathy. Clin. Genet. 4: 173-185,
1973.
15. Meretoja, J.; Hollmen, T.; Meretoja, T.; Penttinen, R.: Partial
characterization of amyloid proteins in inherited amyloidosis with
lattice corneal dystrophy and in secondary amyloidosis. Med. Biol. 56:
17-22, 1978.
16. Paunio, T.; Kiuru, S.; Hongell, V.; Mustonen, E.; Syvanen, A.-C.;
Bengtstrom, M.; Palo, J.; Peltonen, L.: Solid-phase minisequencing
test reveals asp187-to-asn (G654-to-A) mutation of gelsolin in all
affected individuals with Finnish type of familial amyloidosis. Genomics 13:
237-239, 1992.
17. Purcell, J. J., Jr.; Rodrigues, M.; Chishti, M. I.; Riner, R.
N.; Dooley, J. M.: Lattice corneal dystrophy associated with familial
systemic amyloidosis (Meretoja's syndrome). Ophthalmology 90: 1512-1517,
1983.
18. Sack, G. H., Jr.; Dumars, K. W.; Gummerson, K. S.; Law, A.; McKusick,
V. A.: Three forms of dominant amyloid neuropathy. Johns Hopkins
Med. J. 149: 239-247, 1981.
19. Sipila, K.; Aula, P.: Database for the mutations of the Finnish
disease heritage. Hum. Mutat. 19: 16-22, 2002.
20. Starck, T.; Kenyon, K. R.; Hanninen, L. A.; Beyer-Machule, C.;
Fabian, R.; Gorn, R. A.; McMullan, F. D.; Baum, J.; McAdam, K. P.
W. J.: Clinical and histopathologic studies of two families with
lattice corneal dystrophy and familial systemic amyloidosis (Meretoja
syndrome). Ophthalmology 98: 1197-1206, 1991.
21. Winkelman, J. E.; Delleman, J. W.; Ansink, B. J. J.: Ein hereditaeres
Syndrom, bestehend aus peripherer Polyneuropathie, Hautveraenderungen
und gittriger Dystrophie der Hornhaut. Klin. Monatsbl. Augenheilkd. 159:
618-623, 1971.
*FIELD* CS
Skin:
Cutis laxa
Eye:
Lattice corneal dystrophy
Neuro:
Cranial neuropathy, esp. facial paresis;
Bulbar palsy;
Peripheral polyneuropathy, esp. vibration and touch loss;
Autonomic dysfunction does not occur
GI:
Gastrointestinal symptoms are inconstant
GU:
Nephrotic syndrome;
Renal failure
Cardiac:
Amyloid cardiomyopathy
Misc:
Onset in third decade
Lab:
Generalized amyloid deposition;
Mutant gelsolin gene (137350)
Inheritance:
Autosomal dominant
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
terry: 11/16/2010
ckniffin: 1/19/2010
alopez: 10/28/2009
carol: 6/19/2009
carol: 1/14/2009
carol: 1/19/2002
jenny: 7/9/1997
mark: 10/26/1996
terry: 10/18/1996
joanna: 2/26/1996
carol: 1/19/1995
davew: 6/8/1994
mimadm: 4/18/1994
warfield: 4/7/1994
carol: 11/9/1993
carol: 1/28/1993
*RECORD*
*FIELD* NO
105120
*FIELD* TI
#105120 AMYLOIDOSIS, FINNISH TYPE
;;AMYLOIDOSIS V;;
AMYLOIDOSIS, MERETOJA TYPE;;
AMYLOID CRANIAL NEUROPATHY WITH LATTICE CORNEAL DYSTROPHY;;
read moreAMYLOIDOSIS DUE TO MUTANT GELSOLIN
CEREBRAL AMYLOID ANGIOPATHY, GSN-RELATED, INCLUDED;;
CORNEAL DYSTROPHY, LATTICE TYPE II, INCLUDED; LCD2, INCLUDED;;
LATTICE CORNEAL DYSTROPHY, TYPE II, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because the Finnish type of
amyloidosis is caused by mutation in the gelsolin gene (GSN; 137350).
See also corneal lattice dystrophy due to local amyloid deposition
(122200), which occurs as an isolated dominant.
DESCRIPTION
The Finnish type of systemic amyloidosis is characterized clinically by
a unique constellation of features including corneal lattice dystrophy,
and cranial neuropathy, bulbar signs, and skin changes. Some patients
may develop peripheral neuropathy and renal failure. The disorder is
usually inherited in an autosomal dominant pattern; however, homozygotes
with a more severe phenotype have also been reported (Meretoja, 1973).
CLINICAL FEATURES
In a massive investigation in Finland, Meretoja (1973) identified 207
affected persons. Two patients, whose parents were affected and who were
more severely affected than the others, were thought to represent
homozygosity. A few of the patients developed nephrotic syndrome and
renal failure and some had cardiac involvement. Amyloid involvement was
rather widespread at autopsy. Meretoja et al. (1978) collected 307
patients in Finland.
Three Czechoslovakian sisters with bulbar palsy, 'cutis hyperelastica,'
and lattice dystrophy of the cornea, reported by Klaus et al. (1959),
may have had this disorder. Cases were reported from the United States
by Sack et al. (1981), Purcell et al. (1983), Darras et al. (1986), and
Starck et al. (1991); from Holland by Winkelman et al. (1971); and from
Denmark by Boysen et al. (1979).
One of the patients reported by Sack et al. (1981) had onset of facial
paralysis, which began as inability to control a drooping lower lip, at
the age of about 56; the lip became strikingly protuberant and everted
with exposure of the lower gingival mucosa. Five years after onset he
could not wrinkle his forehead and there was an intermittent twitch of
the right side of the lower lip. The extraocular muscles were affected
only minimally and there was no ptosis. A striking feature was laxity of
the skin, which raised the question of cutis laxa. Slit-lamp examination
showed a lattice type of corneal opacity bilaterally. The mother had the
identical disorder beginning at about the same stage of life. The
proband had bulbar manifestations.
Kiuru (1992) reported the clinical findings of 30 patients. Signs of
cranial neuropathy especially affecting the facial nerve were found in
all, and peripheral polyneuropathy mainly affecting vibration and touch
senses was demonstrated in 26 patients. Kiuru et al. (1994) studied the
autonomic nervous system and heart in 30 patients. Minor autonomic
nervous system dysfunction was found in most patients, but clinically
significant autonomic dysfunction or cardiopathy was not characteristic.
MOLECULAR GENETICS
Maury et al. (1990) studied amyloid fibrils isolated from the kidney of
a patient with the Finnish form. The amino acid sequence determined for
part of the protein was identical to that deduced for plasma gelsolin in
the region of amino acids 235-269. Using PCR and allele-specific
oligonucleotide hybridization analysis of genomic DNA in patients with
this disorder, Maury et al. (1990) identified a 654G-A transition in the
GSN gene, resulting in an asp187-to-asn substitution (137350.0001), in
all 5 unrelated patients studied, but not in 45 unrelated control
subjects.
Haltia et al. (1990) likewise showed that the amyloid in this disorder
is antigenically and structurally related to gelsolin. The same mutation
in gelsolin (asp187-to-asn) has been found in all Finnish families
studied to date (Maury et al., 1990; Paunio et al., 1992; de la Chapelle
et al., 1992; Haltia et al., 1992; Sipila and Aula (2002)); furthermore,
it was found also in the affected son of the proband of the
Scottish-American family reported by Sack et al. (1981); see de la
Chapelle et al., (1992).
Maury (1993) reported the findings in 2 sisters who were homozygous for
the asp187-to-asn mutation in gelsolin. In both, the disease was
unusually severe, manifesting with nephrotic syndrome and end-stage
renal failure. Immunohistochemical studies of the kidneys demonstrated
heavy glomerular deposits of gelsolin-derived amyloid. Immunostaining
also demonstrated gelsolin in the tubular epithelium, where it was
Congo-red negative.
Akiya et al. (1996) reported a Japanese brother and half-sister with
lattice corneal dystrophy as part of the Finnish type amyloidosis. They
referred to the Finnish-type as FAP type IV. The patients were 70 and 68
years old, respectively.
