RBCC Red Blood Cell Collection

SLC7A9 (BAT1) [Confidence: low (only semi-automatic identification from reviews)]
B(0,+)-type amino acid transporter 1; B(0,+)AT (Glycoprotein-associated amino acid transporter b0,+AT1; Solute carrier family 7 member 9)

UniProt P82251
ID BAT1_HUMAN Reviewed; 487 AA.
AC P82251; B2R9A6;
DT 24-JAN-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-2000, sequence version 1.
DT 22-JAN-2014, entry version 135.
DE RecName: Full=B(0,+)-type amino acid transporter 1;
DE Short=B(0,+)AT;
DE AltName: Full=Glycoprotein-associated amino acid transporter b0,+AT1;
DE AltName: Full=Solute carrier family 7 member 9;
GN Name=SLC7A9; Synonyms=BAT1;
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], VARIANTS CSNU ARG-105; MET-170; THR-182;
RP ARG-195 AND ARG-259, CHARACTERIZATION OF VARIANT CSNU MET-170,
RP FUNCTION, AND TISSUE SPECIFICITY.
RC TISSUE=Kidney;
RX PubMed=10471498; DOI=10.1038/12652;
RA Feliubadalo L., Font M., Purroy J., Rousaud F., Estivill X., Nunes V.,
RA Golomb E., Centola M., Aksentijevich I., Kreiss Y., Goldman B.,
RA Pras M., Kastner D.L., Pras E., Gasparini P., Bisceglia L., Beccia E.,
RA Gallucci M., De Sanctis L., Ponzone A., Rizzoni G.F., Zelante L.,
RA Bassi M.T., George A.L. Jr., Manzoni M., De Grandi A., Riboni M.,
RA Endsley J.K., Ballabio A., Borsani G., Reig N., Fernandez E.,
RA Estevez R., Pineda M., Torrents D., Camps M., Lloberas J., Zorzano A.,
RA Palacin M.;
RT "Non-type I cystinuria caused by mutations in SLC7A9, encoding a
RT subunit (b0,+AT) of rBAT.";
RL Nat. Genet. 23:52-57(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Kidney;
RX PubMed=10588648; DOI=10.1091/mbc.10.12.4135;
RA Pfeiffer R., Loffing J., Rossier G., Bauch C., Meier C., Eggermann T.,
RA Loffing-Cueni D., Kuehn L.C., Verrey F.;
RT "Luminal heterodimeric amino acid transporter defective in
RT cystinuria.";
RL Mol. Biol. Cell 10:4135-4147(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Kidney;
RX PubMed=11318953; DOI=10.1046/j.1523-1755.2001.0590051821.x;
RA Mizoguchi K., Cha S.H., Chairoungdua A., Kim J.Y., Shigeta Y.,
RA Matsuo H., Fukushima J., Awa Y., Akakura K., Goya T., Ito H.,
RA Endou H., Kanai Y.;
RT "Human cystinuria-related transporter: localization and functional
RT characterization.";
RL Kidney Int. 59:1821-1833(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS CSNU THR-44; LEU-261 AND
RP THR-354, AND VARIANT MET-223.
RX PubMed=12371955; DOI=10.1046/j.1523-1755.2002.00602.x;
RA Leclerc D., Boutros M., Suh D., Wu Q., Palacin M., Ellis J.R.,
RA Goodyer P., Rozen R.;
RT "SLC7A9 mutations in all three cystinuria subtypes.";
RL Kidney Int. 62:1550-1559(2002).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
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 VARIANTS CSNU ARG-10 DEL; LEU-52; ARG-63; LEU-69; VAL-70; ARG-105;
RP MET-123; THR-126; ALA-158 INS; MET-170; THR-182; PHE-187; ILE-193 INS;
RP ARG-195; ARG-230; THR-241; GLU-244 DEL; ARG-259; TRP-333; THR-354;
RP ARG-379 AND THR-382, AND CHARACTERIZATION OF VARIANTS CSNU VAL-70;
RP ARG-105; MET-170; THR-182; TRP-333 AND THR-354.
RX PubMed=11157794; DOI=10.1093/hmg/10.4.305;
RA Font M., Feliubadalo L., Estivill X., Nunes V., Golomb E., Kreiss Y.,
RA Pras E., Bisceglia L., d'Adamo A.P., Zelante L., Gasparini P.,
RA Bassi M.T., George A.L. Jr., Manzoni M., Riboni M., Ballabio A.,
RA Borsani G., Reig N., Fernandez E., Zorzano A., Bertran J., Palacin M.;
RT "Functional analysis of mutations in SLC7A9, and genotype-phenotype
RT correlation in non-type I cystinuria.";
RL Hum. Mol. Genet. 10:305-316(2001).
RN [8]
RP VARIANTS CSNU ARG-105; VAL-224 AND VAL-331.
RX PubMed=12234283; DOI=10.1046/j.1523-1755.2002.00552.x;
RA Botzenhart E., Vester U., Schmidt C., Hesse A., Halber M., Wagner C.,
RA Lang F., Hoyer P., Zerres K., Eggermann T.;
RT "Cystinuria in children: distribution and frequencies of mutations in
RT the SLC3A1 and SLC7A9 genes.";
RL Kidney Int. 62:1136-1142(2002).
RN [9]
RP VARIANTS CSNU THR-182; LEU-261 AND MET-330.
RX PubMed=12820697; DOI=10.1089/109065703321560886;
RA Harnevik L., Fjellstedt E., Molbaek A., Denneberg T., Soderkvist P.;
RT "Mutation analysis of SLC7A9 in cystinuria patients in Sweden.";
RL Genet. Test. 7:13-20(2003).
CC -!- FUNCTION: Involved in the high-affinity, sodium-independent
CC transport of cystine and neutral and dibasic amino acids (system
CC b(0,+)-like activity). Thought to be responsible for the high-
CC affinity reabsorption of cystine in the kidney tubule.
CC -!- SUBUNIT: Disulfide-linked heterodimer with the amino acid
CC transport protein SLC3A1.
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein
CC (Probable).
CC -!- TISSUE SPECIFICITY: Kidney, small intestine, liver and placenta.
CC -!- DISEASE: Cystinuria (CSNU) [MIM:220100]: An autosomal disorder
CC characterized by impaired epithelial cell transport of cystine and
CC dibasic amino acids (lysine, ornithine, and arginine) in the
CC proximal renal tubule and gastrointestinal tract. The impaired
CC renal reabsorption of cystine and its low solubility causes the
CC formation of calculi in the urinary tract, resulting in
CC obstructive uropathy, pyelonephritis, and, rarely, renal failure.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the amino acid-polyamine-organocation (APC)
CC superfamily.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SLC7A9";
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DR EMBL; AF141289; AAD55898.1; -; mRNA.
DR EMBL; AJ249199; CAB54003.1; -; mRNA.
DR EMBL; AB033548; BAB16840.1; -; mRNA.
DR EMBL; AF421181; AAN40878.1; -; Genomic_DNA.
DR EMBL; AF421170; AAN40878.1; JOINED; Genomic_DNA.
DR EMBL; AF421171; AAN40878.1; JOINED; Genomic_DNA.
DR EMBL; AF421172; AAN40878.1; JOINED; Genomic_DNA.
DR EMBL; AF421173; AAN40878.1; JOINED; Genomic_DNA.
DR EMBL; AF421174; AAN40878.1; JOINED; Genomic_DNA.
DR EMBL; AF421175; AAN40878.1; JOINED; Genomic_DNA.
DR EMBL; AF421176; AAN40878.1; JOINED; Genomic_DNA.
DR EMBL; AF421177; AAN40878.1; JOINED; Genomic_DNA.
DR EMBL; AF421178; AAN40878.1; JOINED; Genomic_DNA.
DR EMBL; AF421179; AAN40878.1; JOINED; Genomic_DNA.
DR EMBL; AF421180; AAN40878.1; JOINED; Genomic_DNA.
DR EMBL; AK313708; BAG36453.1; -; mRNA.
DR EMBL; BC017962; AAH17962.1; -; mRNA.
DR RefSeq; NP_001119807.1; NM_001126335.1.
DR RefSeq; NP_001229965.1; NM_001243036.1.
DR RefSeq; NP_055085.1; NM_014270.4.
