Alternative titles; symbols
SNOMEDCT: 226309007; ICD10CM: E74.818; ORPHA: 69076; DO: 9432;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
16p11.2 | Renal glucosuria | 233100 | Autosomal dominant; Autosomal recessive | 3 | SLC5A2 | 182381 |
A number sign (#) is used with this entry because of evidence that renal glucosuria (GLYS) is caused by homozygous, compound heterozygous, or heterozygous mutation in the SLC5A2 gene (182381) on chromosome 16p11.
Patients with familial renal glucosuria have decreased renal tubular resorption of glucose form the urine in the absence of hyperglycemia and any other signs of tubular dysfunction. Glucosuria in these patients can range from less than 1 to over 150 g/1.73 m(2) per day (Santer and Calado, 2010).
Monasterio et al. (1964) did microdissection and electron microscopy in 2 cases of renal glycosuria. Abnormality was limited to the proximal tubules, which showed vacuolization, accumulation of abnormal PAS-positive material, and changes in the brush border. Elsas and Rosenberg (1969) clarified the situation by pointing out that type A (low threshold and low glucose Tm) and type B (low threshold but normal Tm) may be observed in the same family, that both parents may be completely normal or may show abnormality in the renal tubular transport of glucose, and that defective reabsorption of glucose by the kidney need not be accompanied by abnormalities in intestinal glucose transport.
Oemar et al. (1987) described a new form of renal glycosuria in which tubular glucose reabsorption was completely absent. They referred to this as type 0. The patient was a 15-year-old boy whose parents were first cousins twice removed. Both parents appeared to be heterozygotes, as did a brother and a sister. The proband's glycosuria was discovered at age 11 years when he was complaining of enuresis nocturna, polyuria, polydipsia and polyphagia. He was of short stature (3rd percentile). The heterozygotes had more moderate glycosuria.
Yu et al. (2011) reported 4 unrelated Chinese families with persistent glucosuria with normal serum glucose and no other evidence of renal disease. Polyuria and polydipsia were not features. Two families with autosomal recessive inheritance showed greater glucosuria (16 to 27 gm/day) than 2 families with autosomal dominant inheritance (4 to 6.5 gm/day).
Familial renal glucosuria can be inherited in an autosomal recessive or autosomal dominant pattern. Individuals with 2 mutations usually have a more severe phenotype with greater glucose wasting compared to those with 1 mutation (Yu et al., 2011).
Renal glycosuria has often been considered a dominant trait (Hjarne, 1927). Although it is incompletely recessive, i.e., heterozygotes may show mild glycosuria, consistent heavy glycosuria is a feature of the homozygote (Khachadurian and Khachadurian, 1964).
Elsas et al. (1971) provided clear evidence of autosomal recessive inheritance of type A renal glycosuria. They found a family in which both parents and a sib of the affected persons had an intermediate type of defect (i.e., a similar kinetic pattern with a less marked defect).
De Marchi et al. (1983) reported a family in which 7 persons in 3 generations showed renal glycosuria.
Kanai et al. (1994) suggested that the defect in renal glucosuria may reside in SLC5A2, the gene for kidney low affinity sodium/glucose cotransporter, which maps to chromosome 16. The suggestion was confirmed by the finding of mutations in this gene by van den Heuvel et al. (2002).
Heterogeneity
On the basis of studies of 5 unrelated affected families with a total of 25 patients, De Marchi et al. (1984) suggested that a form of renal glycosuria is linked to HLA on chromosome 6p21. Furthermore, 2 cases carrying intra-HLA recombinant haplotypes suggested that the abnormal gene is closer to HLA-A than to HLA-B. Both homozygotes and heterozygotes were identified in the family.
In a Turkish patient with autosomal recessive renal glucosuria, van den Heuvel et al. (2002) demonstrated homozygosity for a nonsense truncating mutation in the SLC5A2 gene (W440X; 182381.0001).
Yu et al. (2011) identified 5 novel mutations in the SLC5A2 gene (see, e.g., 182381.0004-182381.0006) in Chinese patients from 4 unrelated families with renal glucosuria. Affected individuals in 2 families were compound heterozygous for 2 mutations, whereas affected individuals in 2 additional families with a milder phenotype were heterozygous for a mutation. All mutant proteins were expressed in HEK293 cells and showed variable decreased glucose transport activity, ranging from 26 to 71% of normal.
In a Swiss family with SLC16A12-associated (611910.0001) cataract and microcornea (CTRCT47; 612018), in which 5 affected individuals also exhibited renal leak glucosuria, Dhayat et al. (2016) identified a heterozygous missense mutation in the SLC5A2 gene (A89T; 182381.0007) that segregated fully with renal leak glucosuria in the family.
