RBCC Red Blood Cell Collection

SPTLC1 (LCB1) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Serine palmitoyltransferase 1; 2.3.1.50 (Long chain base biosynthesis protein 1; LCB 1; Serine-palmitoyl-CoA transferase 1; SPT 1; SPT1)

UniProt O15269
ID SPTC1_HUMAN Reviewed; 473 AA.
AC O15269; A8K681; Q5VWB4; Q96IX6;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JAN-1998, sequence version 1.
DT 22-JAN-2014, entry version 130.
DE RecName: Full=Serine palmitoyltransferase 1;
DE EC=2.3.1.50;
DE AltName: Full=Long chain base biosynthesis protein 1;
DE Short=LCB 1;
DE AltName: Full=Serine-palmitoyl-CoA transferase 1;
DE Short=SPT 1;
DE Short=SPT1;
GN Name=SPTLC1; Synonyms=LCB1;
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] (ISOFORM 1).
RC TISSUE=Kidney;
RX PubMed=9363775; DOI=10.1111/j.1432-1033.1997.00239.x;
RA Weiss B., Stoffel W.;
RT "Human and murine serine-palmitoyl-CoA transferase. Cloning,
RT expression and characterization of the key enzyme in sphingolipid
RT synthesis.";
RL Eur. J. Biochem. 249:239-247(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), AND VARIANTS
RP HSAN1A TRP-133; TYR-133 AND ASP-144.
RX PubMed=11242114; DOI=10.1038/85879;
RA Dawkins J.L., Hulme D.J., Brahmbhatt S.B., Auer-Grumbach M.,
RA Nicholson G.A.;
RT "Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain
RT base subunit-1, cause hereditary sensory neuropathy type I.";
RL Nat. Genet. 27:309-312(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
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 [4]
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP TISSUE SPECIFICITY.
RX PubMed=17023427; DOI=10.1074/jbc.M608066200;
RA Hornemann T., Richard S., Ruetti M.F., Wei Y., von Eckardstein A.;
RT "Cloning and initial characterization of a new subunit for mammalian
RT serine-palmitoyltransferase.";
RL J. Biol. Chem. 281:37275-37281(2006).
RN [8]
RP FUNCTION, CATALYTIC ACTIVITY, IDENTIFICATION IN THE SPT COMPLEX, AND
RP INTERACTION WITH SPTSSA AND SPTSSB.
RX PubMed=19416851; DOI=10.1073/pnas.0811269106;
RA Han G., Gupta S.D., Gable K., Niranjanakumari S., Moitra P.,
RA Eichler F., Brown R.H. Jr., Harmon J.M., Dunn T.M.;
RT "Identification of small subunits of mammalian serine
RT palmitoyltransferase that confer distinct acyl-CoA substrate
RT specificities.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:8186-8191(2009).
RN [9]
RP BIOPHYSICOCHEMICAL PROPERTIES, AND CHARACTERIZATION OF VARIANT HSAN1A
RP TRP-133.
RX PubMed=20504773; DOI=10.1074/jbc.M110.122259;
RA Gable K., Gupta S.D., Han G., Niranjanakumari S., Harmon J.M.,
RA Dunn T.M.;
RT "A disease-causing mutation in the active site of serine
RT palmitoyltransferase causes catalytic promiscuity.";
RL J. Biol. Chem. 285:22846-22852(2010).
RN [10]
RP INTERACTION WITH ORMDL3.
RX PubMed=20182505; DOI=10.1038/nature08787;
RA Breslow D.K., Collins S.R., Bodenmiller B., Aebersold R., Simons K.,
RA Shevchenko A., Ejsing C.S., Weissman J.S.;
RT "Orm family proteins mediate sphingolipid homeostasis.";
RL Nature 463:1048-1053(2010).
RN [11]
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 [12]
RP PHOSPHORYLATION AT TYR-164, AND MUTAGENESIS OF TYR-164.
RX PubMed=23629659; DOI=10.1074/jbc.M112.409185;
RA Taouji S., Higa A., Delom F., Palcy S., Mahon F.X., Pasquet J.M.,
RA Bosse R., Segui B., Chevet E.;
RT "Phosphorylation of serine palmitoyltransferase long chain-1 (SPTLC1)
RT on tyrosine 164 inhibits its activity and promotes cell survival.";
RL J. Biol. Chem. 288:17190-17201(2013).
RN [13]
RP VARIANT ALA-387.
RX PubMed=15037712;
RA Verhoeven K., Coen K., De Vriendt E., Jacobs A., Van Gerwen V.,
RA Smouts I., Pou-Serradell A., Martin J.-J., Timmerman V., De Jonghe P.;
RT "SPTLC1 mutation in twin sisters with hereditary sensory neuropathy
RT type I.";
RL Neurology 62:1001-1002(2004).
RN [14]
RP VARIANT LEU-151.
RX PubMed=17060578; DOI=10.1212/01.wnl.0000240068.21499.f5;
RA Meggouh F., Bienfait H.M.E., Weterman M.A.J., de Visser M., Baas F.;
RT "Charcot-Marie-Tooth disease due to a de novo mutation of the RAB7
RT gene.";
RL Neurology 67:1476-1478(2006).
RN [15]
RP VARIANT [LARGE SCALE ANALYSIS] TRP-239.
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).
RN [16]
RP VARIANTS HSAN1A PHE-331 AND VAL-352.
RX PubMed=19651702; DOI=10.1093/brain/awp198;
RA Rotthier A., Baets J., De Vriendt E., Jacobs A., Auer-Grumbach M.,
RA Levy N., Bonello-Palot N., Kilic S.S., Weis J., Nascimento A.,
RA Swinkels M., Kruyt M.C., Jordanova A., De Jonghe P., Timmerman V.;
RT "Genes for hereditary sensory and autonomic neuropathies: a genotype-
RT phenotype correlation.";
RL Brain 132:2699-2711(2009).
RN [17]
RP CHARACTERIZATION OF VARIANTS HSAN1A TYR-133; TRP-133 AND ASP-144,
RP CHARACTERIZATION OF VARIANT ALA-387, AND LACK OF ASSOCIATION OF
RP VARIANT ALA-387 WITH HSAN1A.
RX PubMed=19132419; DOI=10.1007/s10048-008-0168-7;
RA Hornemann T., Penno A., Richard S., Nicholson G., van Dijk F.S.,
RA Rotthier A., Timmerman V., von Eckardstein A.;
RT "A systematic comparison of all mutations in hereditary sensory
RT neuropathy type I (HSAN I) reveals that the G387A mutation is not
RT disease associated.";
RL Neurogenetics 10:135-143(2009).
RN [18]
RP VARIANT HSAN1A PHE-331, AND CHARACTERIZATION OF VARIANTS HSAN1A
RP PHE-331 AND VAL-352.
RX PubMed=21618344; DOI=10.1002/humu.21481;
RA Rotthier A., Penno A., Rautenstrauss B., Auer-Grumbach M.,
RA Stettner G.M., Asselbergh B., Van Hoof K., Sticht H., Levy N.,
RA Timmerman V., Hornemann T., Janssens K.;
RT "Characterization of two mutations in the SPTLC1 subunit of serine
RT palmitoyltransferase associated with hereditary sensory and autonomic
RT neuropathy type I.";
RL Hum. Mutat. 32:E2211-E2225(2011).
RN [19]
RP VARIANT HSAN1A TRP-133, AND VARIANT GLY-310.
RX PubMed=22302274; DOI=10.1007/s00415-011-6397-y;
RA Davidson G.L., Murphy S.M., Polke J.M., Laura M., Salih M.A.,
RA Muntoni F., Blake J., Brandner S., Davies N., Horvath R., Price S.,
RA Donaghy M., Roberts M., Foulds N., Ramdharry G., Soler D., Lunn M.P.,
RA Manji H., Davis M.B., Houlden H., Reilly M.M.;
RT "Frequency of mutations in the genes associated with hereditary
RT sensory and autonomic neuropathy in a UK cohort.";
RL J. Neurol. 259:1673-1685(2012).
CC -!- FUNCTION: Serine palmitoyltransferase (SPT). The heterodimer
CC formed with SPTLC2 or SPTLC3 constitutes the catalytic core. The
CC composition of the serine palmitoyltransferase (SPT) complex
CC determines the substrate preference. The SPTLC1-SPTLC2-SPTSSA
CC complex shows a strong preference for C16-CoA substrate, while the
CC SPTLC1-SPTLC3-SPTSSA isozyme uses both C14-CoA and C16-CoA as
CC substrates, with a slight preference for C14-CoA. The SPTLC1-
CC SPTLC2-SPTSSB complex shows a strong preference for C18-CoA
CC substrate, while the SPTLC1-SPTLC3-SPTSSB isozyme displays an
CC ability to use a broader range of acyl-CoAs, without apparent
CC preference.
CC -!- CATALYTIC ACTIVITY: Palmitoyl-CoA + L-serine = CoA + 3-dehydro-D-
CC sphinganine + CO(2).
CC -!- COFACTOR: Pyridoxal phosphate (By similarity).
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.75 mM for serine;
CC Vmax=1350 pmol/min/mg enzyme;
CC -!- PATHWAY: Lipid metabolism; sphingolipid metabolism.
CC -!- SUBUNIT: Heterodimer with SPTLC2 or SPTLC3. Component of the
CC serine palmitoyltransferase (SPT) complex, composed of SPTLC1,
CC either SPTLC2 or SPTLC3, and either SPTSSA or SPTSSB. Interacts
CC with SPTSSA and SPTSSB; the interaction is direct. Interacts with
CC ORMDL3.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Single-pass
CC membrane protein (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O15269-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O15269-2; Sequence=VSP_043127, VSP_043128;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed. Not detected in small
CC intestine.