DR UniGene; Hs.743345; -.
DR ProteinModelPortal; P82251; -.
DR SMR; P82251; 30-365.
DR IntAct; P82251; 2.
DR MINT; MINT-3023541; -.
DR STRING; 9606.ENSP00000023064; -.
DR DrugBank; DB00138; L-Cystine.
DR TCDB; 2.A.3.8.19; the amino acid-polyamine-organocation (apc) family.
DR PhosphoSite; P82251; -.
DR DMDM; 12585187; -.
DR PRIDE; P82251; -.
DR DNASU; 11136; -.
DR Ensembl; ENST00000023064; ENSP00000023064; ENSG00000021488.
DR Ensembl; ENST00000587772; ENSP00000468439; ENSG00000021488.
DR Ensembl; ENST00000590341; ENSP00000464822; ENSG00000021488.
DR GeneID; 11136; -.
DR KEGG; hsa:11136; -.
DR UCSC; uc002ntu.4; human.
DR CTD; 11136; -.
DR GeneCards; GC19M033321; -.
DR HGNC; HGNC:11067; SLC7A9.
DR HPA; HPA042591; -.
DR MIM; 220100; phenotype.
DR MIM; 604144; gene.
DR neXtProt; NX_P82251; -.
DR Orphanet; 93613; Cystinuria type B.
DR PharmGKB; PA35927; -.
DR eggNOG; COG0531; -.
DR HOGENOM; HOG000098892; -.
DR HOVERGEN; HBG000476; -.
DR InParanoid; P82251; -.
DR KO; K13868; -.
DR OMA; ITMHLQM; -.
DR OrthoDB; EOG73BVCR; -.
DR PhylomeDB; P82251; -.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_19419; Amino acid and oligopeptide SLC transporters.
DR Reactome; REACT_604; Hemostasis.
DR GenomeRNAi; 11136; -.
DR NextBio; 42332; -.
DR PRO; PR:P82251; -.
DR ArrayExpress; P82251; -.
DR Bgee; P82251; -.
DR CleanEx; HS_BAT1; -.
DR CleanEx; HS_SLC7A9; -.
DR Genevestigator; P82251; -.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0015184; F:L-cystine transmembrane transporter activity; TAS:ProtInc.
DR GO; GO:0015175; F:neutral amino acid transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0042605; F:peptide antigen binding; ISS:UniProtKB.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0006520; P:cellular amino acid metabolic process; TAS:ProtInc.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0006461; P:protein complex assembly; TAS:ProtInc.
DR InterPro; IPR002293; AA/rel_permease1.
DR PANTHER; PTHR11785; PTHR11785; 1.
DR Pfam; PF13520; AA_permease_2; 1.
DR PIRSF; PIRSF006060; AA_transporter; 1.
PE 1: Evidence at protein level;
KW Amino-acid transport; Complete proteome; Cystinuria; Disease mutation;
KW Disulfide bond; Membrane; Polymorphism; Reference proteome;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 487 B(0,+)-type amino acid transporter 1.
FT /FTId=PRO_0000054258.
FT TOPO_DOM 1 29 Cytoplasmic (Potential).
FT TRANSMEM 30 50 Helical; (Potential).
FT TOPO_DOM 51 60 Extracellular (Potential).
FT TRANSMEM 61 81 Helical; (Potential).
FT TOPO_DOM 82 99 Cytoplasmic (Potential).
FT TRANSMEM 100 120 Helical; (Potential).
FT TOPO_DOM 121 148 Extracellular (Potential).
FT TRANSMEM 149 169 Helical; (Potential).
FT TOPO_DOM 170 178 Cytoplasmic (Potential).
FT TRANSMEM 179 199 Helical; (Potential).
FT TOPO_DOM 200 210 Extracellular (Potential).
FT TRANSMEM 211 231 Helical; (Potential).
FT TOPO_DOM 232 251 Cytoplasmic (Potential).
FT TRANSMEM 252 272 Helical; (Potential).
FT TOPO_DOM 273 296 Extracellular (Potential).
FT TRANSMEM 297 317 Helical; (Potential).
FT TOPO_DOM 318 348 Cytoplasmic (Potential).
FT TRANSMEM 349 369 Helical; (Potential).
FT TOPO_DOM 370 374 Extracellular (Potential).
FT TRANSMEM 375 395 Helical; (Potential).
FT TOPO_DOM 396 409 Cytoplasmic (Potential).
FT TRANSMEM 410 430 Helical; (Potential).
FT TOPO_DOM 431 434 Extracellular (Potential).
FT TRANSMEM 435 455 Helical; (Potential).
FT TOPO_DOM 456 487 Cytoplasmic (Potential).
FT VARIANT 10 10 Missing (in CSNU).
FT /FTId=VAR_018997.
FT VARIANT 44 44 I -> T (in CSNU; type I).
FT /FTId=VAR_014363.
FT VARIANT 52 52 P -> L (in CSNU).
FT /FTId=VAR_018998.
FT VARIANT 63 63 G -> R (in CSNU).
FT /FTId=VAR_018999.
FT VARIANT 69 69 W -> L (in CSNU).
FT /FTId=VAR_019000.
FT VARIANT 70 70 A -> V (in CSNU; mild loss of amino acid
FT transport activity).
FT /FTId=VAR_019001.
FT VARIANT 105 105 G -> R (in CSNU; type III; frequent
FT mutation; severe loss of amino acid
FT transport activity; dbSNP:rs121908480).
FT /FTId=VAR_010256.
FT VARIANT 123 123 T -> M (in CSNU; dbSNP:rs79987078).
FT /FTId=VAR_019002.
FT VARIANT 126 126 A -> T (in CSNU).
FT /FTId=VAR_019003.
FT VARIANT 142 142 V -> A (in dbSNP:rs12150889).
FT /FTId=VAR_048153.
FT VARIANT 158 158 A -> AA (in CSNU).
FT /FTId=VAR_019004.
FT VARIANT 170 170 V -> M (in CSNU; type III; frequent
FT mutation; complete loss of amino acid
FT transport activity).
FT /FTId=VAR_010257.
FT VARIANT 182 182 A -> T (in CSNU; type III; frequent
FT mutation; mild loss of amino acid
FT transport activity; dbSNP:rs79389353).
FT /FTId=VAR_010258.
FT VARIANT 187 187 I -> F (in CSNU).
FT /FTId=VAR_019005.
FT VARIANT 193 193 I -> II (in CSNU).
FT /FTId=VAR_019006.
FT VARIANT 195 195 G -> R (in CSNU; type III).
FT /FTId=VAR_010259.
FT VARIANT 223 223 L -> M (in dbSNP:rs1007160).
FT /FTId=VAR_019007.
FT VARIANT 224 224 A -> V (in CSNU; non-classic type I).
FT /FTId=VAR_022603.
FT VARIANT 230 230 W -> R (in CSNU).
FT /FTId=VAR_019008.
FT VARIANT 241 241 I -> T (in CSNU).
FT /FTId=VAR_019009.
FT VARIANT 244 244 Missing (in CSNU).
FT /FTId=VAR_019010.
FT VARIANT 259 259 G -> R (in CSNU; type III).
FT /FTId=VAR_010260.
FT VARIANT 261 261 P -> L (in CSNU; types I and III).
FT /FTId=VAR_014364.
FT VARIANT 330 330 V -> M (in CSNU; type III).
FT /FTId=VAR_015885.
FT VARIANT 331 331 A -> V (in CSNU; non-classic type I).
FT /FTId=VAR_022604.
FT VARIANT 333 333 R -> W (in CSNU; frequent mutation;
FT severe loss of amino acid transport
FT activity).
FT /FTId=VAR_019011.
FT VARIANT 354 354 A -> T (in CSNU; type III; severe loss of
FT amino acid transport activity).
FT /FTId=VAR_014365.
FT VARIANT 379 379 S -> R (in CSNU).
FT /FTId=VAR_019012.
FT VARIANT 382 382 A -> T (in CSNU).
FT /FTId=VAR_019013.
FT CONFLICT 52 52 P -> S (in Ref. 2; CAB54003).
SQ SEQUENCE 487 AA; 53481 MW; EF2C30DDE15594F1 CRC64;
MGDTGLRKRR EDEKSIQSQE PKTTSLQKEL GLISGISIIV GTIIGSGIFV SPKSVLSNTE
AVGPCLIIWA ACGVLATLGA LCFAELGTMI TKSGGEYPYL MEAYGPIPAY LFSWASLIVI
KPTSFAIICL SFSEYVCAPF YVGCKPPQIV VKCLAAAAIL FISTVNSLSV RLGSYVQNIF
TAAKLVIVAI IIISGLVLLA QGNTKNFDNS FEGAQLSVGA ISLAFYNGLW AYDGWNQLNY
ITEELRNPYR NLPLAIIIGI PLVTACYILM NVSYFTVMTA TELLQSQAVA VTFGDRVLYP
ASWIVPLFVA FSTIGAANGT CFTAGRLIYV AGREGHMLKV LSYISVRRLT PAPAIIFYGI
IATIYIIPGD INSLVNYFSF AAWLFYGLTI LGLIVMRFTR KELERPIKVP VVIPVLMTLI
SVFLVLAPII SKPTWEYLYC VLFILSGLLF YFLFVHYKFG WAQKISKPIT MHLQMLMEVV
PPEEDPE
//