*FIELD* SA
Meretoja (1973)
*FIELD* RF
1. Akiya, S.; Nishio, Y.; Ibi, K.; Uozumi, H.; Takahashi, H.; Hamada,
T.; Onishi, A.; Ishiguchi, H.; Hoshii, Y.; Nakazato, M.: Lattice
corneal dystrophy type II associated with familial amyloid polyneuropathy
type IV. Ophthalmology 103: 1106-1110, 1996.
2. Boysen, G.; Galassi, G.; Kamieniecka, Z.; Schlaeger, J.; Trojaborg,
W.: Familial amyloidosis with cranial neuropathy and corneal lattice
dystrophy. J. Neurol. Neurosurg. Psychiat. 42: 1020-1030, 1979.
3. Darras, B. T.; Adelman, L. S.; Mora, J. S.; Rodziner, R. A.; Munsat,
T. L.: Familial amyloidosis with cranial neuropathy and corneal lattice
dystrophy. Neurology 36: 432-435, 1986.
4. de la Chapelle, A.; Kere, J.; Sack, G. H., Jr.; Tolvanen, R.; Maury,
C. P. J.: Familial amyloidosis, Finnish type: G654-to-A mutation
of the gelsolin gene in Finnish families and an unrelated American
family. Genomics 13: 898-901, 1992.
5. Haltia, M.; Ghiso, J.; Prelli, F.; Gallo, G.; Kiuru, S.; Somer,
H.; Palo, J.; Frangione, G.: Amyloid in familial amyloidosis, Finnish
type, is antigenically and structurally related to gelsolin. Am.
J. Path. 136: 1223-1228, 1990.
6. Haltia, M.; Levy, E.; Meretoja, J.; Fernandez-Madrid, I.; Koivunen,
O.; Frangione, B.: Gelsolin gene mutation--at codon 187--in familial
amyloidosis, Finnish: DNA-diagnostic assay. Am. J. Med. Genet. 42:
357-359, 1992.
7. Kiuru, S.: Familial amyloidosis of the Finnish type (FAF): a clinical
study of 30 patients. Acta Neurol. Scand. 86: 346-353, 1992.
8. Kiuru, S.; Matikainen, E.; Kupari, M.; Haltia, M.; Palo, J.: Autonomic
nervous system and cardiac involvement in familial amyloidosis, Finnish
type (FAF). J. Neurol. Sci. 126: 40-48, 1994.
9. Klaus, E.; Freyberger, E.; Kavka, G.; Vodicka, F.: Familial occurrence
of a bulbar paralytic form of amyotrophic lateral sclerosis with reticular
corneal dystrophy and cutis hyperelastica in 3 sisters. Psychiat.
Neurol. 138: 79-97, 1959.
10. Maury, C. P. J.: Homozygous familial amyloidosis, Finnish type:
demonstration of glomerular gelsolin-derived amyloid and non-amyloid
tubular gelsolin. Clin. Nephrol. 40: 53-56, 1993.
11. Maury, C. P. J.; Alli, K.; Baumann, M.: Finnish hereditary amyloidosis:
amino acid sequence homology between the amyloid fibril protein and
human plasma gelsoline. FEBS Lett. 260: 85-87, 1990.
12. Maury, C. P. J.; Kere, J.; Tolvanen, R.; de la Chapelle, A.:
Finnish hereditary amyloidosis is caused by a single nucleotide substitution
in the gelsolin gene. FEBS Lett. 276: 75-77, 1990.
13. Meretoja, J.: Inherited Systemic Amyloidosis with Lattice Corneal
Dystrophy. Acad. Dissertation: Helsinki (pub.) 1973.
14. Meretoja, J.: Genetic aspects of familial amyloidosis with corneal
lattice dystrophy and cranial neuropathy. Clin. Genet. 4: 173-185,
1973.
15. Meretoja, J.; Hollmen, T.; Meretoja, T.; Penttinen, R.: Partial
characterization of amyloid proteins in inherited amyloidosis with
lattice corneal dystrophy and in secondary amyloidosis. Med. Biol. 56:
17-22, 1978.
16. Paunio, T.; Kiuru, S.; Hongell, V.; Mustonen, E.; Syvanen, A.-C.;
Bengtstrom, M.; Palo, J.; Peltonen, L.: Solid-phase minisequencing
test reveals asp187-to-asn (G654-to-A) mutation of gelsolin in all
affected individuals with Finnish type of familial amyloidosis. Genomics 13:
237-239, 1992.
17. Purcell, J. J., Jr.; Rodrigues, M.; Chishti, M. I.; Riner, R.
N.; Dooley, J. M.: Lattice corneal dystrophy associated with familial
systemic amyloidosis (Meretoja's syndrome). Ophthalmology 90: 1512-1517,
1983.
18. Sack, G. H., Jr.; Dumars, K. W.; Gummerson, K. S.; Law, A.; McKusick,
V. A.: Three forms of dominant amyloid neuropathy. Johns Hopkins
Med. J. 149: 239-247, 1981.
19. Sipila, K.; Aula, P.: Database for the mutations of the Finnish
disease heritage. Hum. Mutat. 19: 16-22, 2002.
20. Starck, T.; Kenyon, K. R.; Hanninen, L. A.; Beyer-Machule, C.;
Fabian, R.; Gorn, R. A.; McMullan, F. D.; Baum, J.; McAdam, K. P.
W. J.: Clinical and histopathologic studies of two families with
lattice corneal dystrophy and familial systemic amyloidosis (Meretoja
syndrome). Ophthalmology 98: 1197-1206, 1991.
21. Winkelman, J. E.; Delleman, J. W.; Ansink, B. J. J.: Ein hereditaeres
Syndrom, bestehend aus peripherer Polyneuropathie, Hautveraenderungen
und gittriger Dystrophie der Hornhaut. Klin. Monatsbl. Augenheilkd. 159:
618-623, 1971.
*FIELD* CS
Skin:
Cutis laxa
Eye:
Lattice corneal dystrophy
Neuro:
Cranial neuropathy, esp. facial paresis;
Bulbar palsy;
Peripheral polyneuropathy, esp. vibration and touch loss;
Autonomic dysfunction does not occur
GI:
Gastrointestinal symptoms are inconstant
GU:
Nephrotic syndrome;
Renal failure
Cardiac:
Amyloid cardiomyopathy
Misc:
Onset in third decade
Lab:
Generalized amyloid deposition;
Mutant gelsolin gene (137350)
Inheritance:
Autosomal dominant
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
terry: 11/16/2010
ckniffin: 1/19/2010
alopez: 10/28/2009
carol: 6/19/2009
carol: 1/14/2009
carol: 1/19/2002
jenny: 7/9/1997
mark: 10/26/1996
terry: 10/18/1996
joanna: 2/26/1996
carol: 1/19/1995
davew: 6/8/1994
mimadm: 4/18/1994
warfield: 4/7/1994
carol: 11/9/1993
carol: 1/28/1993
MIM
137350
*RECORD*
*FIELD* NO
137350
*FIELD* TI
*137350 GELSOLIN; GSN
*FIELD* TX
CLONING
Gelsolin, a protein of leukocytes, platelets, and other cells, severs
read moreactin filaments in the presence of submicromolar calcium, thereby
solating cytoplasmic actin gels. A calcium-independent mechanism
reverses the process. A gelsolin variant with 23 more N-terminal amino
acids is a plasma component probably involved in the clearance of actin,
the most abundant human protein, from the circulation. Kwiatkowski et
al. (1986) isolated a full-length plasma gelsolin cDNA clone. Northern
blot analysis suggested that a single gene encodes both cell and plasma
gelsolins. This protein may be unique in that it is made for both
secretion and intracytoplasmic location.
MAPPING
By Southern blot analysis of somatic cell hybrids and in situ
chromosomal localization, Kwiatkowski et al. (1988) demonstrated that
the GSN gene is located on 9q32-q34. In situ hybridization to cells
containing a Philadelphia chromosome, as well as Southern blot analysis
of a chronic myeloid leukemia cell DNA, indicated that GSN is
centromeric to ABL (189980), which is located in 9q34. Furthermore,
Southern blot analysis of NotI-digested, pulsed-field gel
electrophoresis-separated DNA indicated that GSN is 40 or more kb
centromeric to ABL. Pilz et al. (1992) used interspecies backcrosses to
map the Gsn gene to mouse chromosome 2.
