Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (b(o,+)AT) of rBAT

Lídia Feliubadaló; Mariona Font; Jesús Purroy; Ferran Rousaud; Xavier Estivill; Virginia Nunes; Eliahu Golomb; Michael Centola; Ivona Aksentijevich; Yitshak Kreiss; Boleslaw Goldman; Mordechai Pras; Daniel L. Kastner; Elon Pras; Paolo Gasparini; Luigi Bisceglia; Ercole Beccia; Michele Gallucci; Luisa De Sanctis; Alberto Ponzone; Gian Franco Rizzoni; Leopoldo Zelante; Maria Teresa Bassi; Alfred L. George; Marta Manzoni; Alessandro De Grandi; Mirko Riboni; John K. Endsley; Andrea Ballabio; Giuseppe Borsani; Núria Reig; Esperanza Fernández; Raúl Estévez; Marta Pineda; David Torrents; Marta Camps; Jorge Lloberas; Antonio Zorzano; Manuel Palacin

doi:10.1038/12652

Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (b(o,+)AT) of rBAT

Lídia Feliubadaló, Mariona Font, Jesús Purroy, Ferran Rousaud, Xavier Estivill, Virginia Nunes, Eliahu Golomb, Michael Centola, Ivona Aksentijevich, Yitshak Kreiss, Boleslaw Goldman, Mordechai Pras, Daniel L. Kastner, Elon Pras, Paolo Gasparini, Luigi Bisceglia, Ercole Beccia, Michele Gallucci, Luisa De Sanctis, Alberto PonzoneGian Franco Rizzoni, Leopoldo Zelante, Maria Teresa Bassi, Alfred L. George, Marta Manzoni, Alessandro De Grandi, Mirko Riboni, John K. Endsley, Andrea Ballabio, Giuseppe Borsani, Núria Reig, Esperanza Fernández, Raúl Estévez, Marta Pineda, David Torrents, Marta Camps, Jorge Lloberas, Antonio Zorzano, Manuel Palacin^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

312 Scopus citations

Abstract

Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref, 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (refs 3,4). We have identified a new transcript, encoding a protein (b(o,+)AT, for b(o,+) amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co- transfection of b(o,+)AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b(o,+)AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that b(o,+)AT is the light subunit of rBAT.

Original language	English (US)
Pages (from-to)	52-57
Number of pages	6
Journal	Nature Genetics
Volume	23
Issue number	1
DOIs	https://doi.org/10.1038/12652
State	Published - Sep 1999

Funding

We thank the families for contributing; A. Ros for cell culture; J. García for technical assistance; the YAC Screening Center at San Raffaele Biomedical Science Park and the Serveis Científico-Tècnics de la Universitat de Barcelona for some of the sequences; and R. Rycroft for editorial help. This research was supported in part by Dirección General de Investigación Científica y Técnica research grant PM96/0060 from Spain to M.P.; BIOMED2 CT98-BMH4-3514 EC grant to V.N., M.P. and P.G. and CT97-BMH4-2284 (EURO-IMAGE) EC grant to X.E. and A.B.; Fundació La Marató-TV3 research grant 981930 to V.N. and M.P.; Generalitat de Catalunya Grants 1997 SGR 121 and 1997 SGR 00085, Italian Telethon Foundation grants (E556) to L.Z.; the Merck Genome Research Institute (MGRI grant 37); and Ministero Italiano della Sanità grant to P.G.. E.F. and D.T. are recipients of fellowships from the Ministerio de Educación y Cultura (Spain); M.P., L.F., J.P., M.F., N.R. and R.E. are recipients of fellowships from the Comissió Interdepartamental de Recerca i Innovació Tecnològica (Catalonia, Spain); and J.K.E. was supported by a research fellowship from The National Kidney Foundation.