MIM 220100
*RECORD*
*FIELD* NO
220100
*FIELD* TI
#220100 CYSTINURIA
;;CSNU;;
CYSTINURIA, TYPE I, FORMERLY; CSNU1, FORMERLY;;
CYSTINURIA, TYPE II, FORMERLY;;
read moreCYSTINURIA, TYPE III, FORMERLY; CSNU3, FORMERLY;;
CYSTINURIA, TYPE NON-I, FORMERLY
CYSTINURIA, TYPE A, INCLUDED;;
CYSTINURIA, TYPE B, INCLUDED;;
CYSTINURIA, TYPE A/B, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
cystinuria can be caused by mutation in the SLC3A1 amino acid
transporter gene (104614), which encodes the heavy subunit of the renal
amino acid transporter and is located on chromosome 2p, and/or by
mutation in the SLC7A9 gene (604144), which encodes the light subunit
and is located on chromosome 19. A classification scheme of cystinuria
based on the molecular genetics of the disorder has been proposed (see
NOMENCLATURE).

DESCRIPTION

Cystinuria is an autosomal disorder characterized by impaired epithelial
cell transport of cystine and dibasic amino acids (lysine, ornithine,
and arginine) in the proximal renal tubule and gastrointestinal tract.
The impaired renal reabsorption of cystine and its low solubility causes
the formation of calculi in the urinary tract, resulting in obstructive
uropathy, pyelonephritis, and, rarely, renal failure (summary by Barbosa
et al., 2012).

NOMENCLATURE

Rosenberg et al. (1966) described 3 types of cystinuria based on
excretion patterns of presumed heterozygotes, e.g., the parents and
children of affected individuals, with type I heterozygotes showing
normal amino aciduria, and type II and type III heterozygotes showing
high and moderate hyperexcretion of cystine and dibasic amino acids,
respectively. In contrast to types I and II homozygotes, type III
homozygotes showed a nearly normal increase in cystine plasma levels
after oral cystine administration.

Dello Strologo et al. (2002) pointed out that the traditional
classification system of cystinuria patients, based on excretion of
cystine and dibasic amino acids in obligate heterozygotes, was not
supported by evidence (see later) that all 3 types of the disease are
caused by mutation in only 2 genes, SLC3A1 and SLC7A9. Dello Strologo et
al. (2002) proposed a classification system based on the molecular
genetics of the disorder: type A, due to mutation in the SLC3A1 gene;
type B, due to mutation in the SLC7A9 gene; and type AB, due to a
mutation in both the SLC3A1 and SLC7A9 genes, respectively.

CLINICAL FEATURES

Wollaston (1810) first described a cystine stone. He found that a
glistening yellow bladder stone was composed of an unusual substance,
which he called cystic oxide since it came from the bladder. Later
analysis showed this to be a sulfur-containing amino acid and so this
stone ultimately gave its name not only to cystinuria but also to the
amino acids cystine and cysteine. Marcet (1817) showed that cystine
stones occur also in the kidney. He suspected that the condition might
be familial since 2 of his patients were brothers. Cystinuria was one of
the 4 inborn errors of metabolism discussed by Garrod (1908).

Rosenberg et al. (1966) described 3 forms of cystinuria, each due to
presumed homozygosity of a particular mutant allele at 1 locus. In
cystinuria I, the homozygote excretes relatively large amounts of
cystine, lysine, arginine and ornithine in the urine. Heterozygotes
(e.g., parents) have no abnormal amino aciduria. Urinary stones form in
all 3 types of cystinuria because of the limited solubility of this
amino acid. Cystinuria II is incompletely recessive because
heterozygotes have a moderate degree of amino aciduria, mainly cystine
and lysine, and may occasionally form cystine stones. Observations in
kindreds in which both cystinuria I and cystinuria II are segregating
demonstrate that the genes for these are allelic (Hershko et al., 1965).
In cystinuria III, intestinal transport of all dibasic amino acids is
retained by heterozygotes, and homozygotes excrete cystine in slight
excess. Rosenberg (1966) and others observed families in which 'doubly
heterozygous' persons (I-II, I-III, or II-III) had full-blown
cystinuria. The findings were best explained on the basis of allelism of
the genes responsible for the 3 types.

Brodehl et al. (1967) reported a 2-year-old girl who was discovered to
have isolated hypercystinuria with normal urine levels of arginine,
lysine, and ornithine during an evaluation for candidiasis. A younger
brother had the same pattern of urinary amino acid excretion. Their
unrelated parents and an older sister had normal cystine excretion. The
female proband was also noted to have isolated hyperparathyroidism,
which was suspected to be familial because another sister and brother
had died due to hypocalcemic tetany.

Scriver et al. (1970) presented evidence indicating that cystinuria
patients are at increased risk for impaired cerebral function.
Weinberger et al. (1974) demonstrated an unusually high frequency of
type II or III cystinuria among Libyan Jews.

Kelly (1978) concluded that the excretion rates of obligate carriers
among the relatives of cystinurics suffice to determine the type of
cystinuria in the proband. Among 17 patients he studied, type I was the
most frequent type and often occurred in compound heterozygotes with
type III. When obligatory heterozygotes showed normal amounts of cystine
and dibasic amino acids in the urine, they were called type I. When up
to twice the normal range was excreted in the urine, they were called
type III. When carriers excreted large amounts of cystine and lysine
(9-15 times the normal range but less than in most stone-formers), they
were called type II. On the basis of a study in Brazil, Giugliani et al.
(1985) concluded that there is an increased frequency of heterozygotes
for types II and III cystinuria among urinary stone-formers and that
heterozygosity for these genes is a risk factor for urinary stones.

INHERITANCE

The inheritance pattern of cystinuria is complex. Some patients show
classic autosomal recessive inheritance. However, the urinary excretion
of cystine and dibasic amino acids can vary considerably among
heterozygotes, and may result in nephrolithiasis. Heterozygotes have
been classified biochemically into type I, in which there is a normal
pattern of amino acid excretion (consistent with autosomal recessive
inheritance), and non-type I, in which there is urinary hyperexcretion
of cystine, sometimes resulting in stone formation. Manifesting
heterozygotes suggests that the disease can also be transmitted in an
autosomal dominant pattern with incomplete penetrance (summary by
Barbosa et al., 2012).

CLINICAL MANAGEMENT

On the basis of the extensive experience at St. Bartholomew's Hospital
in London, Stephens (1989) indicated that in many people cystine stones
can be dissolved and new ones prevented by a high fluid intake; that in
those in whom this measure does not succeed, regular treatment with
penicillamine will be effective; that side effects of penicillamine are
rarely severe enough to prevent its use; and that because of the
effectiveness of treatment, early diagnosis is important with
consideration of cystinuria in all persons, regardless of age, who form
urinary stones.

MAPPING

In a mentally handicapped 3-year-old child with cystinuria, Sharland et
al. (1992) found an apparently balanced de novo translocation with
breakpoints at 14q22 and 20p13. Family studies suggested that the child
was a type I/type II compound heterozygote for cystinuria. Sharland et
al. (1992) suggested that the cystinuria locus might be on either 14q22
or 20p13.

