Juvenile Cataract-Associated Mutation of Solute CarrierSLC16A12Impairs Trafficking of the Protein to the Plasma Membrane

Abstract

These data support a model whereby the SLC16A12 (c.643C>T) mutation causes juvenile cataract by a defect in protein trafficking rather than by haploinsufficiency.

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

“…2,3 To determine the distribution of MCT12 and CRT1 along the nephron, we isolated tubular segments by microdissection and quantified mRNA expression by RT-PCR ( Figure 1). MCT12 transcripts are present in all segments but exhibit a four-to five-fold higher expression in proximal convoluted and proximal straight tubules, as well as thick ascending limbs of the loop of Henle, compared with those detected in the more distal segments, including distal convoluted tubules, connecting tubules, and cortical collecting ducts.…”

“…When expressed in HEK293 cells, p.Q2153 MCT12 was retained in the endoplasmatic reticulum (ER), while fulllength MCT12 trafficked to the plasma membrane. 3 Surprisingly, mct12 knockout (KO) rats did not display cataracts nor the glucosuria observed in family members with the heterozygous MCT12 mutation. 3 Thus, the dominant form of cataract observed in the family was suspected to be due to protein misfolding, rather than haploinsufficiency.…”

“…3 Surprisingly, mct12 knockout (KO) rats did not display cataracts nor the glucosuria observed in family members with the heterozygous MCT12 mutation. 3 Thus, the dominant form of cataract observed in the family was suspected to be due to protein misfolding, rather than haploinsufficiency. 3 Absence of glucosuria in mct12 KO rats, and poor correlation of the MCT12 mutation with the glucosuria trait in humans, suggested a dominant negative effect with incomplete penetrance or the presence of a second, independent mutation as the cause for the glucosuria observed in the family.…”

“…3 Thus, the dominant form of cataract observed in the family was suspected to be due to protein misfolding, rather than haploinsufficiency. 3 Absence of glucosuria in mct12 KO rats, and poor correlation of the MCT12 mutation with the glucosuria trait in humans, suggested a dominant negative effect with incomplete penetrance or the presence of a second, independent mutation as the cause for the glucosuria observed in the family. 3 The substrate of MCT12 was unknown until recently, when Abplanalp et al deorphanized the transporter by use of an elegant metabolomics approach in Xenopus laevis oocytes.…”

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

“…Instead, several members have been shown to depend on the association with a highly glycosylated ancillary protein for correct targeting and functional expression at the plasma membrane. MCT1, MCT3, MCT4,3 MCT11,5 and MCT126 were demonstrated to preferably interact with the transmembrane glycoprotein CD147, also known as basigin or EMMPRIN, whereas MCT2 has been shown to form a complex with a closely related glycoprotein gp70, known as embigin 3. Both basigin and embigin belong to the immunoglobulin superfamily and consist of a single transmembrane domain and two to three extracellular immunoglobulin domains depending on the splice variant 3.…”