CC -!- PTM: Phosphorylation at Tyr-164 inhibits activity and promotes
CC cell survival.
CC -!- DISEASE: Hereditary sensory and autonomic neuropathy 1A (HSAN1A)
CC [MIM:162400]: A form of hereditary sensory and autonomic
CC neuropathy, a genetically and clinically heterogeneous group of
CC disorders characterized by degeneration of dorsal root and
CC autonomic ganglion cells, and by prominent sensory abnormalities
CC with a variable degree of motor and autonomic dysfunction. The
CC neurological phenotype is often complicated by severe infections,
CC osteomyelitis, and amputations. HSAN1A is an autosomal dominant
CC axonal form with onset in the second or third decades. Initial
CC symptoms are loss of pain, touch, heat, and cold sensation over
CC the feet, followed by distal muscle wasting and weakness. Loss of
CC pain sensation leads to chronic skin ulcers and distal
CC amputations. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the class-II pyridoxal-phosphate-dependent
CC aminotransferase family.
CC -!- CAUTION: Variant Ala-387 has been originally thought to cause
CC HSAN1A (PubMed:15037712). Subsequently, it has been shown to be a
CC rare, benign polymorphism found in homozygous state in a healthy
CC individual (PubMed:19132419).
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SPTLC1";
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DR EMBL; Y08685; CAA69941.1; -; mRNA.
DR EMBL; AF286717; AAK29328.1; -; Genomic_DNA.
DR EMBL; AF286703; AAK29328.1; JOINED; Genomic_DNA.
DR EMBL; AF286704; AAK29328.1; JOINED; Genomic_DNA.
DR EMBL; AF286705; AAK29328.1; JOINED; Genomic_DNA.
DR EMBL; AF286706; AAK29328.1; JOINED; Genomic_DNA.
DR EMBL; AF286707; AAK29328.1; JOINED; Genomic_DNA.
DR EMBL; AF286708; AAK29328.1; JOINED; Genomic_DNA.
DR EMBL; AF286709; AAK29328.1; JOINED; Genomic_DNA.
DR EMBL; AF286710; AAK29328.1; JOINED; Genomic_DNA.
DR EMBL; AF286711; AAK29328.1; JOINED; Genomic_DNA.
DR EMBL; AF286712; AAK29328.1; JOINED; Genomic_DNA.
DR EMBL; AF286713; AAK29328.1; JOINED; Genomic_DNA.
DR EMBL; AF286714; AAK29328.1; JOINED; Genomic_DNA.
DR EMBL; AF286715; AAK29328.1; JOINED; Genomic_DNA.
DR EMBL; AF286716; AAK29328.1; JOINED; Genomic_DNA.
DR EMBL; AK291546; BAF84235.1; -; mRNA.
DR EMBL; AL391219; CAH70209.1; -; Genomic_DNA.
DR EMBL; AL354751; CAH70209.1; JOINED; Genomic_DNA.
DR EMBL; AL354751; CAH69923.1; -; Genomic_DNA.
DR EMBL; AL354751; CAH69924.1; -; Genomic_DNA.
DR EMBL; AL391219; CAH69924.1; JOINED; Genomic_DNA.
DR EMBL; CH471089; EAW62804.1; -; Genomic_DNA.
DR EMBL; BC007085; AAH07085.1; -; mRNA.
DR RefSeq; NP_001268232.1; NM_001281303.1.
DR RefSeq; NP_006406.1; NM_006415.3.
DR RefSeq; NP_847894.1; NM_178324.2.
DR UniGene; Hs.90458; -.
DR ProteinModelPortal; O15269; -.
DR SMR; O15269; 59-471.
DR DIP; DIP-45626N; -.
DR IntAct; O15269; 7.
DR STRING; 9606.ENSP00000262554; -.
DR BindingDB; O15269; -.
DR ChEMBL; CHEMBL1250343; -.
DR DrugBank; DB00133; L-Serine.
DR DrugBank; DB00114; Pyridoxal Phosphate.
DR GuidetoPHARMACOLOGY; 2509; -.
DR PhosphoSite; O15269; -.
DR PaxDb; O15269; -.
DR PeptideAtlas; O15269; -.
DR PRIDE; O15269; -.
DR Ensembl; ENST00000262554; ENSP00000262554; ENSG00000090054.
DR Ensembl; ENST00000337841; ENSP00000337635; ENSG00000090054.
DR GeneID; 10558; -.
DR KEGG; hsa:10558; -.
DR UCSC; uc004arl.1; human.
DR CTD; 10558; -.
DR GeneCards; GC09M094793; -.
DR H-InvDB; HIX0034871; -.
DR HGNC; HGNC:11277; SPTLC1.
DR HPA; CAB018747; -.
DR HPA; HPA010860; -.
DR MIM; 162400; phenotype.
DR MIM; 605712; gene.
DR neXtProt; NX_O15269; -.
DR Orphanet; 36386; Hereditary sensory and autonomic neuropathy type 1.
DR PharmGKB; PA36106; -.
DR eggNOG; COG0156; -.
DR HOGENOM; HOG000216602; -.
DR HOVERGEN; HBG003992; -.
DR InParanoid; O15269; -.
DR KO; K00654; -.
DR OMA; VNHQRIN; -.
DR OrthoDB; EOG786H30; -.
DR PhylomeDB; O15269; -.
DR BioCyc; MetaCyc:HS01673-MONOMER; -.
DR BRENDA; 2.3.1.50; 2681.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00222; -.
DR ChiTaRS; SPTLC1; human.
DR GeneWiki; SPTLC1; -.
DR GenomeRNAi; 10558; -.
DR NextBio; 40067; -.
DR PRO; PR:O15269; -.
DR ArrayExpress; O15269; -.
DR Bgee; O15269; -.
DR CleanEx; HS_SPTLC1; -.
DR Genevestigator; O15269; -.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0035339; C:SPOTS complex; IDA:UniProtKB.
DR GO; GO:0030170; F:pyridoxal phosphate binding; IEA:InterPro.
DR GO; GO:0004758; F:serine C-palmitoyltransferase activity; IDA:UniProtKB.
DR GO; GO:0046513; P:ceramide biosynthetic process; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0046511; P:sphinganine biosynthetic process; IEA:Ensembl.
DR GO; GO:0030148; P:sphingolipid biosynthetic process; TAS:UniProtKB.
DR GO; GO:0006686; P:sphingomyelin biosynthetic process; IEA:Ensembl.
DR GO; GO:0046512; P:sphingosine biosynthetic process; IEA:Ensembl.
DR Gene3D; 3.40.640.10; -; 1.
DR Gene3D; 3.90.1150.10; -; 1.
DR InterPro; IPR004839; Aminotransferase_I/II.
DR InterPro; IPR015424; PyrdxlP-dep_Trfase.
DR InterPro; IPR015421; PyrdxlP-dep_Trfase_major_sub1.
DR InterPro; IPR015422; PyrdxlP-dep_Trfase_major_sub2.
DR Pfam; PF00155; Aminotran_1_2; 1.
DR SUPFAM; SSF53383; SSF53383; 1.
DR PROSITE; PS00599; AA_TRANSFER_CLASS_2; FALSE_NEG.
PE 1: Evidence at protein level;
KW Acyltransferase; Alternative splicing; Complete proteome;
KW Disease mutation; Endoplasmic reticulum; Lipid metabolism; Membrane;
KW Neuropathy; Phosphoprotein; Polymorphism; Pyridoxal phosphate;
KW Reference proteome; Sphingolipid metabolism; Transferase;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1 473 Serine palmitoyltransferase 1.
FT /FTId=PRO_0000163853.
FT TOPO_DOM 1 15 Lumenal (Potential).
FT TRANSMEM 16 36 Helical; (Potential).
FT TOPO_DOM 37 473 Cytoplasmic (Potential).
FT MOD_RES 164 164 Phosphotyrosine; by ABL.
FT VAR_SEQ 143 143 D -> E (in isoform 2).
FT /FTId=VSP_043127.
FT VAR_SEQ 144 473 Missing (in isoform 2).
FT /FTId=VSP_043128.
FT VARIANT 133 133 C -> W (in HSAN1A; inactive in the
FT heterodimeric SPT complex; largely
FT reduced activity with serine as
FT substrate, but nearly no effect on serine
FT affinity in the heterotrimeric SPT
FT complex; in contrast to wild-type is able
FT to use alanine as substrate leading to
FT the formation of 1-deoxysphinganine (1-
FT deoxySa); does not interfere with SPT
FT complex formation).
FT /FTId=VAR_011392.
FT VARIANT 133 133 C -> Y (in HSAN1A; reduced activity; does
FT not interfere with SPT complex
FT formation).
FT /FTId=VAR_011393.
FT VARIANT 144 144 V -> D (in HSAN1A; reduced activity; does
FT not interfere with SPT complex
FT formation).
FT /FTId=VAR_011394.
FT VARIANT 151 151 R -> L (in dbSNP:rs45461899).
FT /FTId=VAR_037889.
FT VARIANT 239 239 R -> W (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036610.
FT VARIANT 310 310 A -> G (found in a patient with HSAN1A;
FT uncertain pathological significance).
FT /FTId=VAR_068476.
FT VARIANT 331 331 S -> F (in HSAN1A; reduced activity).
FT /FTId=VAR_066245.
FT VARIANT 352 352 A -> V (in HSAN1A; reduced activity).
FT /FTId=VAR_066246.
FT VARIANT 387 387 G -> A (rare polymorphism; does not
FT affect activity; does not interfere with
FT SPT complex formation;
FT dbSNP:rs119482084).
FT /FTId=VAR_037890.
FT MUTAGEN 164 164 Y->F: Increased serine
FT palmitoyltransferase activity and
FT sphingolipid content.
SQ SEQUENCE 473 AA; 52744 MW; BA9E056A869D2EA2 CRC64;
MATATEQWVL VEMVQALYEA PAYHLILEGI LILWIIRLLF SKTYKLQERS DLTVKEKEEL
IEEWQPEPLV PPVPKDHPAL NYNIVSGPPS HKTVVNGKEC INFASFNFLG LLDNPRVKAA
ALASLKKYGV GTCGPRGFYG TFDVHLDLED RLAKFMKTEE AIIYSYGFAT IASAIPAYSK
RGDIVFVDRA ACFAIQKGLQ ASRSDIKLFK HNDMADLERL LKEQEIEDQK NPRKARVTRR
FIVVEGLYMN TGTICPLPEL VKLKYKYKAR IFLEESLSFG VLGEHGRGVT EHYGINIDDI
DLISANMENA LASIGGFCCG RSFVIDHQRL SGQGYCFSAS LPPLLAAAAI EALNIMEENP
GIFAVLKEKC GQIHKALQGI SGLKVVGESL SPAFHLQLEE STGSREQDVR LLQEIVDQCM
NRSIALTQAR YLEKEEKCLP PPSIRVVVTV EQTEEELERA ASTIKEVAQA VLL
//