GENE FUNCTION
Maury et al. (1990) identified amino acid homology between gelsolin and
the amyloid of the Finnish variety of amyloidosis (105120). Haltia et
al. (1990) likewise showed that the amyloid in this disorder is
antigenically and structurally related to gelsolin. Gelsolin is also
known as brevin, or actin-depolymerizing factor; it is the principal
intracellular and extracellular actin-severing protein. Gelsolin and Gc
protein (GC; 139200) together constitute the extracellular
actin-scavenger system (Lee and Galbraith, 1992) which prevents the
toxic effects of actin release into the extracellular space under
circumstances of cell necrosis.
Vasconcellos et al. (1994) showed that the viscous sputum from patients
with cystic fibrosis (219700) contains filamentous actin derived from
leukocytes and that gelsolin, which severs actin filaments, rapidly
decreases the viscosity of CF sputum samples in vitro. They suggested
that gelsolin may have therapeutic potential as a mucolytic agent in CF
patients.
Caspase-mediated proteolysis is a critical and central element of the
apoptotic process; therefore, it was important to identify the
downstream molecular targets of caspases. Kamada et al. (1998)
established a method for cloning the genes of caspase substrates by 2
major modifications of the yeast 2-hybrid system: (1) both large and
small subunits with active caspases were expressed in yeast under ADH1
(103700) promoters and the small subunit was fused to the LexA
DNA-binding domain; and (2) a point mutation was introduced that
substituted serine for the active site cysteine and thereby prevented
proteolytic cleavage of the substrates, possibly stabilizing the
enzyme-substrate complexes in yeast. After screening a mouse embryo cDNA
expression library by using the bait plasmid for caspase-3, Kamada et
al. (1998) obtained 13 clones that encoded proteins binding to
caspase-3, and showed that 10 clones, including gelsolin, an
actin-regulatory protein implicated in apoptosis, were cleaved by
recombinant caspase-3 in vitro. Using the same bait, they also isolated
human gelsolin cDNA from a human thymus cDNA expression library. They
showed that human gelsolin was cleaved during Fas-mediated apoptosis in
vivo and that the caspase-3 cleavage site of human gelsolin was at
asp352 (D352) in a 5-amino acid sequence, DQTD(352)G, findings
consistent with previous observations on murine gelsolin. In addition,
Kamada et al. (1998) ascribed the antiapoptotic activity of gelsolin to
prevention of a step leading to cytochrome c release from the
mitochondria into the cytosol. The results demonstrated the usefulness
of this cloning method for identification of the substrates of caspases
and possibly of other other enzymes.
To investigate the pathogenic mechanisms in gelsolin-related
amyloidosis, Paunio et al. (1994) transfected mammalian mesenchymal
COS-1 cells with a derivative of an expression vector containing cDNA
coding for the wildtype (D187) and mutant forms (N187 and Y187) of
plasma gelsolin. Both disease-associated mutant forms of gelsolin were
found to be abnormally processed, resulting in the secretion of an
aberrant 68-kD gelsolin fragment into the culture medium. This fragment
probably represented a carboxy-terminal part of the protein and
contained the suggested amyloid-forming sequence.
In a functional genomic screen using RNA interference to identify human
genes involved in ciliogenesis control, Kim et al. (2010) identified 2
gelsolin family proteins, GSN and AVIL (613397), which regulate
cytoskeletal actin organization by severing actin filaments. Depletion
of GSN proteins by 2 independent siRNAs significantly reduced ciliated
cell numbers, indicating that actin filament severing is involved in
ciliogenesis. In contrast, silencing of actin-related protein ACTR3
(604222), which is a major constituent of the ARP2/3 complex that is
necessary for nucleating actin polymerization at filament branches,
caused a significant increase in cilium length and also facilitated
ciliogenesis independently of serum starvation. Kim et al. (2010)
concluded that their observations indicated an inhibitory role of
branched actin network formation in ciliogenesis.
BIOCHEMICAL FEATURES
A single-nucleotide mutation at residue 187 (either D187N 137350.0001 or
D187Y 137350.0002) in Finnish amyloidosis occurs within domain 2 of the
actin-regulating protein gelsolin. The mutation somehow allows a masked
cleavage site to be exposed, leading to the first step in the formation
of an amyloidogenic fragment. Kazmirski et al. (2000) performed nuclear
magnetic resonance (NMR) experiments investigating structural and
dynamic changes between wildtype and the D187N gelsolin domain 2. From
their observations, Kazmirski et al. (2000) proposed that the D187N
mutation destabilizes the C-terminal tail of domain 2 resulting in a
more exposed cleavage site and leading to the first proteolysis step in
the formation of the amyloidogenic fragment.
Kazmirski et al. (2002) determined the structure of domain 2 (D2,
residues 151-266) of gelsolin and found that asp187 is part of a
bivalent cadmium ion metal-binding site. Two bivalent calcium ions are
required for a conformational transition of gelsolin to its active form.
Kazmirski et al. (2002) showed that the cadmium-binding site in D2 is
one of these 2 calcium-binding sites and is essential to the stability
of D2. Mutation of asp187 to asn (127350.0001) disrupted calcium binding
in D2, leading to instability upon calcium activation. Instability makes
the domain a target for aberrant proteolysis, thereby enacting the first
step in the cascade leading to familial amyloidosis, Finnish type.
ANIMAL MODEL
To investigate the in vivo function of gelsolin, Witke et al. (1995)
generated transgenic gelsolin-null mice. Although embryonic development
and longevity were normal, platelet shape changes were decreased in the
Gsn-null mice, causing prolonged bleeding times. Neutrophil migration in
vivo into peritoneal exudates and in vitro was delayed. Dermal
fibroblasts had excessive actin stress fibers and migrated more slowly
than wildtype fibroblasts, but had increased contractility in vitro. The
observations established the requirement of gelsolin for rapid motile
responses in cell types involved in stress responses, such as
hemostasis, inflammation, and wound healing. Neither gelsolin nor other
proteins with similar actin filament-severing activity are expressed in
early embryonic cells, which indicated that this mechanism of actin
filament dynamics is not essential for motility during early
embryogenesis.
*FIELD* AV
.0001
AMYLOIDOSIS, FAMILIAL, FINNISH TYPE
AMYLOIDOSIS, MERETOJA TYPE
GSN, ASP187ASN
The amyloid protein in the Finnish type of hereditary amyloidosis
(105120) is a fragment of the actin-filament binding region of a variant
gelsolin molecule. Using PCR and allele-specific oligonucleotide
hybridization analysis of genomic DNA, Maury et al. (1990) identified a
single base mutation, 654G-A. This nucleotide substitution was found in
all 5 unrelated patients with Finnish amyloidosis studied but not in 45
unrelated control subjects. They were guided in the development of the
allele-specific oligonucleotide hybridization method by the
demonstration that the amyloid protein in this disorder has an
asp187-to-asn mutation (D187N) (Maury, 1990, 1991) resulting from the
change of GAC to AAC. Ghiso et al. (1990) and Levy et al. (1990)
likewise identified the D187N change. Hiltunen et al. (1991) found the
D187N mutation in affected members of 3 large families in restricted
areas on the southern coast of Finland. Maury (1991) found the D187N
mutation in 6 other ostensibly unrelated Finnish families. These
included 2 sibs, the offspring of 2 affected parents, who were by DNA
test homozygous for the mutation and showed unusually early onset and
severity of the disease (Maury, 1993). Proteinuria was present by the
teens and amyloid nephropathy with nephrotic syndrome by the 20s.
Hemodialysis and renal transplant were necessary in the 30s.
Contrariwise, in the course of family studies, Maury (1991) found
30-year-old asymptomatic individuals with the mutation but with changes
of lattice corneal dystrophy on examination. (Meretoja (1973) had
suggested that 2 patients who were more severely affected than the
average, and whose parents were affected, represented homozygosity for
this gene.)