De Marchi, S., Cecchin, E., Basile, A., Proto, G., Donadon, W., Jengo, A., Schinella, D., Jus, A., Villalta, D., De Paoli, P., Santini, G., Tesio, F. Close genetic linkage between HLA and renal glycosuria. Am. J. Nephrol. 4: 280-286, 1984. [PubMed: 6524599] [Full Text: https://doi.org/10.1159/000166826]
De Marchi, S., Proto, G., Jengo, A., Collinassi, P., Basile, A. Glicosuria renale: anomalia autosomica dominante o recessiva? Osservazioni sulle modalita di transmissione ereditaria desunte dall'analisi di un albero genealogico con tre generazioni. Minerva Med. 74: 301-306, 1983. [PubMed: 6828258]
Dhayat, N., Simonin, A., Anderegg, M., Pathare, G., Luscher, B. P., Deisl, C., Albano, G., Mordasini, D., Hediger, M. A., Surbek, D. V., Vogt, B., Sass, J. O., Kloeckener-Gruissem, B., Fuster, D. G. Mutation in the monocarboxylate transporter 12 gene affects guanidinoacetate excretion but does not cause glucosuria. J. Am. Soc. Nephrol. 27: 1426-1436, 2016. [PubMed: 26376857] [Full Text: https://doi.org/10.1681/ASN.2015040411]
Elsas, L. J., Busse, D., Rosenberg, L. E. Autosomal recessive inheritance of renal glycosuria. Metabolism 20: 968-975, 1971. [PubMed: 5097684] [Full Text: https://doi.org/10.1016/0026-0495(71)90017-5]
Elsas, L. J., Hillman, R. E., Patterson, J. H., Rosenberg, L. E. Renal and intestinal hexose transport in familial glucose-galactose malabsorption. J. Clin. Invest. 49: 576-585, 1970. [PubMed: 5415683] [Full Text: https://doi.org/10.1172/JCI106268]
Elsas, L. J., Rosenberg, L. E. Familial renal glycosuria: a genetic reappraisal of hexose transport by kidney and intestine. J. Clin. Invest. 48: 1845-1854, 1969. [PubMed: 5822589] [Full Text: https://doi.org/10.1172/JCI106150]
Gjone, E. Idiopatisk renal glykosuria in 3 generationer with high incidence. Nord. Med. 59: 306-307, 1958. [PubMed: 13517633]
Hjarne, V. Study of orthoglycaemic glycosuria with particular reference to its heritability. Acta Med. Scand. 67: 422-571, 1927.
Kanai, Y., Lee, W.-S., You, G., Brown, D., Hediger, M. A. The human kidney low affinity Na(+)/glucose cotransporter SGLT2: delineation of the major renal reabsorptive mechanism for D-glucose. J. Clin. Invest. 93: 397-404, 1994. [PubMed: 8282810] [Full Text: https://doi.org/10.1172/JCI116972]
Khachadurian, A. K., Khachadurian, L. A. The inheritance of renal glycosuria. Am. J. Hum. Genet. 16: 189-194, 1964. [PubMed: 14174800]
Monasterio, G., Oliver, J., Muiesan, G., Pardelli, G., Marinozzi, V., MacDowell, M. Renal diabetes as a congenital tubular dysplasia. Am. J. Med. 37: 44-61, 1964. [PubMed: 14181149] [Full Text: https://doi.org/10.1016/0002-9343(64)90211-6]
Oemar, B. S., Byrd, D. J., Brodehl, J. Complete absence of tubular glucose reabsorption: a new type of renal glucosuria (type 0). Clin. Nephrol. 27: 156-160, 1987. [PubMed: 3568462]
Santer, R., Calado, J. Familial renal glucosuria and SGLT2: from mendelian trait to a therapeutic target. Clin. J. Am. Soc. Nephrol. 5: 133-141, 2010. [PubMed: 19965550] [Full Text: https://doi.org/10.2215/CJN.04010609]
van den Heuvel, L. P., Assink, K., Willemsen, M., Monnens, L. Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2). Hum. Genet. 111: 544-547, 2002. [PubMed: 12436245] [Full Text: https://doi.org/10.1007/s00439-002-0820-5]
Yu, L., Lv, J.-C., Zhou, X., Zhu, L., Hou, P., Zhang, H. Abnormal expression and dysfunction of novel SGLT2 mutations identified in familial renal glucosuria patients. Hum. Genet. 129: 335-344, 2011. [PubMed: 21165652] [Full Text: https://doi.org/10.1007/s00439-010-0927-z]