Pras et al. (1994) showed linkage between a panel of 17 cystinuria
families (8 of which were of Libyan Jewish origin) and markers on the
short arm of chromosome 2. They had directed their attention to this
region of the genome because the SLC3A1 amino acid transporter gene,
whose protein product is involved in cystine, dibasic and neutral amino
acid transport, had been mapped to that site. However, refined linkage
studies limited to the Libyan Jewish families by Wartenfeld et al.
(1997) excluded the disease locus from the region of the SLC3A1 gene.
Pairwise linkage analysis revealed a maximum lod of 9.22 at theta = 0.00
with the marker D19S882. Further analysis placed the gene in an 8-cM
interval between D19S409 and D19S208. Quantitative urinary amino acid
analysis in these families demonstrated non-type I disease; final
determination as to whether these families had type II or type III
remained to be determined by the findings of oral loading tests.

The 3 types of cystinuria were thought to be due to allelism of the
SLC3A1 gene, although the possibility of 2 distinct loci for type I and
type III cystinuria had been suggested by Goodyer et al. (1993) and
others. Calonge et al. (1995) performed linkage analysis in 22 families
with type I and/or type III cystinuria and found that type I/I families
showed homogeneous linkage to SLC3A1, whereas types I/III and III/III
were not linked. Calonge et al. (1995) concluded that type III
cystinuria results from mutation in a gene other than SLC3A1.

By linkage analysis after a genomewide search, Bisceglia et al. (1997)
mapped the CSNU3 locus to 19q13.1. Pairwise linkage analysis in a series
of type III or type II families previously excluded from linkage to the
CSNU1 locus, i.e., the SLC3A1 gene, revealed a maximum lod score of
13.11 at a recombination fraction of 0.0 with marker D19S225.
Preliminary data on type II families seemed to place the disease locus
for this rare type of cystinuria at 19q13.1 also.

Stoller et al. (1999) studied a kindred of 39 persons with cystinuria,
in which one branch demonstrated type II cystinuria and the other had
type III disease. Linkage analysis demonstrated linkage of both types to
the 19q13.1 region. Two individuals in the pedigree were shown by
haplotype analysis to have inherited a copy of the disease haplotype
from each branch of the pedigree (both type II and type III alleles) and
had an extreme stone-forming phenotype. The authors concluded that
phenotypic differences between type II and type III cystinuria are
likely due to allelism at this locus.

BIOCHEMICAL FEATURES

Pras et al. (1998) described the biochemical and clinical features of
the Libyan Jewish cystinuria shown to be linked to 19q13.1. The levels
of cysteine and the dibasic amino acids in heterozygotes supported
previous data that cystinuria in Libyan Jews is not a type I disease.
Oral loading tests performed with lysine showed some degree of
intestinal absorption, but less than that in normal controls. Previous
criteria for determining the disease type, based solely on urinary amino
acid levels, proved useless due to a very wide range of cystine and the
dibasic amino acids excreted by heterozygotes. Urinary cystine levels
were useful in distinguishing between unaffected relatives and
heterozygotes but were not helpful in distinguishing between
heterozygotes and homozygotes. Urinary levels of ornithine or arginine,
and the sum of urinary cystine and the dibasic amino acids, could
distinguish between the last 2 groups. Among stone-formers, 90% were
homozygotes and 10% were heterozygotes; 15% of homozygotes were
asymptomatic.

MOLECULAR GENETICS

Calonge et al. (1994) sought mutations in the SLC3A1 gene because of its
plausible candidacy as the site of the defect in cystinuria. In affected
individuals from 8 different families, they identified 6 missense
mutations in the SLC3A1 gene (which they referred to as rBAT), which
segregated with cystinuria and accounted for 30% of the cystinuria
chromosomes studied. Homozygosity for the most common mutation,
met467-to-thr (104614.0001), was detected in 3 cystinuric sibs. This
M467T mutation nearly abolished the amino acid transport activity
induced by rBAT in Xenopus oocytes. Kastner (1994) also found mutations
in the SLC3A1 gene; 1 patient was a genetic compound of a deletion in
the maternal chromosome and a single base substitution in the paternal
chromosome.

Gasparini et al. (1995) pointed out that all mutations identified in the
SLC3A1 gene to that point belonged to cystinuria type I alleles,
accounting for approximately 44% of all type I cystinuric chromosomes.
After analysis of 70% of the FLC3A1 coding region, they had detected
normal sequences in cystinuria type II and type III cases. The mutant
alleles occurred in homozygous type I/I and in heterozygotes of type
I/III, indicating genetic heterogeneity of cystinuria. They referred to
linkage data also supporting genetic heterogeneity of cystinuria. Their
studies were done in Italians and Spaniards, which may explain their
conclusion that genetic heterogeneity of cystinuria exists; Pras et al.
(1994) failed to find linkage evidence of heterogeneity in Jewish
families which may have come from a more homogeneous background. On the
basis of biochemical data, Goodyer et al. (1993) had suggested a
complementation model with an interaction and expression of mutated
alleles of 2 different genes, 1 for cystinuria type I and the other for
cystinuria type III. First-degree relatives of type I patients had no
abnormal urinary amino acid excretion, while type II and type III
heterozygous individuals showed increased amounts of cystine in the
dibasic amino acids in their urine. Moreover, oral cystine loading fails
to raise serum cystine levels in type I and type II patients but results
in nearly normal elevation of plasma cystine levels in type III
patients, thus demonstrating a different intestinal defect. Gasparini et
al. (1995) suggested that the genes involved in cystinuria types II and
III may be genes coding for cystine transporters expressed in the S1 and
S2 segments of the proximal tubule and/or a functionally associated
subunit of an oligomeric rBAT transporter.

In Libyan Jewish, North American, Italian, and Spanish patients with
non-type I cystinuria, the International Cystinuria Consortium (1999)
identified mutations in the SLC7A9 gene. The Libyan Jewish patients were
homozygous for a founder missense mutation (604144.0001) that abolished
b(0,+)AT amino acid uptake activity when cotransfected with rBAT in COS
cells. In other patients, they identified 4 missense mutations and 2
frameshift mutations. The authors were not able to fully differentiate
between type II and type III phenotypes: according to the urinary amino
acid profile, most of the patients described seemed to have inherited
type III cystinuria from both parents, but there were exceptions. The
results suggested that types II and III, and in some cases type I,
represent allelic differences in SLC7A9. Other factors, genetic and
environmental, were probably involved. In 1 patient, mutations in SLC7A9
(604144.0002) and in SLC3A1 (104614.0001) were found. These preliminary
results suggested that cystinuria is a digenic disease in some of the
mixed type I/non-type I patients and supported the hypothesis of partial
genetic complementation (Goodyer et al., 1993).

The International Cystinuria Consortium (1999) offered 2 hypotheses as
to why mutations in the SLC3A1 gene are recessive, whereas mutations in
the SLC7A9 gene are incompletely recessive. First, if the active b(0,+)
transporter is constituted by more than 1 rBAT and b(0,+)AT subunit, 1
mutated allele of the light subunit might produce a dominant defect,
whereas 1 mutated allele of the rBAT heavy subunit would produce a
trafficking defect. Second, the light subunit might associate with a
protein other than rBAT and express cystine transport activity in a
different proximal tubular segment. In situ hybridization and
immunolocalization studies showed expression of the light subunit in the
epithelial cells of the proximal straight tubule, like the heavy
subunit, but higher expression in the proximal convoluted tubule. Most
of the renal cystine reabsorption occurs in the proximal convoluted
tubule via a low-affinity system not identified at the molecular level.
If the SLC7A9 gene also encodes this transport system, a partial defect
in this major renal reabsorption mechanism would explain the
incompletely recessive phenotype of non-type I cystinuria.

