Elsevier

Molecular Genetics and Metabolism

Volume 77, Issues 1–2, September–October 2002, Pages 189-193
Molecular Genetics and Metabolism

Analysis of MGEA5 on 10q24.1–q24.3 encoding the β-O-linked N-acetylglucosaminidase as a candidate gene for type 2 diabetes mellitus in Pima Indians

https://doi.org/10.1016/S1096-7192(02)00127-0Get rights and content

Abstract

Several diseases including type 2 diabetes mellitus (T2DM) are associated with abnormal O-glycosylation of proteins. β-O-linked N-acetylglucosaminidase (O-GlcNAcase) encoded by MGEA5 on 10g24.1–q24.3 removes N-acetylglucosamine (O-GlcNAc), and we investigated this locus in Pima Indians who have the world’s highest prevalence of T2DM. We detected two variants but there was no association with parameters of insulin resistance or diabetes in ∼1300 Pimas. We conclude that mutations in MGEA5 are unlikely to contribute to T2DM in this population.

Introduction

MGEA5 is a recently described gene coding for the meningioma-expressed antigen-5 [1]. The gene has been positioned at 10q24.l–q24.3 and its product identified as a β-O-linked N-acetylglucosaminidase (O-GlcNAcase), which is expressed in many tissues and catalyzes the removal of N-acetylglucosamine (O-GlcNAc) from glycosylated proteins [2]. Dynamic glycosylation of serine and threonine residues by O-GlcNAc is a widespread mechanism of posttranslational modification of nuclear and cytoplasmic proteins [3], [4] accomplished by O-GlcNAc transferase (OGT), whereas the sugar moiety is selectively removed by O-GlcNAcase. This reversible posttranslational modification affects a variety of cytoplasmic and nuclear proteins and plays an important role that appears to be comparable with the significance of serine/threonine phosphorylation [4]. Aberrant protein glycosylation by GlcNAc has been linked to several disease states including degenerative neurological disorders, cancer and diabetes [4].

Several recent studies reported evidence that increased intracellular O-GlcNAc modification of proteins has been associated with elevated levels of extracellular glucose and glucosamine [5], [6], [7]. One study demonstrated that activation of the hexosamine pathway by glucosamine infusion induces insulin resistance by inhibition of early postreceptor insulin signaling via O-GlcNAc modification of insulin receptor substrates IRS-1 and IRS-2 [8]. In addition, O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc), which is a potential inhibitor of O-GlcNAcase, increased the levels of O-GlcNAc leading to insulin resistance and also increased glycosylation of insulin signaling proteins IRS1 and β-catenin [9]. Thus, hyperglycemia-induced O-GlcNAc modification can perturb normal signaling events required for insulin-mediated glucose homeostasis.

O-GlcNAcase is widely expressed in various tissues and cell types including the insulin-producing β-cells in pancreatic islets. The enzyme is irreversibly inhibited by the diabetes-inducing drug streptozotocin (STZ), a GlcNAc analog with β-cell specific toxicity, which is used to induce diabetes in animal models [10]. It has been proposed that the accumulation of glycosylated proteins in β-cells following exposure to STZ can play a significant role in β-cell loss leading to diabetes [10].

These observations indicate that alterations of genes involved in the regulation of protein O-glycosylation (e.g. OGT on chromosome Xq13 coding for GlcNAc transferase, and MGEA5 on 10q24.l–q24.3 encoding the GlcNAcase) could play a role in the genetic predisposition to diabetes by contributing to β-cell loss and/or insulin resistance. Type 2 diabetes mellitus (T2DM) is the most common form of disturbed glucose homeostasis, representing a complex, heterogeneous disease caused by a combination of genetic and environmental factors [11]. Results of recent genome-wide scans in different populations have revealed evidence for linkage of T2DM with various chromosomes, including an overlapping area on chromosome 10q in Mexican Americans [12], UK Caucasians [13], French [14], and Finns [15]. Furthermore, this area has been tentatively linked with differences in glycated hemoglobin A1C (HbA1C) levels in the Framingham Heart Study [16]. In addition, this genomic region also showed a modest linkage with 2-h plasma glucose (2hPG) measured during an oral glucose tolerance test, and also with whole body glucose disposal in response to a physiological dose of insulin (Mlow) determined by hyperinsulinemic euglycemic clamp in non-diabetic Pima Indians [17]. Although there was no linkage of 10q with overt diabetes in a larger set of Pima families [18], 2-h glucose concentration during the oral glucose tolerance test (2-hPG), and glucose disposal during the low (40 mU/m2 per min) insulin infusion of the glucose clamp (Mlow) are clinical indicators of insulin sensitivity, and their impairment is a predictor of T2DM in this Native American population with the highest documented prevalence of the disease in the world [19]. Also this region is linked with Alzheimer’s disease and contains the gene encoding the insulin degrading enzyme (IDE), which has the ability to degrade β-amyloid [20].

The location of MGEA5 on 10q in the region linked either with T2DM or possibly with insulin resistance in different populations, and the potential pathophysiologic role of the enzyme in the development of abnormal glucose homeostasis through alterations in O-GlcNAc protein modification, led us to investigate the gene as a possible candidate in the Pima Indians.

Section snippets

Subjects

Fifteen diabetic subjects with an early onset (before 25 years) and 15 non-diabetic controls (at least 45 years old with normal glucose tolerance) used in our study are members who have been participating in a longitudinal study of the development of Type 2 diabetes [19] which is diagnosed according to WHO criteria as described [18]. The informative polymorphism (SNP2) was analyzed in the entire population of approximately 1300 Pimas involved in our original linkage studies [18]. A smaller

Results and discussion

The MGEA5 gene has been localized to chromosome 10q24.1–q24.3 [1] and is carried on BAC clone RP11-573E23. The gene consists of 16 exons spanning over ∼34 kb [22] and coding for a 130-kDa protein. An alternatively spliced transcript (MGEA5s) was described recently, which consists of exons 1–10 and extends through intron 11. This transcript has an alternative stop and polyadenylation sites and codes for a 75-kDa protein [22].

We initially screened all exons plus the flanking splice sites, the

Acknowledgements

We thank the members of the Gila River Indian Community for their participation and cooperation in the ongoing longitudinal studies.

References (22)

  • L. Wells et al.

    Glycosylation of nucleocytoplasmic proteins: signal transduction and O-GlcNAc

    Science

    (2001)
  • Cited by (0)

    View full text