Alterations of the 5'untranslated region of SLC16A12 lead to age-related cataract.
PURPOSE. Knowledge of genetic factors predisposing to age-related cataract is very limited. The aim of this study was to identify DNA sequences that either lead to or predispose for this disease. METHODS. The candidate gene SLC16A12, which encodes a solute carrier of the monocarboxylate transporter family, was sequenced in 484 patients with cataract (134 with juvenile cataract, 350 with age-related cataract) and 190 control subjects. Expression studies included luciferase reporter assay and RT-PCR experiments. RESULTS. One patient with age-related cataract showed a novel heterozygous mutation (c.-17A>G) in the 5'untranslated region (5'UTR). This mutation is in cis with the minor G-allele of the single nucleotide polymorphism (SNP) rs3740030 (c.-42T/G), also within the 5'UTR. Using a luciferase reporter assay system, a construct with the patient's haplotype caused a significant upregulation of luciferase activity. In comparison, the SNP G-allele alone promoted less activity, but that amount was still significantly higher than the amount of the common T-allele. Analysis of SLC16A12 transcripts in surrogate tissue demonstrated striking allele-specific differences causing 5'UTR heterogeneity with respect to sequence and quantity. These differences in gene expression were mirrored in an allele-specific predisposition to age-related cataract, as determined in a Swiss population (odds ratio approximately 2.2; confidence intervals, 1.23-4.3). CONCLUSIONS. The monocarboxylate transporter SLC16A12 may contribute to age-related cataract. Sequences within the 5'UTR modulate translational efficiency with pathogenic consequences.
Zuercher
Jurian
J
Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
Neidhardt
John
J
Magyar
Istvan
I
Labs
Stephan
S
Moore
Anthony T
AT
Tanner
Felix C
FC
Waseem
Naushin
N
Schorderet
Daniel F
DF
Munier
Francis L
FL
Bhattacharya
Shomi
S
Berger
Wolfgang
W
Kloeckener-Gruissem
Barbara
B
D020121:5' Untranslated Regions / Q000235:genetics*; D000368:Aged; D000375:Aging / Q000502:physiology*; D002386:Cataract / Q000235:genetics*; D002460:Cell Line; D003001:Cloning, Molecular; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D020022:Genetic Predisposition to Disease; D005822:Genetic Vectors; D006801:Humans; D027501:Monocarboxylic Acid Transporters / Q000235:genetics*; D009131:Muscle, Smooth, Vascular; D009154:Mutation / Q000235:genetics*; D010957:Plasmids; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017534:Radial Artery; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020121:5' Untranslated Regions; D017931:DNA Primers; D027501:Monocarboxylic Acid Transporters; C527548:SLC16A12 protein, human