The International Cystinuria Consortium (2001) reported the genomic
structure of SLC7A9 and 28 new mutations in this gene that, together
with 7 previously reported, characterized 79% of the mutant alleles in
61 non-type I cystinuria patients. Therefore, SLC7A9 appears to be the
main non-type I cystinuria gene. The most frequent SLC7A9 missense
mutations found were gly105 to arg (G105R; 604144.0002), val170 to met
(V170M; 604144.0001), ala182 to thr (A182T; 604144.0003), and arg333 to
trp (R333W; 604144.0008). Among heterozygotes carrying these mutations,
A182T heterozygotes showed the lowest urinary excretion values of
cystine and dibasic amino acids, correlating with significant residual
transport activity in vitro. In contrast, mutations G105R, V170M, and
R333W were associated with a complete or nearly complete loss of
transport activity, leading to a more severe urinary phenotype in
heterozygotes. SLC7A9 mutations located in the putative transmembrane
domains of b(0,+)AT and affecting conserved amino acid residues with a
small side chain were associated with a severe phenotype, while
mutations in nonconserved residues gave rise to a mild phenotype. The
authors presented a genotype-phenotype correlation in non-type I
cystinuria, and hypothesized that a mild urinary phenotype in
heterozygotes may be associated with mutations permitting significant
residual transport activity.

Dello Strologo et al. (2002) studied the amino acid excretion patterns
of 189 heterozygotes with mutations in either SLC3A1 or SLC7A9. All
SLC3A1 carriers and 14% of SLC7A9 carriers showed a normal amino acid
urinary pattern (type I phenotype). The remainder of the SLC7A9 carriers
showed the non-I phenotype: 80.5% were type III and 5.5%, type II. Dello
Strologo et al. (2002) concluded that the traditional classification of
cystinuria patients was imprecise and proposed a new classification
based on genotype: type A, due to mutation in the SLC3A1 gene; type B,
due to mutation in the SLC7A9 gene; and type AB, due to a mutation in
both the SLC3A1 and SLC7A9 genes.

Leclerc et al. (2002) identified 2 missense mutations in the SLC7A9 gene
(see 604144.0009 and 604144.0010) linked to type I alleles in a type I
homozygote and in a patient with mixed (I/II) cystinuria, respectively.
They also found that a single SLC7A9 mutation (799insA; see 601411.0011)
was present on 2 type II and 2 type III alleles in 4 patients with mixed
cystinuria, suggesting that type II and type III cystinuria may be
caused by the same mutation and, therefore, that other factors must
influence urinary cystine excretion.

Harnevik et al. (2003) analyzed the SLC3A1 and SLC7A9 genes in 16
unclassified Swedish cystinuria patients, 15 of whom were stone-forming.
In 1 of the stone-forming patients, Harnevik et al. (2001) had
previously identified compound heterozygosity for mutations in the
SLC3A1 gene (see 104614.0001 and 104614.0008); this patient was found by
Harnevik et al. (2003) to have a mutation in the SLC7A9 gene
(604144.0010) as well. In 9 patients, only 1 mutation in SLC3A1 was
found; 1 patient had only 1 mutation in SLC7A9; and in 4 patients, no
mutations were identified. Harnevik et al. (2003) suggested that other
mechanisms of gene inactivation, such as gene silencing, or additional
genes may contribute to the pathogenesis of cystinuria.

Font-Llitjos et al. (2005) classified 164 unrelated cystinuria patients
and their relatives on the basis of urine excretion of cystine and
dibasic amino acids by obligate heterozygotes and screened for mutations
in the SLC3A1 and SLC7A9 genes. They identified phenotype I
heterozygotes with mutations in SLC7A9 (e.g., 604144.0001-604144.0004
and 604144.0012) and phenotype non-I heterozygotes with duplication of
exons 5 to 9 of the SLC3A1 gene (104614.0007). Font-Llitjos et al.
(2005) also identified 2 individuals of mixed phenotype and digenic
inheritance with 3 mutations each: 1 had a mutation in each SLC3A1
allele and a mutation in 1 SLC7A9 allele (104614.0001, 104614.0007, and
604144.0013, respectively), and the other had a mutation in each SLC7A9
allele and a mutation in 1 SLC3A1 allele (604144.0002, 604144.0012, and
104614.0001, respectively).

In a brother and sister with isolated hypercystinuria previously
reported by Brodehl et al. (1967), Eggermann et al. (2007) identified a
likely causative mutation in the SLC7A9 gene (T123M; 604144.0014). Both
sibs, who had never formed urinary stones, also carried an I260M variant
in the SLC7A9 gene that was not found in more than 100 controls;
however, it was also present in their healthy older sister who had
normal aminoaciduria values, and Eggermann et al. (2007) concluded that
I260M is a rare polymorphism. The female proband had also been noted to
have isolated hypoparathyroidism by Brodehl et al. (1967); during
follow-up with Eggermann et al. (2007), she was diagnosed with
autoimmune polyendocrinopathy type I (APS1; 240300) and found to be
compound heterozygous for 2 common mutations in the AIRE1 gene
(607358.0001 and 607358.0003), which were not found in her healthy
sister or her brother.

Barbosa et al. (2012) reported 12 Portuguese probands with cystinuria,
who were classified as homozygous (7 patients) or heterozygous non-type
I (5 patients) according to the concentration of cystine in the urine.
Among the 7 homozygous patients, 6 had onset of lithiasis or urinary
tract infection in the first or second decades. The seventh patient was
ascertained in infancy due to neonatal hypotonia. The 6 patients with
urinary symptoms all had relatives with lithiasis. Among the 5 non-type
I patients diagnosed as children, 2 presented with lithiasis and 2 were
ascertained during workup for developmental delay and autism spectrum
disorder, respectively. Molecular analysis showed that 6 of the 7
homozygous patients had 2 mutations in the SLC3A1 gene (see, e.g.,
104614.0001; 104614.0007; 104614.0009). Three of the patients were
compound heterozygous for the exon 5-9 duplication (104614.0007) and
another pathogenic SLC3A1 mutation. The seventh patient had 1 mutation
in the SLC7A9 gene and another variant in the SLC7A9 gene that may have
contributed to the disorder. Four of the 5 non-type I patients had a
mutation in the SCL7A9 gene; 1 patient was heterozygous for the exon 5-9
duplication in SLC3A1. Overall, the most common pathogenic mutations in
both genes were large genomic rearrangements (33.3% of mutant alleles)
and M467T in SLC3A1 (104614.0001) (11.1% of mutant alleles).

PATHOGENESIS

Bartoccioni et al. (2008) analyzed assembly of wildtype SLC3A1 and type
I cystinuria SLC3A1 mutants with SLC7A9 and found that most of the
transmembrane domain L89P-mutant SLC3A1 did not heterodimerize with
SLC7A9 and was degraded, but a few L89P mutant/SLC7A9 heterodimers were
stable, consistent with assembly rather than folding defects. Mutants of
the SLC3A1 extracellular domain (e.g., M467T, 604144.0001; M467K,
604144.0002; T216M; and R365W) efficiently assembled with SLC7A9 but
were subsequently degraded. Bartoccioni et al. (2008) suggested that
biogenesis occurs in 2 steps, with early assembly of the subunits
followed by folding of the SLC3A1 extracellular domain, and that defects
in either of these steps lead to the type I cystinuria phenotype.

POPULATION GENETICS

The overall prevalence of cystinuria is approximately 1 in 7,000
neonates, ranging from 1 in 2,500 neonates in Libyan Jews to 1 in
100,000 among Swedes (review by Barbosa et al., 2012).

ANIMAL MODEL

McNamara et al. (1989) found that the cystine defect in cystinuric
stone-forming dogs is reflected in isolated brush-border membranes,
whereas the alteration responsible for the cystinuria of Basenji dogs
with Fanconi syndrome did not appear to have a membrane locus.

In an N-ethyl-N-nitrosourea mutagenesis screen for recessive mutations,
Peters et al. (2003) identified a mutant mouse with elevated
concentrations of lysine, arginine, and ornithine in urine, displaying
the clinical syndrome of urolithiasis and its complications. Positional
cloning of the causative mutation identified a missense mutation in
Slc3a1, leading to an amino acid exchange D140G in the extracellular
domain of the rBAT protein. The mouse model mimics the etiology and
clinical manifestations of human cystinuria type I.

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39. Sharland, M.; Jones, M.; Bain, M.; Chalmers, R.; Hammond, J.;
Patton, M. A.: Balanced translocation (14;20) in a mentally handicapped
child with cystinuria. J. Med. Genet. 29: 507-508, 1992.