Maury (1991) and de la Chapelle et al. (1992) demonstrated the same
D187N mutation in the American family of Scottish extraction reported by
Sack et al. (1981). Maury et al. (1992) presented molecular evidence of
homozygosity in 1 such patient. It appears that these were independent
mutations. This disorder is extraordinarily rare except in Finland where
peculiar historical and demographic factors have been responsible for
the high frequency; if all the cases prove to be due to the
asp187-to-asn mutation, then it would seem likely that the change in the
amino acid sequence at that particular site of the gelsolin molecule is
particularly critical, perhaps uniquely critical, to rendering gelsolin
amyloidogenic. Gorevic et al. (1991) found the asp187-to-asn mutation in
an American patient of Irish descent and his affected 31-year-old
daughter. This family had been reported by Purcell et al. (1983). Haltia
et al. (1992) described a slot-blot analysis for the asp187-to-asn
mutation. Paunio et al. (1992) applied the solid-phase minisequencing
test to determine the nature of the mutation in 94 affected persons and
32 healthy family members from 55 families with the Finnish type of
familial amyloidosis living in Finland. The families represented about
34% (55/160) of all known affected families in Finland. In all affected
individuals, they found the asp187-to-asn gene. Furthermore, they found
the mutation in 54% (20/37) of young at-risk persons with the mutation.
Sunada et al. (1993) found the same mutation as the cause of the Finnish
or Meretoja type of amyloid polyneuropathy in 14 members of a large
Japanese kindred with no known contacts with Finnish or other Caucasian
populations. This further supports the notion that the asp187-to-asn
mutation or other mutations at the same location are specifically
amyloidogenic.
Steiner et al. (1995) used a PCR-based DNA assay to identify the same
G-to-A mutation at position 654 of the GSN gene in an American kindred
with Scandinavian ancestry. The mutation was demonstrated in the
clinically affected proband, her deceased clinically affected father,
and her presumably affected presymptomatic son. The diagnosis of Finnish
type amyloidosis had been made in the proband after the recognition of
lattice corneal dystrophy on routine ophthalmologic examination at age
34. At the age of 38, she was asymptomatic with normal vision and no
evidence of cranial nerve dysfunction, no peripheral neuropathy, and no
evidence of cardiac or renal dysfunction. The father died at age 77 from
complications of systemic amyloidosis diagnosed 9 years before his
death. Manifestations of disease included lattice corneal dystrophy,
facial muscle weakness with lagophthalmos and sagging facial skin,
cardiomyopathy with left ventricular hypertrophy, and aortic root
dilatation, chronic renal insufficiency, hypothyroidism, and
pancytopenia.
From haplotype analysis in 10 Finnish and 2 Japanese families with the
Finnish type of familial amyloidosis, Paunio et al. (1995) demonstrated
a uniform disease haplotype in all the disease-associated chromosomes of
the Finnish families which was different from the one observed in the
Japanese families. Thus, they concluded that these mutations arose
independently.
Sipila and Aula (2002) reported the creation of an up-to-date database
for mutations of Finnish disease heritage, i.e., the more than 30
monogenic disorders that are more prevalent in the Finnish population
than in the rest of the world. They noted that all Finnish cases of
familial amyloidosis of the Finnish type have had the D187N mutation.
.0002
AMYLOIDOSIS, FAMILIAL, FINNISH TYPE
GSN, ASP187TYR
Although de la Chapelle et al. (1992) found the characteristic
asp187-to-asn mutation (137350.0001) in 2 non-Finnish American families
and a Dutch family with the clinically typical corneocranial type of
amyloidosis (due to a 654G-A transition), they found a 654G-T
transversion predicting an asp187-to-tyr substitution (D187Y) in a
Danish family and a Czech family with the same disorder (105120).
Different haplotypes were found in the Danish and Czech families,
suggesting that the mutations arose independently. The substitution of
an uncharged polar amino acid for the acidic aspartic acid at residue
187 creates a beta sheet conformation that may be preferentially or
uniquely amyloidogenic for gelsolin. This is in contrast to the variety
of mutations in transthyretin-related amyloidosis (176300) but resembles
that seen in some early-onset Alzheimer disease families in which a
single residue in the APP gene (e.g., 104760.0002-104760.0004) is
involved.
*FIELD* SA
de la Chapelle et al. (1992); de la Chapelle et al. (1992); Kwiatkowski
et al. (1989); Maury (1991); Maury et al. (1990)
*FIELD* RF
1. de la Chapelle, A.; Kere, J.; Sack, G. H., Jr.; Tolvanen, R.; Maury,
C. P. J.: Familial amyloidosis, Finnish type: G654-to-A mutation
of the gelsolin gene in Finnish families and an unrelated American
family. Genomics 13: 898-901, 1992.
2. de la Chapelle, A.; Tolvanen, R.; Boysen, G.; Santavy, J.; Bleeker-Wagemakers,
L.; Maury, C. P. J.; Kere, J.: Gelsolin-derived familial amyloidosis:
all known mutations worldwide are substitutions of asn or tyr for
asp at residue 187. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A148
only, 1992.
3. de la Chapelle, A.; Tolvanen, R.; Boysen, G.; Santavy, J.; Bleeker-Wagemakers,
L.; Maury, C. P. J.; Kere, J.: Gelsolin-derived familial amyloidosis
caused by asparagine or tyrosine substitution for aspartic acid at
residue 187. Nature Genet. 2: 157-160, 1992.
4. Ghiso, J.; Haltia, M.; Prelli, F.; Novello, J.; Frangione, B.:
Gelsolin variant (asn-187) in familial amyloidosis, Finnish type. Biochem.
J. 272: 827-830, 1990.
5. Gorevic, P. D.; Munoz, P. C.; Gorgone, G.; Purcell, J. J., Jr.;
Rodrigues, M.; Ghiso, J.; Levy, E.; Haltia, M.; Frangione, B.: Amyloidosis
due to a mutation of the gelsolin gene in an American family with
lattice corneal dystrophy type II. New Eng. J. Med. 325: 1780-1785,
1991.
6. Haltia, M.; Ghiso, J.; Prelli, F.; Gallo, G.; Kiuru, S.; Somer,
H.; Palo, J.; Frangione, B.: Amyloid in familial amyloidosis, Finnish
type, is antigenically and structurally related to gelsolin. Am.
J. Path. 136: 1223-1228, 1990.
7. Haltia, M.; Levy, E.; Meretoja, J.; Fernandez-Madrid, I.; Koivunen,
O.; Frangione, B.: Gelsolin gene mutation--at codon 187--in familial
amyloidosis, Finnish: DNA-diagnostic assay. Am. J. Med. Genet. 42:
357-359, 1992.
8. Hiltunen, T.; Kiuru, S.; Hongell, V.; Helio, T.; Palo, J.; Peltonen,
L.: Finnish type of familial amyloidosis: cosegregation of asp187-to-asn
mutation of gelsolin with the disease in three large families. Am.
J. Hum. Genet. 49: 522-528, 1991.
9. Kamada, S.; Kusano, H.; Fujita, H.; Ohtsu, M.; Koya, R. C.; Kuzumaki,
N.; Tsujimoto, Y.: A cloning method for caspase substrates that uses
the yeast two-hybrid system: cloning of the antiapoptotic gene gelsolin. Proc.
Nat. Acad. Sci. 95: 8532-8537, 1998.
10. Kazmirski, S. L.; Howard, M. J.; Isaacson, R. L.; Fersht, A. R.
: Elucidating the mechanism of familial amyloidosis-Finnish type:
NMR studies of human gelsolin domain 2. Proc. Nat. Acad. Sci. 97:
10706-10711, 2000.
11. Kazmirski, S. L.; Isaacson, R. L.; An, C.; Buckle, A.; Johnson,
C. M.; Daggett, V.; Fersht, A. R.: Loss of a metal-binding site in
gelsolin leads to familial amyloidosis-Finnish type. Nature Struct.
Biol. 9: 112-116, 2002.
12. Kim, J.; Lee, J. E.; Heynen-Genel, S.; Suyama, E.; Ono, K.; Lee,
K.; Ideker, T.; Aza-Blanc, P.; Gleeson, J. G.: Functional genomic
screen for modulators of ciliogenesis and cilium length. Nature 464:
1048-1051, 2010.