ASJC Scopus subject areas

Genetics

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10.1038/12652

Cite this

Feliubadaló, L., Font, M., Purroy, J., Rousaud, F., Estivill, X., Nunes, V., Golomb, E., Centola, M., Aksentijevich, I., Kreiss, Y., Goldman, B., Pras, M., Kastner, D. L., Pras, E., Gasparini, P., Bisceglia, L., Beccia, E., Gallucci, M., De Sanctis, L., ... Palacin, M. (1999). Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (b(o,+)AT) of rBAT. Nature Genetics, 23(1), 52-57. https://doi.org/10.1038/12652

@article{3e55b43b0d6443489ad837fecaffb385,

title = "Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (b(o,+)AT) of rBAT",

abstract = "Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref, 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (refs 3,4). We have identified a new transcript, encoding a protein (b(o,+)AT, for b(o,+) amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co- transfection of b(o,+)AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b(o,+)AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that b(o,+)AT is the light subunit of rBAT.",

author = "L{\'i}dia Feliubadal{\'o} and Mariona Font and Jes{\'u}s Purroy and Ferran Rousaud and Xavier Estivill and Virginia Nunes and Eliahu Golomb and Michael Centola and Ivona Aksentijevich and Yitshak Kreiss and Boleslaw Goldman and Mordechai Pras and Kastner, {Daniel L.} and Elon Pras and Paolo Gasparini and Luigi Bisceglia and Ercole Beccia and Michele Gallucci and {De Sanctis}, Luisa and Alberto Ponzone and Rizzoni, {Gian Franco} and Leopoldo Zelante and Bassi, {Maria Teresa} and George, {Alfred L.} and Marta Manzoni and {De Grandi}, Alessandro and Mirko Riboni and Endsley, {John K.} and Andrea Ballabio and Giuseppe Borsani and N{\'u}ria Reig and Esperanza Fern{\'a}ndez and Ra{\'u}l Est{\'e}vez and Marta Pineda and David Torrents and Marta Camps and Jorge Lloberas and Antonio Zorzano and Manuel Palacin",

note = "Funding Information: We thank the families for contributing; A. Ros for cell culture; J. Garc{\'i}a for technical assistance; the YAC Screening Center at San Raffaele Biomedical Science Park and the Serveis Cient{\'i}fico-T{\`e}cnics de la Universitat de Barcelona for some of the sequences; and R. Rycroft for editorial help. This research was supported in part by Direcci{\'o}n General de Investigaci{\'o}n Cient{\'i}fica y T{\'e}cnica research grant PM96/0060 from Spain to M.P.; BIOMED2 CT98-BMH4-3514 EC grant to V.N., M.P. and P.G. and CT97-BMH4-2284 (EURO-IMAGE) EC grant to X.E. and A.B.; Fundaci{\'o} La Marat{\'o}-TV3 research grant 981930 to V.N. and M.P.; Generalitat de Catalunya Grants 1997 SGR 121 and 1997 SGR 00085, Italian Telethon Foundation grants (E556) to L.Z.; the Merck Genome Research Institute (MGRI grant 37); and Ministero Italiano della Sanit{\`a} grant to P.G.. E.F. and D.T. are recipients of fellowships from the Ministerio de Educaci{\'o}n y Cultura (Spain); M.P., L.F., J.P., M.F., N.R. and R.E. are recipients of fellowships from the Comissi{\'o} Interdepartamental de Recerca i Innovaci{\'o} Tecnol{\`o}gica (Catalonia, Spain); and J.K.E. was supported by a research fellowship from The National Kidney Foundation.",

year = "1999",

month = sep,

doi = "10.1038/12652",

language = "English (US)",

volume = "23",

pages = "52--57",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "1",

}

Feliubadaló, L, Font, M, Purroy, J, Rousaud, F, Estivill, X, Nunes, V, Golomb, E, Centola, M, Aksentijevich, I, Kreiss, Y, Goldman, B, Pras, M, Kastner, DL, Pras, E, Gasparini, P, Bisceglia, L, Beccia, E, Gallucci, M, De Sanctis, L, Ponzone, A, Rizzoni, GF, Zelante, L, Bassi, MT, George, AL, Manzoni, M, De Grandi, A, Riboni, M, Endsley, JK, Ballabio, A, Borsani, G, Reig, N, Fernández, E, Estévez, R, Pineda, M, Torrents, D, Camps, M, Lloberas, J, Zorzano, A & Palacin, M 1999, 'Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (b(o,+)AT) of rBAT', Nature Genetics, vol. 23, no. 1, pp. 52-57. https://doi.org/10.1038/12652