MIM 162400
*RECORD*
*FIELD* NO
162400
*FIELD* TI
#162400 NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IA; HSAN1A
;;HSAN IA;;
NEUROPATHY, HEREDITARY SENSORY, TYPE IA; HSN1A;;
read moreHSN IA;;
NEUROPATHY, HEREDITARY SENSORY RADICULAR, AUTOSOMAL DOMINANT, TYPE
1A
*FIELD* TX
A number sign (#) is used with this entry because hereditary sensory
neuropathy type IA (HSAN1A) is caused by heterozygous mutation in the
SPTLC1 gene (605712) on chromosome 9q22.

DESCRIPTION

The hereditary sensory and autonomic neuropathies (HSAN), which are also
referred to as hereditary sensory neuropathies (HSN) in the absence of
significant autonomic features, are a genetically and clinically
heterogeneous group of disorders associated with sensory dysfunction.

HSAN1 is a dominantly inherited sensorimotor axonal neuropathy with
onset in the first or second decades of life.

- Genetic Heterogeneity of HSAN

See also HSAN1C (613640), caused by mutation in the SPTLC2 gene on
14q24; HSN1D (613708), caused by mutation in the ATL1 gene (606439) on
14q; HSN1E (614116), caused by mutation in the DNMT1 gene (126375) on
19p13; HSN1F (615632), caused by mutation in the ATL3 gene (609369) on
chromosome 11q13; HSAN2a (201300), caused by mutation in the HSN2
isoform of the WNK1 gene (605232) on 12p13; HSAN2B (613115), caused by
mutation in the FAM134B gene (613114) on 5p15; HSN2C (614213), caused by
mutation in the KIF1A gene (601255) on 2q37; HSAN3 (223900) caused by
mutation in the IKBKAP gene (603722) on 9q31; HSAN4 (256800) caused by
mutation in the NTRK1 gene (191315) on 1q21; HSAN5 (608654) caused by
mutation in the NGFB gene (162030) on 1p13; HSAN6 (614653), caused by
mutation in the DST gene (113810) on chromosome 6p; and HSAN7 (615548),
caused by mutation in the SCN11A gene (604385) on chromosome 3p22.

Adult-onset HSAN with anosmia (608720) is believed to be another
distinct form of HSAN, and HSAN1B (608088) with cough and
gastroesophageal reflux maps to chromosome 3p24-p22.

CLINICAL FEATURES

Hicks (1922) described an English family in which 10 members suffered
from perforating ulcers of the feet, shooting pains, and deafness. Age
of onset ranged from 15 to 36 years. Presentation was usually with a
corn on a big toe followed by a painless ulcer with bony debris.
Patients later experienced shooting pains similar to the lightning pains
of tabes dorsalis and developed bilateral deafness progressing to total
deafness over several years. Neurologic examination showed disappearance
of ankle and knee jerks and absence of an extensor plantar response.
There was loss of pain, touch, heat, and cold sensation over the feet,
but sensation of the arms remained normal. Cranial nerves were normal,
with the exception of the auditory nerve, pupils reacted normally, and
there was no nystagmus. Hicks (1922) noted that although hereditary
perforating ulcers of the feet had been reported in patients in the
past, there had been no previous mention of accompanying deafness or
shooting pains. Denny-Brown (1951) reported the clinical and autopsy
findings of a 53-year-old woman who was a member of the family reported
by Hicks (1922). When she was 22 years of age, an ulcer formed on her
right great toe, requiring a year to heal. She subsequently suffered
from recurrent ulceration, each episode lasting 6 to 9 months and
sometimes extending to bone. In her early twenties, she first noticed
shooting pains in her legs, sometimes in her arms. Deafness began at the
age of 40 years and progressed to almost total deafness by 53 years of
age. Neurologic examination at 53 years of age showed loss of all
sensation in the lower legs, with loss of pain and temperature sensation
in the thighs and hands. Autopsy showed a small brain and marked loss of
ganglion cells in the sacral and lumbar dorsal root ganglia. Remaining
ganglion cells showed proliferation of subcapsular dendrites and hyaline
bodies, possibly representing an amyloid mass around capillaries. There
were less severe changes in C-8 and T-1 ganglia. The affected families
reported by Ervin and Sternbach (1960) and Silverman and Gilden (1959)
appeared to show autosomal dominant inheritance. Mandell and Smith
(1960) observed sensory radicular neuropathy in 3 generations of a
family. Clinical features included neuropathic arthropathy, recurrent
ulceration of the lower extremities, and signs of radicular sensory
deficiency in both the upper and the lower extremities without any motor
dysfunction. Dyck et al. (1965) described a family with sensory
neuropathy accompanied by peroneal muscular atrophy and pes cavus.
Campbell and Hoffman (1964) and DeLeon (1969) also reported cases in
which amyotrophy was a feature. Using a cholinesterase technique on skin
biopsies from the pad of the great toe of affected persons, Dyck et al.
(1965) found normal numbers of Meissner corpuscles in a 14-year-old boy
with early signs suggestive of the disorder, but no corpuscles in a
37-year-old man and a 28-year-old woman with well-developed disease.