13. Kwiatkowski, D. J.; Ozelius, L.; Schuback, D.; Gusella, J.; Breakefield,
X. O.: The gelsolin (GSN) cDNA clone, from 9q32-34, identifies BclI
and StuI RFLPs. Nucleic Acids Res. 17: 4425 only, 1989.
14. Kwiatkowski, D. J.; Stossel, T. P.; Orkin, S. H.; Mole, J. E.;
Colten, H. R.; Yin, H. L.: Plasma and cytoplasmic gelsolins are encoded
by a single gene and contain a duplicated actin-binding domain. Nature 323:
455-458, 1986.
15. Kwiatkowski, D. J.; Westbrook, C. A.; Bruns, G. A. P.; Morton,
C. C.: Localization of gelsolin proximal to ABL on chromosome 9. Am.
J. Hum. Genet. 42: 565-572, 1988.
16. Lee, W. M.; Galbraith, R. M.: The extracellular actin-scavenger
system and actin toxicity. New Eng. J. Med. 326: 1335-1341, 1992.
17. Levy, E.; Haltia, M.; Fernandez-Madrid, I.; Koivunen, O.; Ghiso,
J.; Prelli, F.; Frangione, B.: Mutation in gelsolin gene in Finnish
hereditary amyloidosis. J. Exp. Med. 172: 1865-1867, 1990.
18. Maury, C. P. J.: Isolation and characterization of cardiac amyloid
in familial amyloid polyneuropathy type IV (Finnish): relation of
the amyloid protein to variant gelsolin. Biochim. Biophys. Acta 1096:
84-86, 1990. Note: Erratum: Biochim. Biophys. Acta 1096: 361 only,
1991.
19. Maury, C. P. J.: Immunohistochemical localization of amyloid
in Finnish hereditary amyloidosis with antibodies to gelsolin peptides. Lab.
Invest. 64: 400-404, 1991.
20. Maury, C. P. J.: Gelsolin-related amyloidosis: identification
of the amyloid protein in Finnish hereditary amyloidosis as a fragment
of variant gelsolin. J. Clin. Invest. 87: 1195-1199, 1991.
21. Maury, C. P. J.: Homozygous familial amyloidosis, Finnish type:
demonstration of glomerular gelsolin-derived amyloid and non-amyloid
tubular gelsolin. Clin. Nephrol. 40: 53-56, 1993.
22. Maury, C. P. J.; Alli, K.; Baumann, M.: Finnish hereditary amyloidosis:
amino acid sequence homology between the amyloid fibril protein and
human plasma gelsoline. FEBS Lett. 260: 85-87, 1990.
23. Maury, C. P. J.; Kere, J.; Tolvanen, R.; de la Chapelle, A.:
Finnish hereditary amyloidosis is caused by a single nucleotide substitution
in the gelsolin gene. FEBS Lett. 276: 75-77, 1990.
24. Maury, C. P. J.; Kere, J.; Tolvanen, R.; de la Chapelle, A.:
Homozygosity for the asn187 gelsolin mutation in Finnish-type familial
amyloidosis is associated with severe renal disease. Genomics 13:
902-903, 1992.
25. Meretoja, J.: Genetic aspects of familial amyloidosis with corneal
lattice dystrophy and cranial neuropathy. Clin. Genet. 4: 173-185,
1973.
26. Paunio, T.; Kangas, H.; Kalkkinen, N.; Haltia, M.; Palo, J.; Peltonen,
L.: Toward understanding the pathogenic mechanisms in gelsolin-related
amyloidosis: in vitro expression reveals an abnormal gelsolin fragment. Hum.
Molec. Genet. 3: 2223-2229, 1994.
27. Paunio, T.; Kiuru, S.; Hongell, V.; Mustonen, E.; Syvanen, A.-C.;
Bengtstrom, M.; Palo, J.; Peltonen, L.: Solid-phase minisequencing
test reveals asp187-to-asn (G654-to-A) mutation of gelsolin in all
affected individuals with Finnish type of familial amyloidosis. Genomics 13:
237-239, 1992.
28. Paunio, T.; Sunada, Y.; Kiuru, S.; Makishita, H.; Ikeda, S.; Weissenbach,
J.; Palo, J.; Peltonen, L.: Haplotype analysis in gelsolin-related
amyloidosis reveals independent origin of identical mutation (G654A)
of gelsolin in Finland and Japan. Hum. Mutat. 6: 60-65, 1995.
29. Pilz, A.; Moseley, H.; Peters, J.; Abbott, C.: Comparative mapping
of mouse chromosome 2 and human chromosome 9q: the genes for gelsolin
and dopamine beta-hydroxylase map to mouse chromosome 2. Genomics 12:
715-719, 1992.
30. Purcell, J. J., Jr.; Rodrigues, M.; Chishti, M. I.; Riner, R.
N.; Dooley, J. M.: Lattice corneal dystrophy associated with familial
systemic amyloidosis (Meretoja's syndrome). Ophthalmology 90: 1512-1517,
1983.
31. Sack, G. H., Jr.; Dumars, K. W.; Gummerson, K. S.; Law, A.; McKusick,
V. A.: Three forms of dominant amyloid neuropathy. Johns Hopkins
Med. J. 149: 239-247, 1981.
32. Sipila, K.; Aula, P.: Database for the mutations of the Finnish
disease heritage. Hum. Mutat. 19: 16-22, 2002.
33. Steiner, R. D.; Paunio, T.; Uemichi, T.; Evans, J. P.; Benson,
M. D.: Asp187-Asn mutation of gelsolin in an American kindred with
familial amyloidosis, Finnish type (FAP IV). Hum. Genet. 95: 327-330,
1995.
34. Sunada, Y.; Shimizu, T.; Nakase, H.; Ohta, S.; Asaoka, T.; Amano,
S.; Sawa, M.; Kagawa, Y.; Kanazawa, I.; Mannen, T.: Inherited amyloid
polyneuropathy type IV (gelsolin variant) in a Japanese family. Ann.
Neurol. 33: 57-62, 1993.
35. Vasconcellos, C. A.; Allen, P. G.; Wohl, M. E.; Drazen, J. M.;
Janmey, P. A.; Stossel, T. P.: Reduction in viscosity of cystic fibrosis
sputum in vitro by gelsolin. Science 263: 969-971, 1994.
36. Witke, W.; Sharpe, A. H.; Hartwig, J. H.; Azuma, T.; Stossel,
T. P.; Kwiatkowski, D. J.: Hemostatic, inflammatory, and fibroblast
responses are blunted in mice lacking gelsolin. Cell 81: 41-51,
1995.
*FIELD* CN
Ada Hamosh - updated: 5/10/2010
Victor A. McKusick - updated: 1/15/2002
Victor A. McKusick - updated: 1/3/2002
Victor A. McKusick - updated: 10/26/2000
Victor A. McKusick - updated: 8/11/1998
*FIELD* CD
Victor A. McKusick: 6/25/1986
*FIELD* ED
terry: 12/20/2012
alopez: 5/10/2010
alopez: 2/5/2002
carol: 1/19/2002
mcapotos: 1/16/2002
terry: 1/15/2002
alopez: 1/3/2002
terry: 1/3/2002
mcapotos: 11/8/2000
mcapotos: 10/31/2000
terry: 10/26/2000
carol: 8/14/1998
terry: 8/11/1998
mark: 9/3/1997
alopez: 7/10/1997
mark: 6/14/1997
terry: 8/3/1995
mark: 5/17/1995
carol: 1/26/1995
warfield: 4/8/1994
carol: 11/9/1993
carol: 7/21/1993
*RECORD*
*FIELD* NO
137350
*FIELD* TI
*137350 GELSOLIN; GSN
*FIELD* TX
CLONING
Gelsolin, a protein of leukocytes, platelets, and other cells, severs
read moreactin filaments in the presence of submicromolar calcium, thereby
solating cytoplasmic actin gels. A calcium-independent mechanism
reverses the process. A gelsolin variant with 23 more N-terminal amino
acids is a plasma component probably involved in the clearance of actin,
the most abundant human protein, from the circulation. Kwiatkowski et
al. (1986) isolated a full-length plasma gelsolin cDNA clone. Northern
blot analysis suggested that a single gene encodes both cell and plasma
gelsolins. This protein may be unique in that it is made for both
secretion and intracytoplasmic location.
