Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria

Dhayat, Nasser; Simonin, Alexandre; Anderegg, Manuel Andreas; Pathare, Ganesh Tukaram; Lüscher, Benjamin; Deisl, Christine; Albano, Giuseppe; Mordasini, David; Hediger, Matthias; Surbek, Daniel; Vogt, Bruno; Sass, Jörn; Kloeckener-Gruissem, Barbara; Fuster, Daniel Guido (2015). Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria. Journal of the American Society of Nephrology, 27(5), pp. 1426-1436. American Society of Nephrology 10.1681/ASN.2015040411

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A heterozygous mutation (c.643C>A; p.Q215X) in the monocarboxylate transporter 12-encoding gene MCT12 (also known as SLC16A12) 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 MCT12 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 MCT12 mutation exhibited reduced plasma levels and increased fractional excretion of guanidinoacetate, but normal creatine levels, suggesting that MCT12 may function as a guanidinoacetate transporter in vivo. However, functional studies in Xenopus 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 SGLT2 (also known as SLC5A2) 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 MCT12 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 MCT12 and SGLT2 mutation. Thus, glucosuria is not part of the MCT12 mutation syndrome.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Nephrologie / Hypertonie
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Gynaecology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Pränatale Medizin

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Dhayat, Nasser; Simonin, Alexandre; Anderegg, Manuel Andreas; Pathare, Ganesh Tukaram; Lüscher, Benjamin; Deisl, Christine; Albano, Giuseppe; Mordasini, David; Hediger, Matthias; Surbek, Daniel; Vogt, Bruno and Fuster, Daniel Guido

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1046-6673

Publisher:

American Society of Nephrology

Language:

English

Submitter:

Nasser Dhayat

Date Deposited:

28 Sep 2015 12:06

Last Modified:

19 Sep 2017 18:44

Publisher DOI:

10.1681/ASN.2015040411

PubMed ID:

26376857

Uncontrolled Keywords:

cell and transport physiology, familial nephropathy, genetic renal disease

BORIS DOI:

10.7892/boris.72014

URI:

https://boris.unibe.ch/id/eprint/72014

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