Dyck et al. (1983) noted that 'burning feet' may be the only
manifestation of dominantly inherited sensory neuropathy. The symptoms
are ameliorated by cold and aggravated by heat. Restless legs and
lancinating pain are other presentations of the disorder, which often
resulted in severe distal sensory loss, mutilating acropathy, and
neurotrophic arthropathy.

In a detailed clinical study of a patient with HSN1, including
audiometric testing, autonomic functions, electromyography, transcranial
magnetic stimulation, and brain imaging, Hageman et al. (1992)
determined that there were no signs of central nervous system
involvement and stated that HSN1 is a disorder of the dorsal root
ganglia and peripheral nerves.

Wallace (1968, 1970) studied an extensively affected Australian kindred.
In a study of this kindred and 3 other Australian kindreds with HSAN1,
Nicholson et al. (1996) found that a typical history included lightning
pains, painless skin injuries and ulceration, and signs including distal
sensory loss to sharp, hot, and cold sensation, with loss of distal
reflexes and distal muscle wasting. Nerve conduction velocities showed
an axonal neuropathy, particularly of the lower limbs.

Dubourg et al. (2000) reported a French family with autosomal dominant
hereditary sensory neuropathy suggestive of linkage to chromosome 9q.
Mean age at onset was 34 years. All patients presented with distal
sensory loss and distal muscle weakness of both the upper and lower
limbs. Four patients had foot ulcerations, and 3 patients had
hyperhidrosis. Motor nerve conduction velocities were normal or mildly
decreased, consistent with an axonal neuropathy. Sensory nerve action
potentials were either reduced or could not be recorded.

- Clinical Variability

Rotthier et al. (2009) reported a French Gypsy patient with an unusually
severe form of HSAN1. The patient had congenital onset, insensitivity to
pain with eschar and foot ulceration, pes cavus/equinovarus, vocal cord
paralysis, and gastroesophageal reflux. The patient also had severe
growth and mental retardation, microcephaly, hypotonia, amyotrophy, and
respiratory insufficiency. Nerve conduction studies showed absent
sensory and motor responses in the upper and lower limbs. Genetic
analysis identified a de novo heterozygous mutation in the SPTLC1 gene
(S331F; 605712.0005). The phenotype expanded the clinical spectrum of
HSAN1.

MAPPING

Nicholson et al. (1996) undertook a genomewide linkage screen in 4
Australian kindreds with hereditary sensory neuropathy, including 1
family that had been reported by Jackson (1949) and followed up by
Wallace (1968, 1970). Nicholson et al. (1996) found that the disease
locus, which they symbolized HSN1, mapped to an 8-cM region flanked by
D9S318 and D9S176 on 9q22.1-q22.3. Multipoint linkage analysis suggested
a most likely location at D9S287, within a 4.9-cM confidence interval.

Blair et al. (1997) refined the mapping of HSN1 to a 3- to 4-cM interval
within the 9q22.1-q22.3 region, and excluded GAS1 (139185) and XPA
(611153) as candidate genes. Using composite mapping data, Blair et al.
(1998) estimated the HSN1 critical region, flanked by D9S1781 and
FB19B7, at 3 to 4 Mb.

PATHOGENESIS

In studies of Chinese hamster ovary (CHO) cells and yeast, Gable et al.
(2010) demonstrated that the mutant SPTLC1 C133W protein (605712.0002)
provided sufficient SPT activity to support growth, although total
enzyme activity was only 10 to 20% of wildtype. Yeast and CHO cells
expressing the C133W mutant along with SPTLC2 (605713) and SSSPTA
(613540) or SSSPTB (610412) showed a preferential condensation of
palmitoyl-CoA to alanine rather than serine. These results were not
found with wildtype SPTLC1. Kinetic studies showed that the mutant
protein had the same affinity to serine as the wildtype protein, but a
lower Vmax for serine. These results suggested that the mutation
perturbs the active site of the protein, facilitating the formation of
alanine condensation products. However, small increases in extracellular
serine levels were able to inhibit the reaction with alanine. The
palmitoyl-CoA/alanine product, 1-deoxysphinganine (1-deoxySa), was shown
to increased endoplasmic reticulum stress and the unfolded protein
response, which may ultimately be toxic to neurons. Gable et al. (2010)
concluded that their findings were consistent with a gain of function
that is responsible for the HSAN1 phenotype.

SPT catalyzes the condensation of serine and palmitoyl-CoA, the initial
step in the de novo synthesis of sphingolipids. Penno et al. (2010)
showed that HSAN1A-related mutations in the SPTLC1 gene induced a shift
in the substrate specificity of SPT, which leads to the formation of 2
atypical deoxysphingoid bases: 1-deoxysphinganine from condensation with
alanine and 1-deoxymethylsphinganine from condensation with glycine.
Neither of these metabolites can be converted to complex sphingolipids
or degraded, resulting in their intracellular accumulation. These
atypical agents showed pronounced neurotoxic effects on neurite
formation in cultured sensory neurons, and was associated with disturbed
neurofilament structure. Penno et al. (2010) found increased levels of
these atypical agents in lymphocytes and plasma of HSAN1A patients with
different SPTLC1 mutations. The findings indicated that HSAN1 results
from gain-of-function mutations that cause the formation of atypical and
neurotoxic sphingolipid metabolites, rather than from lack of de novo
sphingolipid synthesis.

POPULATION GENETICS

Nicholson et al. (2001) found that 3 Australian families of English
extraction and 3 English families had the same SPTLC1 mutation
(605712.0002), the same chromosome 9 haplotype, and the same phenotype.
They therefore concluded that the Australian and English families had
the same founder who, on the basis of historical information, lived in
southern England before 1800. The phenotype caused by this mutation is
the same as that in the English families of Campbell and Hoffman (1964)
and possibly in the original English family of Hicks (1922).

MOLECULAR GENETICS

In all affected members of 11 HSN1 families, Dawkins et al. (2001)
identified mutations in the SPTLC1 gene (C133Y, 605712.0001; C133W,
605712.0002; V144D, 605712.0003). Bejaoui et al. (2001) independently
identified 2 of the same SPTLC1 mutations in 2 unrelated families with
HSN1.

In twin sisters with HSN1 from a Belgian family originally reported by
Montanini (1958), Verhoeven et al. (2004) identified a mutation in the
SPTLC1 gene (G387A; 605712.0004).

The findings of Hornemann et al. (2009) cast doubt on the pathogenicity
of the G387A mutation. By in vitro functional expression assays in
HEK293 cells, Hornemann et al. (2009) found that none of the 4 SPTLC1
mutations, C133Y, C133W, V144D, or G387A, interfered with formation of
the SPT complex. The first 3 mutant proteins resulted in 40 to 50%
decreased SPT activity, but the G387A protein showed no effect on SPT
activity. Further studies showed that the G387A protein could rescue a
SPTLC1-deficient cell line. Finally, Hornemann et al. (2009) identified
an unaffected woman who was homozygous for the G387A mutation,
suggesting that it is not pathogenic. Hornemann et al. (2009) postulated
that the G387A variant, and perhaps the other 3 SPTLC1 variants
previously associated with HSN1, may not be directly disease-causing,
but rather have an indirect or bystander effect by increasing the risk
for HSN1 in conjunction with another mutation.