MAPPING
By Southern blot analysis of somatic cell hybrids and in situ
chromosomal localization, Kwiatkowski et al. (1988) demonstrated that
the GSN gene is located on 9q32-q34. In situ hybridization to cells
containing a Philadelphia chromosome, as well as Southern blot analysis
of a chronic myeloid leukemia cell DNA, indicated that GSN is
centromeric to ABL (189980), which is located in 9q34. Furthermore,
Southern blot analysis of NotI-digested, pulsed-field gel
electrophoresis-separated DNA indicated that GSN is 40 or more kb
centromeric to ABL. Pilz et al. (1992) used interspecies backcrosses to
map the Gsn gene to mouse chromosome 2.
GENE FUNCTION
Maury et al. (1990) identified amino acid homology between gelsolin and
the amyloid of the Finnish variety of amyloidosis (105120). Haltia et
al. (1990) likewise showed that the amyloid in this disorder is
antigenically and structurally related to gelsolin. Gelsolin is also
known as brevin, or actin-depolymerizing factor; it is the principal
intracellular and extracellular actin-severing protein. Gelsolin and Gc
protein (GC; 139200) together constitute the extracellular
actin-scavenger system (Lee and Galbraith, 1992) which prevents the
toxic effects of actin release into the extracellular space under
circumstances of cell necrosis.
Vasconcellos et al. (1994) showed that the viscous sputum from patients
with cystic fibrosis (219700) contains filamentous actin derived from
leukocytes and that gelsolin, which severs actin filaments, rapidly
decreases the viscosity of CF sputum samples in vitro. They suggested
that gelsolin may have therapeutic potential as a mucolytic agent in CF
patients.
Caspase-mediated proteolysis is a critical and central element of the
apoptotic process; therefore, it was important to identify the
downstream molecular targets of caspases. Kamada et al. (1998)
established a method for cloning the genes of caspase substrates by 2
major modifications of the yeast 2-hybrid system: (1) both large and
small subunits with active caspases were expressed in yeast under ADH1
(103700) promoters and the small subunit was fused to the LexA
DNA-binding domain; and (2) a point mutation was introduced that
substituted serine for the active site cysteine and thereby prevented
proteolytic cleavage of the substrates, possibly stabilizing the
enzyme-substrate complexes in yeast. After screening a mouse embryo cDNA
expression library by using the bait plasmid for caspase-3, Kamada et
al. (1998) obtained 13 clones that encoded proteins binding to
caspase-3, and showed that 10 clones, including gelsolin, an
actin-regulatory protein implicated in apoptosis, were cleaved by
recombinant caspase-3 in vitro. Using the same bait, they also isolated
human gelsolin cDNA from a human thymus cDNA expression library. They
showed that human gelsolin was cleaved during Fas-mediated apoptosis in
vivo and that the caspase-3 cleavage site of human gelsolin was at
asp352 (D352) in a 5-amino acid sequence, DQTD(352)G, findings
consistent with previous observations on murine gelsolin. In addition,
Kamada et al. (1998) ascribed the antiapoptotic activity of gelsolin to
prevention of a step leading to cytochrome c release from the
mitochondria into the cytosol. The results demonstrated the usefulness
of this cloning method for identification of the substrates of caspases
and possibly of other other enzymes.
To investigate the pathogenic mechanisms in gelsolin-related
amyloidosis, Paunio et al. (1994) transfected mammalian mesenchymal
COS-1 cells with a derivative of an expression vector containing cDNA
coding for the wildtype (D187) and mutant forms (N187 and Y187) of
plasma gelsolin. Both disease-associated mutant forms of gelsolin were
found to be abnormally processed, resulting in the secretion of an
aberrant 68-kD gelsolin fragment into the culture medium. This fragment
probably represented a carboxy-terminal part of the protein and
contained the suggested amyloid-forming sequence.
In a functional genomic screen using RNA interference to identify human
genes involved in ciliogenesis control, Kim et al. (2010) identified 2
gelsolin family proteins, GSN and AVIL (613397), which regulate
cytoskeletal actin organization by severing actin filaments. Depletion
of GSN proteins by 2 independent siRNAs significantly reduced ciliated
cell numbers, indicating that actin filament severing is involved in
ciliogenesis. In contrast, silencing of actin-related protein ACTR3
(604222), which is a major constituent of the ARP2/3 complex that is
necessary for nucleating actin polymerization at filament branches,
caused a significant increase in cilium length and also facilitated
ciliogenesis independently of serum starvation. Kim et al. (2010)
concluded that their observations indicated an inhibitory role of
branched actin network formation in ciliogenesis.
BIOCHEMICAL FEATURES
A single-nucleotide mutation at residue 187 (either D187N 137350.0001 or
D187Y 137350.0002) in Finnish amyloidosis occurs within domain 2 of the
actin-regulating protein gelsolin. The mutation somehow allows a masked
cleavage site to be exposed, leading to the first step in the formation
of an amyloidogenic fragment. Kazmirski et al. (2000) performed nuclear
magnetic resonance (NMR) experiments investigating structural and
dynamic changes between wildtype and the D187N gelsolin domain 2. From
their observations, Kazmirski et al. (2000) proposed that the D187N
mutation destabilizes the C-terminal tail of domain 2 resulting in a
more exposed cleavage site and leading to the first proteolysis step in
the formation of the amyloidogenic fragment.
Kazmirski et al. (2002) determined the structure of domain 2 (D2,
residues 151-266) of gelsolin and found that asp187 is part of a
bivalent cadmium ion metal-binding site. Two bivalent calcium ions are
required for a conformational transition of gelsolin to its active form.
Kazmirski et al. (2002) showed that the cadmium-binding site in D2 is
one of these 2 calcium-binding sites and is essential to the stability
of D2. Mutation of asp187 to asn (127350.0001) disrupted calcium binding
in D2, leading to instability upon calcium activation. Instability makes
the domain a target for aberrant proteolysis, thereby enacting the first
step in the cascade leading to familial amyloidosis, Finnish type.
ANIMAL MODEL
To investigate the in vivo function of gelsolin, Witke et al. (1995)
generated transgenic gelsolin-null mice. Although embryonic development
and longevity were normal, platelet shape changes were decreased in the
Gsn-null mice, causing prolonged bleeding times. Neutrophil migration in
vivo into peritoneal exudates and in vitro was delayed. Dermal
fibroblasts had excessive actin stress fibers and migrated more slowly
than wildtype fibroblasts, but had increased contractility in vitro. The
observations established the requirement of gelsolin for rapid motile
responses in cell types involved in stress responses, such as
hemostasis, inflammation, and wound healing. Neither gelsolin nor other
proteins with similar actin filament-severing activity are expressed in
early embryonic cells, which indicated that this mechanism of actin
filament dynamics is not essential for motility during early
embryogenesis.
*FIELD* AV
.0001
AMYLOIDOSIS, FAMILIAL, FINNISH TYPE
AMYLOIDOSIS, MERETOJA TYPE
GSN, ASP187ASN
The amyloid protein in the Finnish type of hereditary amyloidosis
(105120) is a fragment of the actin-filament binding region of a variant
gelsolin molecule. Using PCR and allele-specific oligonucleotide
hybridization analysis of genomic DNA, Maury et al. (1990) identified a
single base mutation, 654G-A. This nucleotide substitution was found in
all 5 unrelated patients with Finnish amyloidosis studied but not in 45
unrelated control subjects. They were guided in the development of the
allele-specific oligonucleotide hybridization method by the
demonstration that the amyloid protein in this disorder has an
asp187-to-asn mutation (D187N) (Maury, 1990, 1991) resulting from the
change of GAC to AAC. Ghiso et al. (1990) and Levy et al. (1990)
likewise identified the D187N change. Hiltunen et al. (1991) found the
D187N mutation in affected members of 3 large families in restricted
areas on the southern coast of Finland. Maury (1991) found the D187N
mutation in 6 other ostensibly unrelated Finnish families. These
included 2 sibs, the offspring of 2 affected parents, who were by DNA
test homozygous for the mutation and showed unusually early onset and
severity of the disease (Maury, 1993). Proteinuria was present by the
teens and amyloid nephropathy with nephrotic syndrome by the 20s.