40. Stephens, A. D.: Cystinuria and its treatment: 25 years experience
at St. Bartholomew's Hospital. J. Inherit. Metab. Dis. 12: 197-209,
1989.

41. Stoller, M. L.; Bruce, J. E.; Bruce, C. A.; Foroud, T.; Kirkwood,
S. C.; Stambrook, P. J.: Linkage of type II and type III cystinuria
to 19q13.1: codominant inheritance of two cystinuric alleles at 19q13.1
produces an extreme stone-forming phenotype. Am. J. Med. Genet. 86:
134-139, 1999.

42. Thier, S. O.; Segal, S.: Cystinuria.In: Stanbury, J. B.; Wyngaarden,
J. B.; Fredrickson, D. S.: The Metabolic Basis of Inherited Disease.
New York: McGraw-Hill (pub.) (4th ed.): 1978. Pp. 1504-1519.

43. Wartenfeld, R.; Golomb, E.; Katz, G.; Bale, S. J.; Goldman, B.;
Pras, M.; Kastner, D. L.; Pras, E.: Molecular analysis of cystinuria
in Libyan Jews: exclusion of the SLC3A1 gene and mapping of a new
locus on 19q. Am. J. Hum. Genet. 60: 617-624, 1997.

44. Weinberger, A.; Sperling, O.; Rabinovitz, M.; Brosh, S.; Adam,
A.; De Vries, A.: High frequency of cystinuria among Jews of Libyan
origin. Hum. Hered. 24: 568-572, 1974.

45. Wollaston, W. H.: On cystic oxide, a new species of urinary calculus. Phil.
Trans. Roy. Soc. London 100: 223-230, 1810.

*FIELD* CS
INHERITANCE:
Autosomal dominant;
Autosomal recessive

GENITOURINARY:
Urinary tract infections;
[Kidneys];
Nephrolithiasis;
Renal failure;
[Ureters];
Nephrolithiasis;
[Bladder];
Nephrolithiasis

LABORATORY ABNORMALITIES:
Increased urinary excretion of cystine;
Increase urinary excretion of lysine, arginine, and ornithine

MISCELLANEOUS:
Onset in first or second decade;
Variable severity;
Both recessive and dominant inheritance have been reported;
Some heterozygotes may have increased urinary excretion of cystine
and may develop stones

MOLECULAR BASIS:
Caused by mutation in the solute carrier family 3 (cystine, dibasic,
and neutral amino acid transporter), member 1 gene (SLC3A1, 104614.0001);
Caused by mutation in the solute carrier family 7 (cationic amino
acid transporter, y+ system), member 9 gene (SLC7A9, 604144.0001)

*FIELD* CN
Cassandra L. Kniffin - revised: 9/11/2012

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

*FIELD* ED
joanna: 09/14/2012
ckniffin: 9/11/2012

*FIELD* CN
Cassandra L. Kniffin - updated: 9/11/2012
Marla J. F. O'Neill - updated: 12/17/2009
Marla J. F. O'Neill - updated: 7/17/2007
George E. Tiller - updated: 3/27/2006
Marla J. F. O'Neill - reorganized: 3/7/2006
Marla J. F. O'Neill - updated: 3/7/2006

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
carol: 09/12/2012
ckniffin: 9/11/2012
carol: 12/5/2011
carol: 12/3/2010
wwang: 1/5/2010
terry: 12/17/2009
terry: 6/3/2009
terry: 2/24/2009
wwang: 7/18/2007
terry: 7/17/2007
alopez: 3/27/2006
carol: 3/7/2006
carol: 2/28/2006
terry: 4/18/2005
carol: 11/24/2003
terry: 11/17/1998
mark: 3/15/1996
terry: 3/12/1996
mark: 12/20/1995
terry: 11/6/1995
mark: 10/19/1995
davew: 8/19/1994
pfoster: 4/22/1994
carol: 4/11/1994
mimadm: 2/19/1994

MIM 604144
*RECORD*
*FIELD* NO
604144
*FIELD* TI
*604144 SOLUTE CARRIER FAMILY 7 (CATIONIC AMINO ACID TRANSPORTER, y+ SYSTEM),
MEMBER 9; SLC7A9
read more*FIELD* TX

CLONING

The International Cystinuria Consortium (1999), which is comprised of
workers from 5 groups, identified a human kidney SLC7A9 cDNA. The SLC7A9
cDNA is polyadenylated and contains an open reading frame encoding a
487-amino acid protein. The protein, designated b(0,+)AT for b(0,+)
amino acid transporter, belongs to a family of light subunits of amino
acid transporters expressed in kidney, liver, small intestine, and
placenta. Northern blot analysis revealed that the SLC7A9 gene was
expressed as an approximately 1.9-kb transcript in these tissues. The
tissue distribution of b(0,+)AT was consistent with that of a renal
basic amino acid transporter (see SLC3A1, or rBAT; 104614) light
subunit. As expected, b(0,+)AT brought rBAT to the plasma membrane in
cotransfected COS cells. In contrast, transfection of rBAT alone
resulted in the blockage of the expressed protein in the endoplasmic
reticulum. These data suggested that b(0,+)AT is indeed the light
subunit of b(0,+).

MAPPING

By YAC library and BAC contig screening, the International Cystinuria
Consortium (1999) mapped the SLC7A9 gene to chromosome 19 between
microsatellite markers D19S776 and D19S786, in the refined locus for
non-type I cystinuria (220100), suggesting SLC7A9 as a candidate gene
for that form of the disorder.

MOLECULAR GENETICS

The International Cystinuria Consortium (1999) identified mutations in
the SLC7A9 gene in Libyan Jewish, North American, Italian, and Spanish
non-type I cystinuria patients. The Libyan Jewish patients were
homozygous for a founder missense mutation (V170M; 604144.0001) that
abolished b(0,+)AT amino acid uptake activity when cotransfected with
rBAT in COS cells. In other patients, they identified 4 missense
mutations and 2 frameshift mutations. The data established that
mutations in the SLC7A9 gene cause non-type I cystinuria.

The International Cystinuria Consortium (1999) suggested that the
functional studies of b(0,+)AT and rBAT which they described and the
fact that mutations in their genes cause non-type I and type I
cystinuria (220100), respectively, supported the hypothesis that
b(0,+)AT and rBAT are the light and heavy subunits, respectively, of the
amino acid transporter b(0,+). Consistent with this, they stated that
the 2 subunits form a disulfide-linked heterodimer, and that a fusion of
the 2 proteins expressed b(0,+) transport activity in oocytes.

The International Cystinuria Consortium (2001) reported the genomic
structure of SLC7A9 (13 exons) and 28 new mutations in this gene that,
together with 7 previously reported, characterized 79% of the mutant
alleles in 61 non-type I cystinuria patients. Therefore, SLC7A9 appears
to be the main non-type I cystinuria gene. The most frequent SLC7A9
missense mutations found were gly105 to arg (G105R; 604144.0002), val170
to met (V170M; 604144.0001), ala182 to thr (A182T; 604144.0003), and
arg333 to trp (R333W; 604144.0008). Among heterozygotes carrying these
mutations, A182T heterozygotes showed the lowest urinary excretion
values of cystine and dibasic amino acids, correlating with significant
residual transport activity in vitro. In contrast, mutations G105R,
V170M, and R333W were associated with a complete or nearly complete loss
of transport activity, leading to a more severe urinary phenotype in
heterozygotes. SLC7A9 mutations located in the putative transmembrane
domains of b(0,+)AT and affecting conserved amino acid residues with a
small side chain were associated with a severe phenotype, while
mutations in nonconserved residues gave rise to a mild phenotype. The
authors presented a genotype-phenotype correlation in non-type I
cystinuria, and hypothesized that a mild urinary phenotype in
heterozygotes may be associated with mutations permitting significant
residual transport activity.