*FIELD* SA
Clarke and Groves (1909); Danon and Carpenter (1985); Miller et al.
(1976); Ogryzlo (1946); Schultze (1917); Smith (1934); Tocantins
and Reimann (1939)
*FIELD* RF
1. Bejaoui, K.; Wu, C.; Scheffler, M. D.; Haan, G.; Ashby, P.; Wu,
L.; de Jong, P.; Brown, R. H., Jr.: SPTLC1 is mutated in hereditary
sensory neuropathy, type 1. Nature Genet. 27: 261-262, 2001.

2. Blair, I. P.; Dawkins, J. L.; Nicholson, G. A.: Fine mapping of
the hereditary sensory neuropathy type I locus on chromosome 9q21.1-q22.3:
exclusion of GAS1 and XPA. Cytogenet. Cell Genet. 78: 140-141, 1997.

3. Blair, I. P.; Hulme, D.; Dawkins, J. L.; Nicholson, G. A.: A YAC-based
transcript map of human chromosome 9q22.1-q22.3 encompassing the loci
for hereditary sensory neuropathy type I and multiple self-healing
squamous epithelioma. Genomics 51: 277-281, 1998.

4. Campbell, A. M. G.; Hoffman, H. L.: Sensory radicular neuropathy
associated with muscle wasting in two cases. Brain 87: 67-74, 1964.

5. Clarke, J. M.; Groves, E. W. H.: Remarks on syringomyelia (sacro-lumbar
type) occurring in a brother and sister. Brit. Med. J. 2: 737-740,
1909.

6. Danon, M. J.; Carpenter, S.: Hereditary sensory neuropathy: biopsy
study of an autosomal dominant variety. Neurology 35: 1226-1229,
1985.

7. Dawkins, J. L.; Hulme, D. J.; Brahmbhatt, S. B.; Auer-Grumbach,
M.; Nicholson, G. A.: Mutations in SPTLC1, encoding serine palmitoyltransferase,
long chain base subunit-1, cause hereditary sensory neuropathy type
I. Nature Genet. 27: 309-312, 2001.

8. DeLeon, G. A.: Progressive ventral sensory loss in sensory radicular
neuropathy and hypertrophic neuritis. Johns Hopkins Med. J. 125:
53-61, 1969.

9. Denny-Brown, D.: Hereditary sensory radicular neuropathy. J.
Neurol. Neurosurg. Psychiat. 14: 237-252, 1951.

10. Dubourg, O.; Barhoumi, C.; Azzedine, H.; Birouk, N.; Brice, A.;
Bouche, P.; Leguern, E.: Phenotypic and genetic study of a family
with hereditary sensory neuropathy and prominent weakness. Muscle
Nerve 23: 1508-1514, 2000.

11. Dyck, P. J.; Kennel, A. J.; Magal, I. V.; Kraybill, E. N.: A
Virginia kinship with hereditary sensory neuropathy: peroneal muscular
atrophy and pes cavus. Mayo Clin. Proc. 40: 685-694, 1965.

12. Dyck, P. J.; Low, P. A.; Stevens, J. C.: 'Burning feet' as the
only manifestation of dominantly inherited sensory neuropathy. Mayo
Clin. Proc. 58: 426-429, 1983.

13. Ervin, F. R.; Sternbach, R. A.: Hereditary insensitivity to pain. Trans.
Am. Neurol. Assoc. 86: 70-74, 1960.

14. Gable, K.; Gupta, S. D.; Han, G.; Niranjanakumari, S.; Harmon,
J. M.; Dunn, T. M.: A disease-causing mutation in the active site
of serine palmitoyltransferase causes catalytic promiscuity. J. Biol.
Chem. 285: 22846-22852, 2010.

15. Hageman, G.; Hilhorst, B. G. J.; Rozeboom, A. R.: Is there involvement
of the central nervous system in hereditary sensory radicular neuropathy? Clin.
Neurol. Neurosurg. 94: 49-54, 1992.

16. Hicks, E. P.: Hereditary perforating ulcer of the foot. Lancet 199:
319-321, 1922. Note: Originally Volume I.

17. Hornemann, T.; Penno, A.; Richard, S.; Nicholson, G.; van Dijk,
F. S.; Rotthier, A.; Timmerman, V.; von Eckardstein, A.: A systematic
comparison of all mutations in hereditary sensory neuropathy type
I (HSAN I) reveals that the G387A mutation is not disease associated. Neurogenetics 10:
135-143, 2009.

18. Jackson, M.: Familial lumbo-sacral syringomyelia and the significance
of developmental errors of the spinal cord and column. Med. J. Aust. 1:
434-439, 1949.

19. Mandell, A. J.; Smith, C. K.: Hereditary sensory radicular neuropathy. Neurology 10:
627-630, 1960.

20. Miller, R. G.; Nielsen, S. L.; Sumner, A. J.: Hereditary sensory
neuropathy and tonic pupils. Neurology 26: 931-935, 1976.

21. Montanini, R.: Acropatia ulcero-mutilante, amiotrofia frusta
tipo Charcot-Marie e alessia in due gemelle univitelline. Riv. Neurol. 28:
593-609, 1958.

22. Nicholson, G. A.; Dawkins, J. L.; Blair, I. P.; Auer-Grumbach,
M.; Brahmbhatt, S. B.; Hulme, D. J.: Hereditary sensory neuropathy
type I: haplotype analysis shows founders in southern England and
Europe. Am. J. Hum. Genet. 69: 655-659, 2001.

23. Nicholson, G. A.; Dawkins, J. L.; Blair, I. P.; Kennerson, M.
L.; Gordon, M. J.; Cherryson, A. K.; Nash, J.; Bananis, T.: The gene
for hereditary sensory neuropathy type I (HSN-1) maps to chromosome
9q22.1-q22.3. Nature Genet. 13: 101-104, 1996.

24. Ogryzlo, M. A.: A familial peripheral neuropathy of unknown etiology
resembling Morvan's disease. Canad. Med. Assoc. J. 54: 547-553,
1946.

25. Penno, A.; Reilly, M. M.; Houlden, H.; Laura, M.; Rentsch, K.;
Niederkofler, V.; Stoeckli, E. T.; Nicholson, G.; Eichler, F.; Brown,
R. H., Jr.; von Eckardstein, A.; Hornemann, T.: Hereditary sensory
neuropathy type 1 is caused by the accumulation of two neurotoxic
sphingolipids. J. Biol. Chem. 285: 11178-11187, 2010.

26. Rotthier, A.; Baets, J.; De Vriendt, E.; Jacobs, A.; Auer-Grumbach,
M.; Levy, N.; Bonello-Palot, N.; Kilic, S. S.; Weis, J.; Nascimento,
A.; Swinkels, M.; Kruyt, M. C., Jordanova, A.; De Jonghe, P.; Timmerman,
V.: Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype
correlation. Brain 132: 2699-2711, 2009.

27. Schultze, F.: Familiaer auftretendes malum perforans der Fuesse
(familiaere lumbale Syringomyelie). Dtsch. Med. Wschr. 43: 545-547,
1917.

28. Silverman, F. N.; Gilden, J. J.: Congenital insensitivity to
pain, a neurologic syndrome with bizarre skeletal lesions. Radiology 72:
176-190, 1959.

29. Smith, E. M.: Familial neurotrophic osseous atrophy: a familial
neurotrophic condition of the feet with anesthesia and loss of bone. JAMA 102:
593-595, 1934.

30. Tocantins, L. M.; Reimann, H. A.: Perforating ulcers of feet,
with osseous atrophy in family with other evidences of dysgenesis
(hare lip, cleft palate): an instance of probable myelodysplasia. JAMA 112:
2251-2255, 1939.

31. Verhoeven, K.; Coen, K.; De Vriendt, E.; Jacobs, A.; Van Gerwen,
V.; Smouts, I.; Pou-Serradell, A.; Martin, J.-J.; Timmerman, V.; De
Jonghe, P.: SPTLC1 mutation in twin sisters with hereditary sensory
neuropathy type I. Neurology 62: 1001-1002, 2004.

32. Wallace, D. C.: Hereditary sensory radicular neuropathy.In: Archdall
Medical Monograph 8. Sydney: Australasian Med. Pub. Co. Ltd.
1970.