Hemodialysis and renal transplant were necessary in the 30s.
Contrariwise, in the course of family studies, Maury (1991) found
30-year-old asymptomatic individuals with the mutation but with changes
of lattice corneal dystrophy on examination. (Meretoja (1973) had
suggested that 2 patients who were more severely affected than the
average, and whose parents were affected, represented homozygosity for
this gene.)
Maury (1991) and de la Chapelle et al. (1992) demonstrated the same
D187N mutation in the American family of Scottish extraction reported by
Sack et al. (1981). Maury et al. (1992) presented molecular evidence of
homozygosity in 1 such patient. It appears that these were independent
mutations. This disorder is extraordinarily rare except in Finland where
peculiar historical and demographic factors have been responsible for
the high frequency; if all the cases prove to be due to the
asp187-to-asn mutation, then it would seem likely that the change in the
amino acid sequence at that particular site of the gelsolin molecule is
particularly critical, perhaps uniquely critical, to rendering gelsolin
amyloidogenic. Gorevic et al. (1991) found the asp187-to-asn mutation in
an American patient of Irish descent and his affected 31-year-old
daughter. This family had been reported by Purcell et al. (1983). Haltia
et al. (1992) described a slot-blot analysis for the asp187-to-asn
mutation. Paunio et al. (1992) applied the solid-phase minisequencing
test to determine the nature of the mutation in 94 affected persons and
32 healthy family members from 55 families with the Finnish type of
familial amyloidosis living in Finland. The families represented about
34% (55/160) of all known affected families in Finland. In all affected
individuals, they found the asp187-to-asn gene. Furthermore, they found
the mutation in 54% (20/37) of young at-risk persons with the mutation.
Sunada et al. (1993) found the same mutation as the cause of the Finnish
or Meretoja type of amyloid polyneuropathy in 14 members of a large
Japanese kindred with no known contacts with Finnish or other Caucasian
populations. This further supports the notion that the asp187-to-asn
mutation or other mutations at the same location are specifically
amyloidogenic.
Steiner et al. (1995) used a PCR-based DNA assay to identify the same
G-to-A mutation at position 654 of the GSN gene in an American kindred
with Scandinavian ancestry. The mutation was demonstrated in the
clinically affected proband, her deceased clinically affected father,
and her presumably affected presymptomatic son. The diagnosis of Finnish
type amyloidosis had been made in the proband after the recognition of
lattice corneal dystrophy on routine ophthalmologic examination at age
34. At the age of 38, she was asymptomatic with normal vision and no
evidence of cranial nerve dysfunction, no peripheral neuropathy, and no
evidence of cardiac or renal dysfunction. The father died at age 77 from
complications of systemic amyloidosis diagnosed 9 years before his
death. Manifestations of disease included lattice corneal dystrophy,
facial muscle weakness with lagophthalmos and sagging facial skin,
cardiomyopathy with left ventricular hypertrophy, and aortic root
dilatation, chronic renal insufficiency, hypothyroidism, and
pancytopenia.
From haplotype analysis in 10 Finnish and 2 Japanese families with the
Finnish type of familial amyloidosis, Paunio et al. (1995) demonstrated
a uniform disease haplotype in all the disease-associated chromosomes of
the Finnish families which was different from the one observed in the
Japanese families. Thus, they concluded that these mutations arose
independently.
Sipila and Aula (2002) reported the creation of an up-to-date database
for mutations of Finnish disease heritage, i.e., the more than 30
monogenic disorders that are more prevalent in the Finnish population
than in the rest of the world. They noted that all Finnish cases of
familial amyloidosis of the Finnish type have had the D187N mutation.
.0002
AMYLOIDOSIS, FAMILIAL, FINNISH TYPE
GSN, ASP187TYR
Although de la Chapelle et al. (1992) found the characteristic
asp187-to-asn mutation (137350.0001) in 2 non-Finnish American families
and a Dutch family with the clinically typical corneocranial type of
amyloidosis (due to a 654G-A transition), they found a 654G-T
transversion predicting an asp187-to-tyr substitution (D187Y) in a
Danish family and a Czech family with the same disorder (105120).
Different haplotypes were found in the Danish and Czech families,
suggesting that the mutations arose independently. The substitution of
an uncharged polar amino acid for the acidic aspartic acid at residue
187 creates a beta sheet conformation that may be preferentially or
uniquely amyloidogenic for gelsolin. This is in contrast to the variety
of mutations in transthyretin-related amyloidosis (176300) but resembles
that seen in some early-onset Alzheimer disease families in which a
single residue in the APP gene (e.g., 104760.0002-104760.0004) is
involved.
*FIELD* SA
de la Chapelle et al. (1992); de la Chapelle et al. (1992); Kwiatkowski
et al. (1989); Maury (1991); Maury et al. (1990)
*FIELD* RF
1. de la Chapelle, A.; Kere, J.; Sack, G. H., Jr.; Tolvanen, R.; Maury,
C. P. J.: Familial amyloidosis, Finnish type: G654-to-A mutation
of the gelsolin gene in Finnish families and an unrelated American
family. Genomics 13: 898-901, 1992.
2. de la Chapelle, A.; Tolvanen, R.; Boysen, G.; Santavy, J.; Bleeker-Wagemakers,
L.; Maury, C. P. J.; Kere, J.: Gelsolin-derived familial amyloidosis:
all known mutations worldwide are substitutions of asn or tyr for
asp at residue 187. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A148
only, 1992.
3. de la Chapelle, A.; Tolvanen, R.; Boysen, G.; Santavy, J.; Bleeker-Wagemakers,
L.; Maury, C. P. J.; Kere, J.: Gelsolin-derived familial amyloidosis
caused by asparagine or tyrosine substitution for aspartic acid at
residue 187. Nature Genet. 2: 157-160, 1992.
4. Ghiso, J.; Haltia, M.; Prelli, F.; Novello, J.; Frangione, B.:
Gelsolin variant (asn-187) in familial amyloidosis, Finnish type. Biochem.
J. 272: 827-830, 1990.
5. Gorevic, P. D.; Munoz, P. C.; Gorgone, G.; Purcell, J. J., Jr.;
Rodrigues, M.; Ghiso, J.; Levy, E.; Haltia, M.; Frangione, B.: Amyloidosis
due to a mutation of the gelsolin gene in an American family with
lattice corneal dystrophy type II. New Eng. J. Med. 325: 1780-1785,
1991.
6. Haltia, M.; Ghiso, J.; Prelli, F.; Gallo, G.; Kiuru, S.; Somer,
H.; Palo, J.; Frangione, B.: Amyloid in familial amyloidosis, Finnish
type, is antigenically and structurally related to gelsolin. Am.
J. Path. 136: 1223-1228, 1990.
7. Haltia, M.; Levy, E.; Meretoja, J.; Fernandez-Madrid, I.; Koivunen,
O.; Frangione, B.: Gelsolin gene mutation--at codon 187--in familial
amyloidosis, Finnish: DNA-diagnostic assay. Am. J. Med. Genet. 42:
357-359, 1992.
8. Hiltunen, T.; Kiuru, S.; Hongell, V.; Helio, T.; Palo, J.; Peltonen,
L.: Finnish type of familial amyloidosis: cosegregation of asp187-to-asn
mutation of gelsolin with the disease in three large families. Am.
J. Hum. Genet. 49: 522-528, 1991.
9. Kamada, S.; Kusano, H.; Fujita, H.; Ohtsu, M.; Koya, R. C.; Kuzumaki,
N.; Tsujimoto, Y.: A cloning method for caspase substrates that uses
the yeast two-hybrid system: cloning of the antiapoptotic gene gelsolin. Proc.
Nat. Acad. Sci. 95: 8532-8537, 1998.
10. Kazmirski, S. L.; Howard, M. J.; Isaacson, R. L.; Fersht, A. R.
: Elucidating the mechanism of familial amyloidosis-Finnish type:
NMR studies of human gelsolin domain 2. Proc. Nat. Acad. Sci. 97:
10706-10711, 2000.
