{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:47:21Z","timestamp":1791978441160,"version":"4.4.0"},"reference-count":22,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2016,5]]},"abstract":"\n A heterozygous mutation (c.643C>A; p.Q215X) in the monocarboxylate transporter 12-encoding gene\n MCT12<\/jats:italic>\n (also known as\n SLC16A12<\/jats:italic>\n ) that mediates creatine transport was recently identified as the cause of a syndrome with juvenile cataracts, microcornea, and glucosuria in a single family. Whereas the\n MCT12<\/jats:italic>\n mutation cosegregated with the eye phenotype, poor correlation with the glucosuria phenotype did not support a pathogenic role of the mutation in the kidney. Here, we examined MCT12 in the kidney and found that it resides on basolateral membranes of proximal tubules. Patients with\n MCT12<\/jats:italic>\n mutation exhibited reduced plasma levels and increased fractional excretion of guanidinoacetate, but normal creatine levels, suggesting that MCT12 may function as a guanidinoacetate transporter\n in vivo<\/jats:italic>\n . However, functional studies in\n Xenopus<\/jats:italic>\n oocytes revealed that MCT12 transports creatine but not its precursor, guanidinoacetate. Genetic analysis revealed a separate, undescribed heterozygous mutation (c.265G>A; p.A89T) in the sodium\/glucose cotransporter 2-encoding gene\n SGLT2<\/jats:italic>\n (also known as\n SLC5A2<\/jats:italic>\n ) in the family that segregated with the renal glucosuria phenotype. When overexpressed in HEK293 cells, the mutant SGLT2 transporter did not efficiently translocate to the plasma membrane, and displayed greatly reduced transport activity. In summary, our data indicate that MCT12 functions as a basolateral exit pathway for creatine in the proximal tubule. Heterozygous mutation of\n MCT12<\/jats:italic>\n affects systemic levels and renal handling of guanidinoacetate, possibly through an indirect mechanism. Furthermore, our data reveal a digenic syndrome in the index family, with simultaneous\n MCT12<\/jats:italic>\n and\n SGLT2<\/jats:italic>\n mutation. Thus, glucosuria is not part of the\n MCT12<\/jats:italic>\n mutation syndrome.\n <\/jats:p>","DOI":"10.1681\/asn.2015040411","type":"journal-article","created":{"date-parts":[[2015,9,16]],"date-time":"2015-09-16T23:58:38Z","timestamp":1442447918000},"page":"1426-1436","source":"Crossref","is-referenced-by-count":27,"title":["Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria"],"prefix":"10.1681","volume":"27","author":[{"given":"Nasser","family":"Dhayat","sequence":"first","affiliation":[{"name":"Division of Nephrology, Hypertension and Clinical Pharmacology, and"},{"name":"Department of Clinical Research, University of Bern, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Simonin","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Medicine,"},{"name":"Swiss National Centre of Competence in Research Transcure, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Anderegg","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Hypertension and Clinical Pharmacology, and"},{"name":"Institute of Biochemistry and Molecular Medicine,"},{"name":"Swiss National Centre of Competence in Research Transcure, and"},{"name":"Department of Clinical Research, University of Bern, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganesh","family":"Pathare","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Hypertension and Clinical Pharmacology, and"},{"name":"Institute of Biochemistry and Molecular Medicine,"},{"name":"Swiss National Centre of Competence in Research Transcure, and"},{"name":"Department of Clinical Research, University of Bern, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin P","family":"L\u00fcscher","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University Hospital of Bern, Switzerland;"},{"name":"Swiss National Centre of Competence in Research Transcure, and"},{"name":"Department of Clinical Research, University of Bern, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Deisl","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Hypertension and Clinical Pharmacology, and"},{"name":"Institute of Biochemistry and Molecular Medicine,"},{"name":"Swiss National Centre of Competence in Research Transcure, and"},{"name":"Department of Clinical Research, University of Bern, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Albano","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Hypertension and Clinical Pharmacology, and"},{"name":"Institute of Biochemistry and Molecular Medicine,"},{"name":"Swiss National Centre of Competence in Research Transcure, and"},{"name":"Department of Clinical Research, University of Bern, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Mordasini","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Hypertension and Clinical Pharmacology, and"},{"name":"Department of Clinical Research, University of Bern, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias A.","family":"Hediger","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University Hospital of Bern, Switzerland;"},{"name":"Institute of Biochemistry and Molecular Medicine,"},{"name":"Swiss National Centre of Competence in Research Transcure, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel V.","family":"Surbek","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University Hospital of Bern, Switzerland;"},{"name":"Swiss National Centre of Competence in Research Transcure, and"},{"name":"Department of Clinical Research, University of Bern, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Vogt","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Hypertension and Clinical Pharmacology, and"},{"name":"Department of Clinical Research, University of Bern, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rn Oliver","family":"Sass","sequence":"additional","affiliation":[{"name":"Division of Clinical Chemistry and Biochemistry, Children\u2019s Research Center, University