Clinical and genetic analysis in a family with familial renal glucosuria: Identification of an N101K mutation in the sodium–glucose cotransporter 2 encoded by a solute carrier family 5 member 2 gene

Abstract

We report the identification of a mutation in the solute carrier family 5 member 2 (SLC5A2) gene, which encodes sodium-glucose cotransporter 2, in a family with familial renal glucosuria. The proband was a 26-year-old Japanese man referred to the diabetes division with repeated glucosuria without hyperglycemia. His mother, uncle and grandfather also had a history of glucosuria. A heterozygous missense mutation (c.303T>A: p.N101K) in SLC5A2 was identified in the patient and his mother, but not in 200 chromosomes from 100 healthy and unrelated individuals, or in 3,408 Japanese individuals in the Tohoku Medical Megabank. Furthermore, bioinformatics software predicted that this lesion would be pathogenic. We infer that the mutation led to clinically relevant sodium-glucose cotransporter 2 dysfunction. The patient showed no symptoms of hypoglycemia, but continuous glucose monitoring confirmed asymptomatic hypoglycemia.

Six Exonic Variants in the SLC5A2 Gene Cause Exon Skipping in a Minigene Assay

“…Familial renal glucosuria (FRG) is a rare renal tubular disease, which is characterized by persistent glucosuria without aberrant glucose metabolism and any other symptoms of tubular malfunction (Calado et al, 2008;Aires et al, 2015;Wang et al, 2019). The vast majority of FRG patients are associated with SLC5A2 (OMIM 182381) pathogenic variants (Calado et al, 2008;Sada et al, 2019;Wang et al, 2019). The full-length SLC5A2 gene is 7.7 kb located on chromosome 16p11.2 and encodes for a 672 amino acid low-affinity sodium/glucose co-transporter 2 (SGLT2) with a total of 14 exons (Wells et al, 1993).…”

A novel SLC5A2 heterozygous variant in a family with familial renal glucosuria

“…In most cases of these reports, the variants are homozygous or compound heterozygous for FRG, and obvious racial differences are not reported. In Japan, a heterozygous variant has been reported, and there is no case that carries the same variants as our patients 8 . Missense variants account for loss of function, as with other variants.…”

A young‐onset type 2 diabetic Chinese girl with familial renal glycosuria caused by a novel mutation in SLC5A2: A case report

“…It has been confirmed that mutations in the solute carrier family 5 members 2 (SLC5A2) gene, which encodes sodium-glucose cotransporter 2 (SGLT2), are responsible for this disease. 2 The SLC5A2 gene is a 7.7 kb gene containing 14 exons and encoding protein SGLT2, with 672 amino acids and an inferred secondary structure consisting of 14 transmembrane-spanning domains and expressed in the S1 and S2 segments of the proximal convoluted tubule, which account for 90% of renal glucose reabsorption. 3 FRG may be transmitted in an autosomal dominant pattern, although current studies demonstrated that its inheritance may be codominant with incomplete penetrance.…”

“…Familial renal glycosuria (FRG) is a rare genetic disorder of proximal tubular glucose transport, characterized by excessive urinary glucose excretion even if blood glucose level is in normal range. It has been confirmed that mutations in the solute carrier family 5 members 2 ( SLC5A2 ) gene, which encodes sodium‐glucose cotransporter 2 (SGLT2), are responsible for this disease 2 . The SLC5A2 gene is a 7.7 kb gene containing 14 exons and encoding protein SGLT2, with 672 amino acids and an inferred secondary structure consisting of 14 transmembrane‐spanning domains and expressed in the S1 and S2 segments of the proximal convoluted tubule, which account for 90% of renal glucose reabsorption 3 .…”