11. Kazmirski, S. L.; Isaacson, R. L.; An, C.; Buckle, A.; Johnson,
C. M.; Daggett, V.; Fersht, A. R.: Loss of a metal-binding site in
gelsolin leads to familial amyloidosis-Finnish type. Nature Struct.
Biol. 9: 112-116, 2002.
12. Kim, J.; Lee, J. E.; Heynen-Genel, S.; Suyama, E.; Ono, K.; Lee,
K.; Ideker, T.; Aza-Blanc, P.; Gleeson, J. G.: Functional genomic
screen for modulators of ciliogenesis and cilium length. Nature 464:
1048-1051, 2010.
13. Kwiatkowski, D. J.; Ozelius, L.; Schuback, D.; Gusella, J.; Breakefield,
X. O.: The gelsolin (GSN) cDNA clone, from 9q32-34, identifies BclI
and StuI RFLPs. Nucleic Acids Res. 17: 4425 only, 1989.
14. Kwiatkowski, D. J.; Stossel, T. P.; Orkin, S. H.; Mole, J. E.;
Colten, H. R.; Yin, H. L.: Plasma and cytoplasmic gelsolins are encoded
by a single gene and contain a duplicated actin-binding domain. Nature 323:
455-458, 1986.
15. Kwiatkowski, D. J.; Westbrook, C. A.; Bruns, G. A. P.; Morton,
C. C.: Localization of gelsolin proximal to ABL on chromosome 9. Am.
J. Hum. Genet. 42: 565-572, 1988.
16. Lee, W. M.; Galbraith, R. M.: The extracellular actin-scavenger
system and actin toxicity. New Eng. J. Med. 326: 1335-1341, 1992.
17. Levy, E.; Haltia, M.; Fernandez-Madrid, I.; Koivunen, O.; Ghiso,
J.; Prelli, F.; Frangione, B.: Mutation in gelsolin gene in Finnish
hereditary amyloidosis. J. Exp. Med. 172: 1865-1867, 1990.
18. Maury, C. P. J.: Isolation and characterization of cardiac amyloid
in familial amyloid polyneuropathy type IV (Finnish): relation of
the amyloid protein to variant gelsolin. Biochim. Biophys. Acta 1096:
84-86, 1990. Note: Erratum: Biochim. Biophys. Acta 1096: 361 only,
1991.
19. Maury, C. P. J.: Immunohistochemical localization of amyloid
in Finnish hereditary amyloidosis with antibodies to gelsolin peptides. Lab.
Invest. 64: 400-404, 1991.
20. Maury, C. P. J.: Gelsolin-related amyloidosis: identification
of the amyloid protein in Finnish hereditary amyloidosis as a fragment
of variant gelsolin. J. Clin. Invest. 87: 1195-1199, 1991.
21. Maury, C. P. J.: Homozygous familial amyloidosis, Finnish type:
demonstration of glomerular gelsolin-derived amyloid and non-amyloid
tubular gelsolin. Clin. Nephrol. 40: 53-56, 1993.
22. Maury, C. P. J.; Alli, K.; Baumann, M.: Finnish hereditary amyloidosis:
amino acid sequence homology between the amyloid fibril protein and
human plasma gelsoline. FEBS Lett. 260: 85-87, 1990.
23. Maury, C. P. J.; Kere, J.; Tolvanen, R.; de la Chapelle, A.:
Finnish hereditary amyloidosis is caused by a single nucleotide substitution
in the gelsolin gene. FEBS Lett. 276: 75-77, 1990.
24. Maury, C. P. J.; Kere, J.; Tolvanen, R.; de la Chapelle, A.:
Homozygosity for the asn187 gelsolin mutation in Finnish-type familial
amyloidosis is associated with severe renal disease. Genomics 13:
902-903, 1992.
25. Meretoja, J.: Genetic aspects of familial amyloidosis with corneal
lattice dystrophy and cranial neuropathy. Clin. Genet. 4: 173-185,
1973.
26. Paunio, T.; Kangas, H.; Kalkkinen, N.; Haltia, M.; Palo, J.; Peltonen,
L.: Toward understanding the pathogenic mechanisms in gelsolin-related
amyloidosis: in vitro expression reveals an abnormal gelsolin fragment. Hum.
Molec. Genet. 3: 2223-2229, 1994.
27. Paunio, T.; Kiuru, S.; Hongell, V.; Mustonen, E.; Syvanen, A.-C.;
Bengtstrom, M.; Palo, J.; Peltonen, L.: Solid-phase minisequencing
test reveals asp187-to-asn (G654-to-A) mutation of gelsolin in all
affected individuals with Finnish type of familial amyloidosis. Genomics 13:
237-239, 1992.
28. Paunio, T.; Sunada, Y.; Kiuru, S.; Makishita, H.; Ikeda, S.; Weissenbach,
J.; Palo, J.; Peltonen, L.: Haplotype analysis in gelsolin-related
amyloidosis reveals independent origin of identical mutation (G654A)
of gelsolin in Finland and Japan. Hum. Mutat. 6: 60-65, 1995.
29. Pilz, A.; Moseley, H.; Peters, J.; Abbott, C.: Comparative mapping
of mouse chromosome 2 and human chromosome 9q: the genes for gelsolin
and dopamine beta-hydroxylase map to mouse chromosome 2. Genomics 12:
715-719, 1992.
30. Purcell, J. J., Jr.; Rodrigues, M.; Chishti, M. I.; Riner, R.
N.; Dooley, J. M.: Lattice corneal dystrophy associated with familial
systemic amyloidosis (Meretoja's syndrome). Ophthalmology 90: 1512-1517,
1983.
31. Sack, G. H., Jr.; Dumars, K. W.; Gummerson, K. S.; Law, A.; McKusick,
V. A.: Three forms of dominant amyloid neuropathy. Johns Hopkins
Med. J. 149: 239-247, 1981.
32. Sipila, K.; Aula, P.: Database for the mutations of the Finnish
disease heritage. Hum. Mutat. 19: 16-22, 2002.
33. Steiner, R. D.; Paunio, T.; Uemichi, T.; Evans, J. P.; Benson,
M. D.: Asp187-Asn mutation of gelsolin in an American kindred with
familial amyloidosis, Finnish type (FAP IV). Hum. Genet. 95: 327-330,
1995.
34. Sunada, Y.; Shimizu, T.; Nakase, H.; Ohta, S.; Asaoka, T.; Amano,
S.; Sawa, M.; Kagawa, Y.; Kanazawa, I.; Mannen, T.: Inherited amyloid
polyneuropathy type IV (gelsolin variant) in a Japanese family. Ann.
Neurol. 33: 57-62, 1993.
35. Vasconcellos, C. A.; Allen, P. G.; Wohl, M. E.; Drazen, J. M.;
Janmey, P. A.; Stossel, T. P.: Reduction in viscosity of cystic fibrosis
sputum in vitro by gelsolin. Science 263: 969-971, 1994.
36. Witke, W.; Sharpe, A. H.; Hartwig, J. H.; Azuma, T.; Stossel,
T. P.; Kwiatkowski, D. J.: Hemostatic, inflammatory, and fibroblast
responses are blunted in mice lacking gelsolin. Cell 81: 41-51,
1995.
*FIELD* CN
Ada Hamosh - updated: 5/10/2010
Victor A. McKusick - updated: 1/15/2002
Victor A. McKusick - updated: 1/3/2002
Victor A. McKusick - updated: 10/26/2000
Victor A. McKusick - updated: 8/11/1998
*FIELD* CD
Victor A. McKusick: 6/25/1986
*FIELD* ED
terry: 12/20/2012
alopez: 5/10/2010
alopez: 2/5/2002
carol: 1/19/2002
mcapotos: 1/16/2002
terry: 1/15/2002
alopez: 1/3/2002
terry: 1/3/2002
mcapotos: 11/8/2000
mcapotos: 10/31/2000
terry: 10/26/2000
carol: 8/14/1998
terry: 8/11/1998
mark: 9/3/1997
alopez: 7/10/1997
mark: 6/14/1997
terry: 8/3/1995
mark: 5/17/1995
carol: 1/26/1995
warfield: 4/8/1994
carol: 11/9/1993
carol: 7/21/1993