Dello Strologo et al. (2002) studied the amino acid excretion patterns
of 189 heterozygotes with mutations in either SLC3A1 or SLC7A9. All
SLC3A1 carriers and 14% of SLC7A9 carriers showed a normal amino acid
urinary pattern (type I phenotype). The remainder of the SLC7A9 carriers
showed the non-I phenotype: 80.5% were type III and 5.5%, type II. Dello
Strologo et al. (2002) concluded that the traditional classification of
cystinuria patients was imprecise and proposed a new classification
based on genotype: type A, due to mutation in the SLC3A1 gene; type B,
due to mutation in the SLC7A9 gene; and type AB, due to mutation in both
the SLC3A1 and SLC7A9 genes.

Leclerc et al. (2002) identified 2 missense mutations in the SLC7A9 gene
(see 604144.0009 and 604144.0010) linked to type I alleles in a type I
homozygote and in a patient with mixed (I/II) cystinuria, respectively.
They also found that a single SLC7A9 mutation (799insA, see 601411.0011)
was present on 2 type II and 2 type III alleles in 4 patients with mixed
cystinuria, suggesting that type II and type III cystinuria may be
caused by the same mutation and, therefore, that other factors must
influence urinary cystine excretion.

In a 34-year-old Swedish man with cystinuria and cystine stones, in whom
Harnevik et al. (2001) had previously identified compound heterozygosity
for mutations in SLC3A1 (see 104614.0001 and 104614.0008), Harnevik et
al. (2003) identified a mutation (604144.0010) in the SLC7A9 gene as
well.

In a study of 164 unrelated cystinuria patients and their relatives,
Font-Llitjos et al. (2005) found 20 heterozygotes with mutations in
SLC7A9 who had a type I phenotype (e.g., 604144.0001-604144.0004,
604144.0012). They also identified 2 families with mixed cystinuria and
mutations in both genes who had aminoaciduria phenotypes suggesting
digenic inheritance (see 604144.0002 and 604144.0013).

In a brother and sister with isolated hypercystinuria previously
reported by Brodehl et al. (1967), Eggermann et al. (2007) identified a
likely causative mutation in the SLC7A9 gene (T123M; 604144.0014). Both
sibs also carried an I260M variant in the SLC7A9 gene that was not found
in more than 100 controls; however, it was also present in their healthy
older sister who had normal aminoaciduria values. Eggermann et al.
(2007) concluded that I260M is a rare polymorphism.

ANIMAL MODEL

Feliubadalo et al. (2003) generated Slc7a9-deficient mice. Homozygous
mutant mice ('stones' mice) expressed no b(0,+)AT protein but
significant amounts of the rBAT protein covalently linked to
unidentified light subunit(s). Homozygous mutant mice showed massive
excretion of cystine and dibasic amino acids, whereas heterozygotes
showed lower but significant hyperexcretion of these amino acids
(phenotype non-I). Approximately 40% of the homozygous mutants developed
cystine calculi in the urinary system during the first month of life
which grew throughout the life span of the animals. Histopathologic
renal changes included tubular and pelvic dilatation, tubular necrosis,
tubular hyaline droplets, and chronic interstitial nephritis. That some
stones mice, generated in a mixed genetic background, developed cystine
calculi from an early age, while others did not develop them in their
first year of life, suggested the involvement of modifier genes in the
lithiasis phenotype.

*FIELD* AV
.0001
CYSTINURIA
SLC7A9, VAL170MET

In 23 Libyan Jewish patients with cystinuria defined as non-type I (see
220100), the International Cystinuria Consortium (1999) identified a
homozygous 693G-A transition in the SLC7A9 gene, resulting in a
val170-to-met (V170M) substitution. The authors stated that these
patients showed a urinary phenotype range between type II and type III
cystinuria; 20 patients were homozygous for the mutation and 3 were
heterozygous.

By applying 2 methods of linkage disequilibrium analysis, Colombo (2000)
estimated that the founder mutation V170M in Libyan Jews occurred at
least 14 to 15 generations ago. These results placed the most recent
common ancestor bearing the mutation back to 1500 to 1530, at, or
before, the time of settlement of a small number of often intramarrying
Jewish families of Iberian origin in Libya following their expulsion
from Spain in 1492 and Portugal in 1497.

In 4 of 16 heterozygotes with the V170M mutation, Font-Llitjos et al.
(2005) found the urinary excretion of cystine and dibasic amino acids to
be within the range of type I heterozygotes.

.0002
CYSTINURIA
SLC7A9, GLY105ARG

In North American and Italian patients with cystinuria defined as
non-type I (see 220100), the International Cystinuria Consortium (1999)
identified a G-to-A transition at nucleotide 496 of the SLC7A9 gene,
resulting in a gly105-to-arg substitution. Some of the patients were
homozygous and others were heterozygous for the mutation. This was the
most common mutation identified in North American and Italian patients
as the cause of this disorder.

In 1 of 32 heterozygotes with the G105R mutation, Font-Llitjos et al.
(2005) found the urinary excretion of cystine and dibasic amino acids to
be within the range of type I heterozygotes.

In a patient with a mixed cystinuria phenotype (see 220100),
Font-Llitjos et al. (2005) identified 3 mutations: compound
heterozygosity for the SLC7A9 mutations G105R and Y232C (604144.0012),
and an M467T substitution in the SLC3A1 gene (104614.0001). The patient
had very low urine amino acid levels. Double heterozygotes in this
family (G105R/+ and M467T/+) had higher urinary excretion levels than
single heterozygotes (G105R/+ or M467T/+), suggesting digenic
cystinuria.

.0003
CYSTINURIA
SLC7A9, ALA182THR

In 4 unrelated Spanish patients and 1 Italian patient with cystinuria
defined as non-type I (see 220100), the International Cystinuria
Consortium (1999) identified heterozygosity for a G-to-A transition at
nucleotide 729 of the SLC7A9 gene, resulting in an ala182-to-thr
substitution. These patients had a very mild phenotype similar to type I
or mild type III phenotypes.

In 6 of 11 heterozygotes with the A182T mutation, Font-Llitjos et al.
(2005) found the urinary excretion of cystine and dibasic amino acids to
be within the range of type I heterozygotes.

.0004
CYSTINURIA
SLC7A9, GLY195ARG

In an Italian patient with cystinuria defined as non-type I (see
220100), the International Cystinuria Consortium (1999) identified a
G-to-A transition at nucleotide 768 of the SLC7A9 gene, resulting in a
gly195-to-arg (G195R) substitution.

In 1 of 2 heterozygotes with the G195R mutation, Font-Llitjos et al.
(2005) found the urinary excretion of cystine and dibasic amino acids to
be within the range of type I heterozygotes.

.0005
CYSTINURIA
SLC7A9, GLY259ARG

In an Italian female with cystinuria defined as non-type I (see 220100)
whose parents were consanguineous, the International Cystinuria
Consortium (1999) identified homozygosity for a G-to-A transition at
nucleotide 960, resulting in a gly259-to-arg substitution.

.0006
CYSTINURIA
SLC7A9, 2-BP DEL, 596TG

In a North American patient with cystinuria defined as non-type I (see
220100), the International Cystinuria Consortium (1999) identified a
2-bp deletion at nucleotide 596 of the SLC7A9 gene, resulting in a
frameshift, in homozygous or hemizygous state.

.0007
CYSTINURIA
SLC7A9, 1-BP INS, 520T

In a North American patient with cystinuria defined as non-type I (see
220100), the International Cystinuria Consortium (1999) identified a
1-bp insertion at nucleotide 520 of the SLC7A9 gene, resulting in a
frameshift.

.0008
CYSTINURIA
SLC7A9, ARG333TRP

In patients with cystinuria defined as non-type I (see 220100), the
International Cystinuria Consortium (2001) identified a C-to-T
transition at nucleotide 1182, resulting in an arg333-to-trp
substitution. The mutation was found in 8% of mutant alleles, third in
frequency behind gly105 to arg (604144.0002) and val170 to met
(604144.0001).

.0009
CYSTINURIA
SLC7A9, ILE44THR

In a patient with cystinuria defined as type I (220100), Leclerc et al.
(2002) identified a 316T-C transition in exon 3 of the SLC7A9 gene,
resulting in an ile44-to-thr (I44T) substitution. The patient's father
was heterozygous for this mutation; the maternal mutation was unknown.