33. Wallace, D. C.: A Study of an Hereditary Neuropathy. Thesis:
Univ. of Sydney (pub.) 1968.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Ears];
Deafness, sensorineural (reported in 1 family)

SKELETAL:
[Hands];
Osteomyelitis or necrosis, distal, due to sensory neuropathy;
Autoamputation;
[Feet];
Pes cavus;
Osteomyelitis or necrosis, distal, due to sensory neuropathy;
Autoamputation

SKIN, NAILS, HAIR:
[Skin];
Ulcers, distal, painless, due to sensory neuropathy

NEUROLOGIC:
[Peripheral nervous system];
Distal sensory loss of all modalities (pain, temperature, touch, vibration);
Taste is spared;
Sharp, 'lightning'-like pain;
Distal limb muscular atrophy due to peripheral neuropathy;
Distal limb muscular weakness due to peripheral neuropathy;
Distal hyporeflexia;
Distal areflexia;
Lower limbs more severely affected than upper limbs;
Autonomic involvement is variable;
Motor involvement is variable;
EMG shows chronic axonal neuropathy;
Decreased sensory nerve action potentials;
Dorsal spinal columns are diminished in size;
Dorsal nerve roots and ganglia cells show degenerative changes;
Distal nerve biopsy shows decreased numbers of small myelinated and
unmyelinated fibers;
Loss of large myelinated fibers

MISCELLANEOUS:
Onset in the second to fourth decades of life;
One patient with severe congenital onset has been reported;
Phenotypic overlap with Charcot-Marie-Tooth disease 2B (CMT2B, 600882)

MOLECULAR BASIS:
Caused by mutation in the long-chain base subunit 1 of the serine
palmitoyltransferase gene (SPTLC1, 605712.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 11/12/2010
Cassandra L. Kniffin - revised: 5/18/2004

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 04/02/2012
ckniffin: 11/12/2010
ckniffin: 11/30/2004
ckniffin: 9/13/2004
ckniffin: 9/3/2004
ckniffin: 5/18/2004

*FIELD* CN
Cassandra L. Kniffin - updated: 11/12/2010
Cassandra L. Kniffin - updated: 9/23/2010
Cassandra L. Kniffin - updated: 5/14/2009
Cassandra L. Kniffin - updated: 2/6/2009
Cassandra L. Kniffin - updated: 9/1/2005
Cassandra L. Kniffin - updated: 5/18/2004
Denise L. M. Goh - updated: 4/10/2003
Carol A. Bocchini - reorganized: 10/5/2001
Victor A. McKusick - updated: 9/27/2001
Ada Hamosh - updated: 3/2/2001
Sheryl A. Jankowski - updated: 12/22/1998
Victor A. McKusick - updated: 12/2/1997

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
ckniffin: 02/10/2014
carol: 12/4/2013
ckniffin: 12/3/2013
alopez: 5/29/2012
ckniffin: 5/29/2012
carol: 9/16/2011
ckniffin: 9/15/2011
alopez: 7/29/2011
ckniffin: 7/27/2011
wwang: 2/23/2011
ckniffin: 1/28/2011
carol: 11/16/2010
ckniffin: 11/12/2010
wwang: 10/6/2010
ckniffin: 9/23/2010
terry: 12/16/2009
terry: 6/3/2009
wwang: 5/27/2009
ckniffin: 5/14/2009
wwang: 2/6/2009
terry: 2/3/2009
carol: 7/12/2007
wwang: 9/6/2005
ckniffin: 9/1/2005
ckniffin: 8/17/2005
tkritzer: 9/8/2004
ckniffin: 8/27/2004
alopez: 8/17/2004
terry: 7/27/2004
tkritzer: 6/11/2004
carol: 5/21/2004
ckniffin: 5/18/2004
cwells: 11/5/2003
carol: 4/29/2003
carol: 4/10/2003
carol: 10/5/2001
mcapotos: 10/4/2001
terry: 9/27/2001
alopez: 3/2/2001
terry: 3/2/2001
carol: 10/22/1999
psherman: 1/6/1999
psherman: 12/22/1998
carol: 7/8/1998
carol: 5/20/1998
mark: 12/10/1997
terry: 12/2/1997
randy: 8/31/1996
terry: 5/14/1996
terry: 5/6/1996
mimadm: 12/2/1994
terry: 7/15/1994
warfield: 4/21/1994
carol: 10/26/1993
carol: 8/31/1993
supermim: 3/16/1992

MIM 605712
*RECORD*
*FIELD* NO
605712
*FIELD* TI
*605712 SERINE PALMITOYLTRANSFERASE, LONG-CHAIN BASE SUBUNIT 1; SPTLC1
;;SPT1;;
LCB1
read more*FIELD* TX

DESCRIPTION

Serine palmitoyltransferase (SPT; EC 2.3.1.50) is the key enzyme in
sphingolipid biosynthesis. It catalyzes the first and rate-limiting
step: the pyridoxal-5-prime-phosphate-dependent condensation of L-serine
and palmitoyl-CoA to 3-oxosphinganine (Weiss and Stoffel, 1997).

SPT contains 2 main subunits: the common SPTLC1 subunit and either
SPTLC2 (605713) or its isoform SPTLC2L (SPTLC3; 611120), depending on
the tissue in which biosynthesis occurs (Hornemann et al., 2006). There
are also 2 highly related isoforms of a third subunit, SSSPTA (613540)
and SSSPTB (610412), that confer acyl-CoA preference of the SPT enzyme
and are essential for maximal enzyme activity (Han et al., 2009).

CLONING

Weiss and Stoffel (1997) cloned and characterized 2 complete human and
murine cDNA sequences corresponding to the SPTLC1 and SPTLC2 (605713)
genes, similar to yeast LCB1 and LCB2 genes, respectively. The SPTLC1
cDNA contains an open reading frame of 1,422 nucleotides and encodes a
473-amino acid protein (Bejaoui et al., 2001). By Northern blot
analysis, Dawkins et al. (2001) detected a single 3-kb SPTLC1 transcript
in all 7 tissues tested, including spinal cord. A search of the UniGene
database identified corresponding cDNA clones expressed in 29 different
tissues, indicating that SPTLC1 is ubiquitously expressed.

By quantitative real-time PCR analysis, Hornemann et al. (2006) detected
SPTLC1 expression in all 24 human tissues examined except for small
intestine. Western blot analysis detected SPTLC1 at 55 kD.
Overexpression of SPTLC1 in HEK293 cells showed no increase in SPT
activity, suggesting that SPTLC2 and SPTLC3 (611120) are the limiting
factors for SPT activity.

GENE STRUCTURE

Dawkins et al. (2001) determined that the SPTLC1 gene contains 15 exons
and established the intron/exon boundaries.

MAPPING

The International Radiation Hybrid Mapping Consortium mapped the SPTLC1
gene to chromosome 9 (TMAP WI-8025). Dawkins et al. (2001) noted that
the SPTLC1 gene maps to chromosome 9q22.1-q22.3.

MOLECULAR GENETICS

Dawkins et al. (2001) identified mutations in SPTLC1 in 11 families with
hereditary sensory neuropathy type I (HSN1; 162400). One family carried
a C133Y mutation in exon 5 (605712.0001); 8 families carried a C133W
mutation in exon 5 (605712.0002); and 2 families carried a V144D
mutation in exon 6 (605712.0003). All 6 families with definite or
probable linkage to chromosome 9 were found to have mutations in SPTLC1.
The families were of Australian/English, Australian/Scottish, English,
Austrian/German, or Canadian extraction. Dawkins et al. (2001) noted
that ceramide produced by catabolism of sphingomyelin mediates
programmed cell death and that increased de novo ceramide synthesis due
to an increase in SPT activity has been demonstrated to cause apoptosis
in a number of tissues (Perry et al., 2000), including differentiating
neuronal cells (Herget et al., 2000). Dawkins et al. (2001) determined
that the mutations were associated with increased de novo glucosyl
ceramide synthesis in lymphoblast cell lines in affected individuals.
Increased de novo ceramide synthesis triggers apoptosis, and is
associated with massive cell death during neural tube closure, raising
the possibility that neural degeneration in HSN1 is due to
ceramide-induced apoptotic cell death. Dawkins et al. (2001) labeled
lipids with C14-serine and showed that lymphoblast lines from HSN1
patients synthesize higher levels of glucosyl ceramide than do
comparable lines from healthy controls. Glucosyl ceramide synthesis in 5
HSN1 patients was 175% of the levels in 8 controls.