TY - JOUR

T1 - Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (b(o,+)AT) of rBAT

AU - Feliubadaló, Lídia

AU - Font, Mariona

AU - Purroy, Jesús

AU - Rousaud, Ferran

AU - Estivill, Xavier

AU - Nunes, Virginia

AU - Golomb, Eliahu

AU - Centola, Michael

AU - Aksentijevich, Ivona

AU - Kreiss, Yitshak

AU - Goldman, Boleslaw

AU - Pras, Mordechai

AU - Kastner, Daniel L.

AU - Pras, Elon

AU - Gasparini, Paolo

AU - Bisceglia, Luigi

AU - Beccia, Ercole

AU - Gallucci, Michele

AU - De Sanctis, Luisa

AU - Ponzone, Alberto

AU - Rizzoni, Gian Franco

AU - Zelante, Leopoldo

AU - Bassi, Maria Teresa

AU - George, Alfred L.

AU - Manzoni, Marta

AU - De Grandi, Alessandro

AU - Riboni, Mirko

AU - Endsley, John K.

AU - Ballabio, Andrea

AU - Borsani, Giuseppe

AU - Reig, Núria

AU - Fernández, Esperanza

AU - Estévez, Raúl

AU - Pineda, Marta

AU - Torrents, David

AU - Camps, Marta

AU - Lloberas, Jorge

AU - Zorzano, Antonio

AU - Palacin, Manuel

N1 - Funding Information: We thank the families for contributing; A. Ros for cell culture; J. García for technical assistance; the YAC Screening Center at San Raffaele Biomedical Science Park and the Serveis Científico-Tècnics de la Universitat de Barcelona for some of the sequences; and R. Rycroft for editorial help. This research was supported in part by Dirección General de Investigación Científica y Técnica research grant PM96/0060 from Spain to M.P.; BIOMED2 CT98-BMH4-3514 EC grant to V.N., M.P. and P.G. and CT97-BMH4-2284 (EURO-IMAGE) EC grant to X.E. and A.B.; Fundació La Marató-TV3 research grant 981930 to V.N. and M.P.; Generalitat de Catalunya Grants 1997 SGR 121 and 1997 SGR 00085, Italian Telethon Foundation grants (E556) to L.Z.; the Merck Genome Research Institute (MGRI grant 37); and Ministero Italiano della Sanità grant to P.G.. E.F. and D.T. are recipients of fellowships from the Ministerio de Educación y Cultura (Spain); M.P., L.F., J.P., M.F., N.R. and R.E. are recipients of fellowships from the Comissió Interdepartamental de Recerca i Innovació Tecnològica (Catalonia, Spain); and J.K.E. was supported by a research fellowship from The National Kidney Foundation.

PY - 1999/9

Y1 - 1999/9

N2 - Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref, 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (refs 3,4). We have identified a new transcript, encoding a protein (b(o,+)AT, for b(o,+) amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co- transfection of b(o,+)AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b(o,+)AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that b(o,+)AT is the light subunit of rBAT.

AB - Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref, 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (refs 3,4). We have identified a new transcript, encoding a protein (b(o,+)AT, for b(o,+) amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co- transfection of b(o,+)AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b(o,+)AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that b(o,+)AT is the light subunit of rBAT.

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U2 - 10.1038/12652

DO - 10.1038/12652

M3 - Article

C2 - 10471498

AN - SCOPUS:0032821201

SN - 1061-4036

VL - 23

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EP - 57

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (b(o,+)AT) of rBAT

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