.0010
CYSTINURIA
SLC7A9, PRO261LEU

In a patient with cystinuria defined as mixed (type I/II) (see 220100),
Leclerc et al. (2002) identified compound heterozygosity in the SLC7A9
gene: the patient had a 967C-T transition in exon 8 resulting in a
pro261-to-leu (P261L) substitution on the I allele, and a frameshift
mutation in exon 6 (604144.0011) on the II allele. The patient's father
was heterozygous for the former and his mother for the latter.

In a 34-year-old Swedish man with cystinuria and cystine stones
(220100), Harnevik et al. (2001) identified compound heterozygosity for
an M467T substitution (104614.0001) in 1 allele of the SLC3A1 gene and
an R362H substitution (104614.0008) in the other allele of the SLC3A1
gene. This patient was subsequently found by Harnevik et al. (2003) to
have a mutation in the SLC7A9 gene (604144.0010) as well.

.0011
CYSTINURIA
SLC7A9, 1-BP INS, 799A

In 4 patients with cystinuria defined as mixed (type I/II) (see 220100),
Leclerc et al. (2002) identified a 1-bp insertion (799insA) in exon 6 of
the SLC7A9 gene, predicted to create a downstream termination signal.
The mutation was heterozygous in all 4 patients and was found on type II
alleles in 2 of the patients and on type III alleles in the other 2.
Leclerc et al. (2002) suggested that type II and type III cystinuria may
be caused by the same mutation and that other factors must therefore
influence urinary cystine excretion.

See 604144.0010 and Leclerc et al. (2002).

.0012
CYSTINURIA
SLC7A9, TYR232CYS

In a patient with cystinuria defined as type I (see 220100),
Font-Llitjos et al. (2005) identified a 695A-to-G transition in exon 6
of the SLC7A9 gene, resulting in a tyr232cys (Y232C) substitution.

See 604144.0001 and Font-Llitjos et al. (2005).

.0013
CYSTINURIA
SLC7A9, 789+2T-C

In 2 sisters with a mixed cystinuria phenotype (see 220100),
Font-Llitjos et al. (2005) identified 3 mutations: a 789+2C-T transition
in 1 allele of the SLC7A9 gene, and an M467T (104614.0001) substitution
in 1 allele of the SLC3A1 gene and a duplication of exons 5 to 9 of the
SLC3A1 gene (104614.0007) in the other allele. One sister had very high
amino acid levels in the urine; the other was on dialysis. M467T
heterozygotes in this family had a type I excretion pattern, whereas
heterozygotes with duplication of exons 5 to 9 had a non-I phenotype.
The authors stated that the 789+2T-C mutation is associated with high
aminoaciduria in heterozygotes.

.0014
CYSTINURIA
SLC7A9, THR123MET

In a non-type I cystinuria patient and in 2 patients with untyped
cystinuria (see 220100), the International Cystinuria Consortium (2001)
identified heterozygosity for a 553C-T transition in exon 4 of the
SLC7A9 gene, resulting in a thr123-to-met (T123M) substitution.

In a brother and sister with isolated hypercystinuria previously
reported by Brodehl et al. (1967), Eggermann et al. (2007) identified
the T123M mutation in the SLC7A9 gene.

.0015
CYSTINURIA
SLC7A9, IVS5AS, C-A, -3

In 2 Italian patients with cystinuria (220100), Schmidt et al. (2005)
identified a C-to-A transversion in intron 5 of the SLC7A9 gene,
resulting in a splice acceptor site mutation. Functional expression
studies in COS-7 cells showed that the mutation resulted in 2 spliced
mRNA products missing exon 6 and exons 5 and 6, respectively. Both
patients were compound heterozygotes; one also had a large SLC7A9
deletion, and the other had an R333W mutation (604144.0008).

*FIELD* RF
1. Brodehl, J.; Gellissen, K.; Kowalewski, S.: Isolierter Defekt
der tubulaeren Cystin-Rueckresorption in einer Familie mit idiopathischem
Hypoparathyroidismus. Klin. Wschr. 45: 38-40, 1967.

2. Colombo, R.: Dating the origin of the V170M mutation causing non-type
I cystinuria in Libyan Jews by linkage disequilibrium and physical
mapping of the SLC7A9 gene. Genomics 69: 131-134, 2000.

3. Dello Strologo, L.; Pras, E.; Pontesilli, C.; Beccia, E.; Ricci-Barbini,
V.; de Sanctis, L.; Ponzone, A.; Gallucci, M.; Bisceglia, L.; Zelante,
L.; Jimenez-Vidal, M.; Font, M.; Zorzano, A.; Rousaud, F.; Nunes,
V.; Gasparini, P.; Palacin, M.; Rizzoni, G.: Comparison between SLC3A1
and SLC7A9 cystinuria patients and carriers: a need for a new classification. J.
Am. Soc. Nephrol. 13: 2547-2553, 2002.

4. Eggermann, T.; Elbracht, M.; Haverkamp, F.; Schmidt, C.; Zerres,
K.: Isolated cystinuria (OMIM 238200) is not a separate entity but
is caused by a mutation in the cystinuria gene SLC7A9. (Letter) Clin.
Genet. 71: 597-598, 2007.

5. Feliubadalo, L.; Arbones, M. L.; Manas, S.; Chillaron, J.; Visa,
J.; Rodes, M.; Rousaud, F.; Zorzano, A.; Palacin, M.; Nunes, V.:
Slc7a9-deficient mice develop cystinuria non-I and cystine urolithiasis. Hum.
Molec. Genet. 12: 2097-2108, 2003.

6. Font-Llitjos, M.; Jimenez-Vidal, M.; Bisceglia, L.; Di Perna, M.;
de Sanctis, L.; Rousaud, F.; Zelante, L.; Palacin, M.; Nunes, V:
New insights into cystinuria: 40 new mutations, genotype-phenotype
correlation, and digenic inheritance causing partial phenotype. J.
Med. Genet. 42: 58-68, 2005.

7. Harnevik, L.; Fjellstedt, E.; Molbaek, A.; Denneberg, T.; Soderkvist,
P.: Mutation analysis of SLC7A9 in cystinuria patients in Sweden. Genet.
Test. 7: 13-20, 2003.

8. Harnevik, L.; Fjellstedt, E.; Molbaek, A.; Tiselius, H.-G.; Denneberg,
T.; Soderkvist, P.: Identification of 12 novel mutations in the SLC3A1
gene in Swedish cystinuria patients. Hum. Mutat. 18: 516-525, 2001.

9. International Cystinuria Consortium: Functional analysis of
mutations in SLC7A9, and genotype-phenotype correlation in non-type
I cystinuria. Hum. Molec. Genet. 10: 305-316, 2001.

10. International Cystinuria Consortium: Non-type I cystinuria
caused by mutations in SLC7A9, encoding a subunit (b(0,+)AT) of rBAT. Nature
Genet. 23: 52-57, 1999.

11. Leclerc, D.; Boutros, M.; Suh, D.; Wu, Q.; Palacin, M.; Ellis,
J. R.; Goodyer, P.; Rozen, R.: SLC7A9 mutations in all three cystinuria
subtypes. Kidney Int. 62: 1550-1559, 2002.

12. Schmidt, C.; Lahme, S.; Zerres, K.; Eggermann, T.: Functional
analysis of a new splice site mutation, c.605-3C-A, in the cystinuria
gene SLC7A9 leading to exon skipping. Molec. Genet. Metab. 84: 172-175,
2005.

*FIELD* CN
Cassandra L. Kniffin - updated: 1/14/2008
Marla J. F. O'Neill - updated: 7/17/2007
George E. Tiller - updated: 3/28/2006
Marla J. F. O'Neill - reorganized: 3/7/2006
Marla J. F. O'Neill - updated: 2/28/2006
George E. Tiller - updated: 4/23/2001
Paul J. Converse - updated: 12/11/2000

*FIELD* CD
Victor A. McKusick: 8/30/1999

*FIELD* ED
ckniffin: 09/12/2012
carol: 1/21/2008
ckniffin: 1/14/2008
carol: 8/13/2007
wwang: 7/18/2007
terry: 7/17/2007
alopez: 3/28/2006
carol: 3/7/2006
carol: 2/28/2006
cwells: 5/9/2001
cwells: 5/1/2001
cwells: 4/23/2001
mgross: 12/12/2000
terry: 12/11/2000
alopez: 8/30/1999