Bejaoui et al. (2001) independently identified the C133Y and C133W
mutations in 2 unrelated families with HSN1. Bejaoui et al. (2002) found
that the C133Y and C133W mutations do not alter the steady state levels
of the SPTLC1 or the SPTLC2 subunit. They did, however, result in
reduced SPT activity and sphingolipid synthesis. The mutations did not
complement the SPT deficiency found in a mutant CHO cell strain with
defective SPT activity secondary to a lack of SPTLC1. Overproduction of
either the C133Y or C133W subunit inhibited SPT activity in CHO cells
despite the presence of wildtype SPTLC1. The mutant SPTLC1 proteins
could also interact with the wildtype SPTLC2 subunit. The results
indicated that both of these mutations have a dominant-negative effect
on the SPT enzyme.

By in vitro functional expression assays in HEK293 cells, Hornemann et
al. (2009) found that none of the 4 SPTLC1 mutations, C133Y, C133W,
V144D, or G387A (605712.0004), interfered with formation of the SPT
complex. The first 3 mutant proteins resulted in 40 to 50% decreased SPT
activity, but the G387A protein showed no effect on SPT activity.
Further studies showed that the G387A protein could rescue a
SPTLC1-deficient cell line. Hornemann et al. (2009) also identified
homozygosity for the G387A variant in an unaffected mother of a
heterozygous carrier with HSN1, and it was found in 1 of 190 controls.
These findings indicated that G387A is not pathogenic. Hornemann et al.
(2009) postulated that the G387A variant, and perhaps the other 3 SPTLC1
variants previously associated with HSN1, may not be directly
disease-causing, but rather have an indirect or bystander effect by
increasing the risk for HSN1 in conjunction with another mutation.

SPT catalyzes the condensation of serine and palmitoyl-CoA, the initial
step in the de novo synthesis of sphingolipids. Penno et al. (2010)
showed that HSAN1A-related mutations in the SPTLC1 gene induce a shift
in the substrate specificity of SPT, which leads to the formation of 2
atypical deoxysphingoid bases: 1-deoxysphinganine from condensation with
alanine, and 1-deoxymethylsphinganine from condensation with glycine.
Neither of these metabolites can be converted to complex sphingolipids
or degraded, resulting in their intracellular accumulation. These
atypical agents showed pronounced neurotoxic effects on neurite
formation in cultured sensory neurons, and was associated with disturbed
neurofilament structure. Penno et al. (2010) found increased levels of
these atypical agents in lymphoblasts and plasma from HSAN1A patients
with different SPTLC1 mutations. The findings indicated that HSAN1
results from gain-of-function mutations that cause the formation of
atypical and neurotoxic sphingolipid metabolites, rather than from lack
of de novo sphingolipid synthesis.

ANIMAL MODEL

McCampbell et al. (2005) created transgenic mouse lines that
ubiquitously overexpressed either wildtype or C133W-mutant SPTLC1. The
C133W-mutant mice developed age-dependent weight loss and mild sensory
and motor impairments. Aged C133W-mutant mice lost large myelinated
axons in the ventral root of the spinal cord and demonstrated myelin
thinning. There was also a loss of large myelinated axons in the dorsal
roots, although the unmyelinated fibers were preserved. In the dorsal
root ganglia, IB4 staining was diminished, whereas expression of the
injury-induced transcription factor ATF3 (603148) was increased.

*FIELD* AV
.0001
NEUROPATHY, HEREDITARY SENSORY, TYPE I
SPTLC1, CYS133TYR

In a family of Austrian/German origin with HSN1 (162400), Dawkins et al.
(2001) identified a G-to-A transition at nucleotide 398 in exon 5 of the
SPTLC1 gene resulting in a cys133-to-tyr (C133Y) substitution.
Cysteine-133 of SPTLC1 is invariant in human, mouse, Drosophila, and
yeast. This mutation was also identified by Bejaoui et al. (2001) in a
family of German origin.

.0002
NEUROPATHY, HEREDITARY SENSORY, TYPE I
SPTLC1, CYS133TRP

In 8 families of Australian/English, Australian/Scottish, English, or
Canadian extraction with HSN1 (162400), Dawkins et al. (2001) identified
a T-to-G transversion at nucleotide 399 in exon 5 of the SPTLC1 gene,
resulting in a cysteine-to-tryptophan substitution at codon 133 (C133W).
Cysteine-133 of SPTLC1 is invariant in human, mouse, Drosophila, and
yeast. In a family of Canadian origin, Bejaoui et al. (2001)
independently identified this mutation.

Nicholson et al. (2001) performed haplotype analysis on 3 Australian
families of English extraction and 3 English families (2 of which had
been described elsewhere) with the cys133-to-trp mutation and
demonstrated the same chromosome 9 haplotype as well as the same
phenotype in all. They suggested that these families may have had a
common founder who, on the basis of historical information, lived in
southern England before 1800. The phenotype caused by the 399T-G SPTLC1
mutation is the same as that in the families reported by Campbell and
Hoffman (1964) and possibly the original family reported by Hicks
(1922), all of which were English.

In Chinese hamster ovary (CHO) cells and yeast, Gable et al. (2010)
demonstrated that the C133W-mutant protein was expressed and formed a
stable heterodimer with SPTLC2 (605713), but did not confer catalytic
SPT activity even when cotransfected with wildtype SPTLC1, thus showing
a dominant-negative effect. Coexpression of the mutant protein with the
catalytic enhancers SSSPTB (610412) and SSSPTA (613540) provided
sufficient SPT activity to support growth in yeast, although total
enzyme activity was only 10 to 20% of wildtype. Yeast and CHO cells
expressing the C133W mutant along with SPTLC2 and SSSPTA or SSSPTB
showed preferential condensation of palmitoyl-CoA to alanine rather than
serine. These results were not found with wildtype SPTLC1. Kinetic
studies showed that the mutant protein had the same affinity to serine
as the wildtype protein, but a lower Vmax for serine. These findings
suggest that the C133W mutation perturbs the active site of the protein,
facilitating the formation of alanine condensation products. However,
small increases in extracellular serine levels were able to inhibit the
reaction with alanine. The palmitoyl-CoA/alanine product,
1-deoxysphinganine (1-deoxySa), was shown to increase endoplasmic
reticulum stress and the unfolded protein response, which may ultimately
be toxic to neurons.

.0003
NEUROPATHY, HEREDITARY SENSORY, TYPE I
SPTLC1, VAL144ASP

In 2 families of Australian/Scottish and Australian/English extraction
with HSN1 (162400), Dawkins et al. (2001) identified a T-to-A
transversion at nucleotide 431 in exon 6 of the SPTLC1 gene, resulting
in a valine-to-aspartic acid substitution at codon 144 (V144D).
Valine-144 of SPTLC1 is conserved in human, mouse, Drosophila, and
yeast.

.0004
NEUROPATHY, HEREDITARY SENSORY, TYPE I
SPTLC1, GLY387ALA

In twin sisters with HSN1 (162400) from a Belgian family originally
reported by Montanini (1958), Verhoeven et al. (2004) identified a
1160G-C transversion in exon 13 of the SPTLC1 gene, resulting in a
gly387-to-ala (G387A) substitution. The mutation was not identified in
300 control chromosomes.

By in vitro functional studies, Hornemann et al. (2009) demonstrated
that overexpression of the G387A protein did not decrease SPT activity.
In addition, expression of the G387A protein could rescue a
SPTLC1-deficient cell line. Finally, homozygosity for G387A was
identified in an unaffected mother of a heterozygous G387A mutation
carrier with HSN1. The variant was also found in 1 of 190 unrelated
controls. All of these findings indicated that it is likely not
pathogenic. Hornemann et al. (2009) postulated that the G387A variant,
and perhaps the other 3 SPTLC1 variants previously associated with HSN1,
may not be directly disease-causing, but rather have an indirect or
bystander effect by increasing the risk for HSN1 in conjunction with
another mutation.

