Analysis on the mutation of SLC5A2 gene in Chinese patients with familial renal glucosuria and investigation on the association of genotype and phenotype

Abstract

Objective To describe and analyze the clinical characters of patients with FRG from 7 Chinese families. Then analyze and identify their mutations in SGLT2 gene, and explore the association of genotype and phenotype. Methods Quantitative test for 24-hour urine glucose and other laboratory tests were carried out among 7 probands (14 patients in all) and their family members from 7 pedigrees (totaling 23 subjects). All coding regions, including intron-exon boundaries, were analyzed using PCR followed by direct sequence analysis. Results Five novel mutations in SLC5A2 gene were identified in this investigation, including four missense mutations (A Serine to Glycine at position 335 (c.1003A >G, p.S335G), a Glutamine to Arginine at position 448 (c.1343A >G, p. Q448R), an alanine to proline at position 474 (p.A474P, c.1420G >C) and a glycine to aspartic acid at position 580 (c.1739G >A, p.G580D) and a deletion in intron 7 (c.886(-10_-31)del). By the minigene studies using the pSPL3 plasmids, we confirmed the deletion c.886(-10_-31)del as a splicing mutation. In this study, the mutation c.886(-10_-31)del accounted for about 43% of the total alleles (12/28). These patients with compound heterozygous or homozygous mutations manifested middle degree or severe glycosuria (Quantitative test for 24-hour urine glucose: 10.56-50.68 g/1.73 m2), however those with heterozygous variants presented with mild to moderate glycosuria (Quantitative test for 24-hour urine glucose ≤ 2.45 g/1.73 m2). This fits co-dominant inheritance pattern. Conclusions Five novel mutations which may be related to FRG are found in this study, and c.886(-10-31) del may be a high frequency mutation in Chinese patients. Key words: Renal glucosuria, familial; SGLT2 gene; Mutation; Genotype