Children\u2019s Hospital, Z\u00fcrich, Switzerland;"},{"name":"Department of Natural Sciences, Bonn-Rhein-Sieg University of Applied Sciences, Rheinbach, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Kloeckener-Gruissem","sequence":"additional","affiliation":[{"name":"Institute of Medical Molecular Genetics, University of Z\u00fcrich, Z\u00fcrich, Switzerland; and"},{"name":"Department of Biology, Swiss Federal Institute of Technology in Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel G.","family":"Fuster","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Hypertension and Clinical Pharmacology, and"},{"name":"Institute of Biochemistry and Molecular Medicine,"},{"name":"Swiss National Centre of Competence in Research Transcure, and"},{"name":"Department of Clinical Research, University of Bern, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2015,9,16]]},"reference":[{"key":"B1-20230819","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1055\/s-2007-962943","article-title":"[Juvenile cataract associated with microcornea and glucosuria: a new syndrome]","volume":"224","author":"Vandekerckhove","year":"2007","journal-title":"Klin Monbl Augenheilkd"},{"key":"B2-20230819","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1016\/j.ajhg.2007.12.013","article-title":"Mutation of solute carrier SLC16A12 associates with a syndrome combining juvenile cataract with microcornea and renal glucosuria.","volume":"82","author":"Kloeckener-Gruissem","year":"2008","journal-title":"Am J Hum Genet"},{"key":"B3-20230819","doi-asserted-by":"crossref","first-page":"6774","DOI":"10.1167\/iovs.10-6579","article-title":"Juvenile cataract-associated mutation of solute carrier SLC16A12 impairs trafficking of the protein to the plasma membrane.","volume":"52","author":"Castorino","year":"2011","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B4-20230819","doi-asserted-by":"crossref","first-page":"3218","DOI":"10.1093\/hmg\/ddt175","article-title":"The cataract and glucosuria associated monocarboxylate transporter MCT12 is a new creatine transporter.","volume":"22","author":"Abplanalp","year":"2013","journal-title":"Hum Mol Genet"},{"key":"B5-20230819","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1152\/physrev.2000.80.3.1107","article-title":"Creatine and creatinine metabolism.","volume":"80","author":"Wyss","year":"2000","journal-title":"Physiol Rev"},{"key":"B6-20230819","first-page":"325","article-title":"Biosynthesis of guanidinoacetic acid in isolated renal tubules.","volume":"30","author":"Takeda","year":"1992","journal-title":"Eur J Clin Chem Clin Biochem"},{"key":"B7-20230819","first-page":"113","article-title":"Intranephron distribution of glycine-amidinotransferase activity in rats.","volume":"15","author":"Takeda","year":"1992","journal-title":"Ren Physiol Biochem"},{"key":"B8-20230819","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1042\/bj1260325","article-title":"Distribution of creatine, guanidinoacetate and enzymes for their biosynthesis in the animal kingdom. 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Nephrol"},{"key":"B12-20230819","doi-asserted-by":"crossref","first-page":"F167","DOI":"10.1152\/ajprenal.00162.2010","article-title":"Regulation of the creatine transporter by AMP-activated protein kinase in kidney epithelial cells.","volume":"299","author":"Li","year":"2010","journal-title":"Am J Physiol Renal Physiol"},{"key":"B13-20230819","doi-asserted-by":"crossref","first-page":"604","DOI":"10.7326\/0003-4819-150-9-200905050-00006","article-title":"A new equation to estimate glomerular filtration rate.","volume":"150","author":"Levey","year":"2009","journal-title":"Ann Intern Med"},{"key":"B14-20230819","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1056\/NEJMoa1114248","article-title":"Estimating glomerular filtration rate from serum creatinine and cystatin C.","volume":"367","author":"Inker","year":"2012","journal-title":"N Engl J Med"},{"key":"B15-20230819","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S0009-8981(01)00480-6","article-title":"Analysis of guanidinoacetate and creatine by isotope dilution electrospray tandem mass spectrometry.","volume":"308","author":"Bodamer","year":"2001","journal-title":"Clin Chim Acta"},{"key":"B16-20230819","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1373\/clinchem.2004.034538","article-title":"Determination of guanidinoacetate and creatine in urine and plasma by liquid chromatography-tandem mass spectrometry.","volume":"50","author":"Cognat","year":"2004","journal-title":"Clin Chem"},{"key":"B17-20230819","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.1167\/iovs.10-5193","article-title":"Alterations of the 5'untranslated region of SLC16A12 lead to age-related cataract.","volume":"51","author":"Zuercher","year":"2010","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B18-20230819","first-page":"F459","article-title":"Cloning of a human kidney cDNA with similarity to the sodium-glucose cotransporter.","volume":"263","author":"Wells","year":"1992","journal-title":"Am J Physiol"},{"key":"B19-20230819","doi-asserted-by":"crossref","first-page":"38293","DOI":"10.1074\/jbc.M110.115089","article-title":"Nedd4-1 and beta-arrestin-1 are key regulators of Na+\/H+ exchanger 1 ubiquitylation, endocytosis, and function.","volume":"285","author":"Simonin","year":"2010","journal-title":"J Biol Chem"},{"key":"B20-20230819","doi-asserted-by":"crossref","first-page":"51002","DOI":"10.1074\/jbc.M405674200","article-title":"ERK1\/2 controls Na,K-ATPase activity and transepithelial sodium transport in the principal cell of the cortical collecting duct of the mouse kidney.","volume":"279","author":"Michlig","year":"2004","journal-title":"J Biol Chem"},{"key":"B21-20230819","doi-asserted-by":"crossref","first-page":"F1021","DOI":"10.1152\/ajprenal.0085.2001","article-title":"Distribution of transcellular calcium and sodium 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