.0005
NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE I, SEVERE
SPTLC1, SER331PHE

In a French Gypsy with HSAN1 (162400), Rotthier et al. (2009) identified
a de novo heterozygous 992C-T transition in the SPTLC1 gene, resulting
in a ser331-to-phe (S331F) substitution in a conserved residue. The
patient had an unusually severe phenotype, with congenital onset,
insensitivity to pain with eschar and foot ulceration, pes
cavus/equinovarus, vocal cord paralysis, and gastroesophageal reflux.
The patient also had severe growth and mental retardation, microcephaly,
hypotonia, amyotrophy, and respiratory insufficiency. Nerve conduction
studies showed absent sensory and motor responses in the upper and lower
limbs. The mutation was absent from 600 control chromosomes. The
phenotype expanded the clinical spectrum of HSAN1.

.0006
NEUROPATHY, HEREDITARY SENSORY, TYPE I
SPTLC1, ALA352VAL

In an Austrian patient with HSN1 (162400), Rotthier et al. (2009)
identified a heterozygous 1055C-T transition in the SPTLC1 gene,
resulting in an ala352-to-val (A352V) substitution. The patient had
onset at age 16 years of severe sensory loss of the lower extremities
with peroneal atrophy and decreased distal reflexes. There was mild pes
cavus and lancinating pain in the lower extremities. DNA from family
members was not available.

*FIELD* RF
1. Bejaoui, K.; Uchida, Y.; Yasuda, S.; Ho, M.; Nishijima, M.; Brown,
R. H., Jr.; Holleran, W. M.; Hanada, K.: Hereditary sensory neuropathy
type 1 mutations confer dominant negative effects on serine palmitoyltransferase,
critical for sphingolipid synthesis. J. Clin. Invest. 110: 1301-1308,
2002.

2. Bejaoui, K.; Wu, C.; Scheffler, M. D.; Haan, G.; Ashby, P.; Wu,
L.; de Jong, P.; Brown, R. H., Jr.: SPTLC1 is mutated in hereditary
sensory neuropathy, type 1. Nature Genet. 27: 261-262, 2001.

3. Campbell, A. M. G.; Hoffman, H. L.: Sensory radicular neuropathy
associated with muscle wasting in two cases. Brain 87: 67-74, 1964.

4. Dawkins, J. L.; Hulme, D. J.; Brahmbhatt, S. B.; Auer-Grumbach,
M.; Nicholson, G. A.: Mutations in SPTLC1, encoding serine palmitoyltransferase,
long chain base subunit-1, cause hereditary sensory neuropathy type
I. Nature Genet. 27: 309-312, 2001.

5. Gable, K.; Gupta, S. D.; Han, G.; Niranjanakumari, S.; Harmon,
J. M.; Dunn, T. M.: A disease-causing mutation in the active site
of serine palmitoyltransferase causes catalytic promiscuity. J. Biol.
Chem. 285: 22846-22852, 2010.

6. Han, G.; Gupta, S. D.; Gable, K.; Niranjanakumari, S.; Moitra,
P.; Eichler, F.; Brown, R. H., Jr.; Harmon, J. M.; Dunn, T. M.: Identification
of small subunits of mammalian serine palmitoyltransferase that confer
distinct acyl-CoA substrate specificities. Proc. Nat. Acad. Sci. 106:
8186-8191, 2009. Note: Erratum: Proc. Nat. Acad. Sci. 106: 9931 only,
2009.

7. Herget, T.; Esdar, C.; Oehrlein, S. A.; Heinrich, M.; Schutze,
S.; Maelicke, A.; van Echten-Deckert, G.: Production of ceramides
causes apoptosis during early neural differentiation in vitro. J.
Biol. Chem. 275: 30344-30354, 2000.

8. Hicks, E. P.: Hereditary perforating ulcer of the foot. Lancet 199:
319-321, 1922. Note: Originally Volume I.

9. Hornemann, T.; Penno, A.; Richard, S.; Nicholson, G.; van Dijk,
F. S.; Rotthier, A.; Timmerman, V.; von Eckardstein, A.: A systematic
comparison of all mutations in hereditary sensory neuropathy type
I (HSAN I) reveals that the G387A mutation is not disease associated. Neurogenetics 10:
135-143, 2009.

10. Hornemann, T.; Richard, S.; Rutti, M. F.; Wei, Y.; von Eckardstein,
A.: Cloning and initial characterization of a new subunit for mammalian
serine-palmitoyltransferase. J. Biol. Chem. 281: 37275-37281, 2006.

11. McCampbell, A.; Truong, D.; Broom, D. C.; Allchorne, A.; Gable,
K.; Cutler, R. G.; Mattson, M. P.; Woolf, C. J.; Frosch, M. P.; Harmon,
J. M.; Dunn, T. M.; Brown, R. H., Jr.: Mutant SPTLC1 dominantly inhibits
serine palmitoyltransferase activity in vivo and confers an age-dependent
neuropathy. Hum. Molec. Genet. 14: 3507-3521, 2005.

12. Montanini, R.: Acropatia ulcero-mutilante, amiotrofia frusta
tipo Charcot-Marie e alessia in due gemelle univitelline. Riv. Neurol. 28:
593-609, 1958.

13. Nicholson, G. A.; Dawkins, J. L.; Blair, I. P.; Auer-Grumbach,
M.; Brahmbhatt, S. B.; Hulme, D. J.: Hereditary sensory neuropathy
type I: haplotype analysis shows founders in southern England and
Europe. Am. J. Hum. Genet. 69: 655-659, 2001.

14. Penno, A.; Reilly, M. M.; Houlden, H.; Laura, M.; Rentsch, K.;
Niederkofler, V.; Stoeckli, E. T.; Nicholson, G.; Eichler, F.; Brown,
R. H., Jr.; von Eckardstein, A.; Hornemann, T.: Hereditary sensory
neuropathy type 1 is caused by the accumulation of two neurotoxic
sphingolipids. J. Biol. Chem. 285: 11178-11187, 2010.

15. Perry, D. K.; Carton, J.; Shah, A. K.; Meredith, F.; Uhlinger,
D. J.; Hannun, Y. A.: Serine palmitoyltransferase regulates de novo
ceramide generation during etoposide-induced apoptosis. J. Biol.
Chem. 275: 9078-9084, 2000.

16. Rotthier, A.; Baets, J.; De Vriendt, E.; Jacobs, A.; Auer-Grumbach,
M.; Levy, N.; Bonello-Palot, N.; Kilic, S. S.; Weis, J.; Nascimento,
A.; Swinkels, M.; Kruyt, M. C., Jordanova, A.; De Jonghe, P.; Timmerman,
V.: Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype
correlation. Brain 132: 2699-2711, 2009.

17. Verhoeven, K.; Coen, K.; De Vriendt, E.; Jacobs, A.; Van Gerwen,
V.; Smouts, I.; Pou-Serradell, A.; Martin, J.-J.; Timmerman, V.; De
Jonghe, P.: SPTLC1 mutation in twin sisters with hereditary sensory
neuropathy type I. Neurology 62: 1001-1002, 2004.

18. Weiss, B.; Stoffel, W.: Human and murine serine-palmitoyl-CoA
transferase: cloning, expression and characterization of the key enzyme
in sphingolipid synthesis. Europ. J. Biochem. 249: 239-247, 1997.

*FIELD* CN
Cassandra L. Kniffin - updated: 11/12/2010
Cassandra L. Kniffin - updated: 9/23/2010
George E. Tiller - updated: 9/3/2009
Cassandra L. Kniffin - updated: 5/14/2009
Jennifer L. Goldstein - updated: 6/19/2007
Denise L. M. Goh - updated: 4/10/2003
Carol A. Bocchini - reorganized: 10/5/2001
Victor A. McKusick - updated: 9/27/2001

*FIELD* CD
Ada Hamosh: 3/2/2001

*FIELD* ED
carol: 10/01/2013
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ckniffin: 11/12/2010
wwang: 10/6/2010
ckniffin: 9/23/2010
terry: 1/20/2010
wwang: 9/17/2009
terry: 9/3/2009
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ckniffin: 5/14/2009
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carol: 6/19/2007
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tkritzer: 9/8/2004
ckniffin: 8/27/2004
carol: 5/21/2004
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carol: 4/10/2003
carol: 7/30/2002
mcapotos: 10/5/2001
carol: 10/5/2001
mcapotos: 10/4/2001
terry: 9/27/2001
alopez: 3/5/2001
alopez: 3/2/2001