Diabetes-linked zinc transporter ZnT8 is a homodimeric protein expressed by distinct rodent endocrine cell types in the pancreas and other glands

Murgia, Chiara; Devirgiliis, Chiara; Mancini, Emiliano; Donadel, Giulia; Zalewski, Peter D.; Perozzi, Giuditta

doi:10.1016/j.numecd.2008.09.004

Cited by 88 publications

(83 citation statements)

References 33 publications

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“…This association can partly be explained by a significant association between TPOAb and ZnT8RA, one of the two most common variants of the ZnT8A [6]. The association between thyroid autoantibodies and autoantibodies against ZnT8A is interesting since the zinc transporter is abundant in the cubical cells lining the thyroid follicle [10]. It would therefore be interesting to find out whether ZnT8A is found in patients with AITD without type 1 diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, autoantibodies to the zinc transporter 8 (ZnT8A) have been shown to contribute to the diagnostic sensitivity of diabetes [6][7][8]. Interestingly enough, ZnT8 is not only expressed in beta cells [9] but also in the cubical cells lining the thyroid follicle [10]. SLC30A8 encodes three amino acid variants of ZnT8A to amino acids at position 325 (arginine [ZnT8RA], tryptophan [ZnT8QA] or glutamine [ZnT8QA]), having possible consequences for the association with HLA-DQ genotype [8].…”

Section: Introductionmentioning

confidence: 99%

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Thyroid autoimmunity in relation to islet autoantibodies and HLA-DQ genotype in newly diagnosed type 1 diabetes in children and adolescents

et al. 2013

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Aims/hypothesis The aim of this work was to investigate, in children newly diagnosed with type 1 diabetes: (1) the prevalence of autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TGAb); and (2) the association between TPOAb, TGAb or both, with either islet autoantibodies or HLA-DQ genes. Methods Blood samples from 2,433 children newly diagnosed with type 1 diabetes were analysed for TPOAb and TGAb in addition to autoantibodies against arginine zinc transporter 8 (ZnT8RA), tryptophan zinc transporter 8 (ZnT8WA), glutamine zinc transporter 8 (ZnT8QA), glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated protein-2 (IA-2A), HLA-DQA-B1 genotypes, thyroid-stimulating hormone (TSH) and free thyroxine (T4). Results At type 1 diabetes diagnosis, 12% of the children had thyroid autoantibodies (60% were girls; p<0.0001). GADA was positively associated with TPOAb (p<0.001) and with TGAb (p<0.001). In addition, ZnT8A was associated with both TPOAb (p=0.039) and TGAb (p=0.015). DQB1*05:01 in any genotype was negatively associated with TPOAb (OR 0.55, 95% CI 0.37, 0.83, p value corrected for multiple comparisons (p c )=0.012) and possibly with TGAb (OR 0.55, 95% CI 0.35, 0.87, p c =0.07). Thyroid autoimmunity in children newly diagnosed with type 1 diabetes was rarely (0.45%) associated with onset of clinical thyroid disease based on TSH and free T4. Conclusions/interpretation GADA and ZnT8A increased the risk for thyroid autoimmunity at the time of clinical diagnosis of type 1 diabetes, while HLA-DQB1*05:01 reduced the risk. However, the associations between thyroid autoimmunity and HLA-DQ genotype were weak and did not fully explain the co-occurrence of islet and thyroid autoimmunity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Thyroid autoimmunity in relation to islet autoantibodies and HLA-DQ genotype in newly diagnosed type 1 diabetes in children and adolescents

et al. 2013

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“…2D). Moreover, based on the high evolutionary conservation (data not shown) along with the putative homodimer model interface (formed by superimposing the one modeled monomer onto one interacting YiiP monomer), ZnT-2 is likely to form a homodimer that is similar to multiple zinc transporters that have been shown to form homodimeric or heterodimeric structures including ZnT-3, ZnT-5, ZnT-6, and ZnT-8 (42,44,45).…”

Section: Znt-2 Mutations and Neonatal Zinc Deficiencymentioning

confidence: 99%

“…First, the zinc transporters ZnT-3, ZnT-4, and ZnT-8 which are close homologues of ZnT-2, form homodimers or heterodimers (42,44,45). Second, there is high evolutionary conservation along the putative interface of the homodimeric ZnT-2 model, which was created based on the crystal structure of the E. coli homodimeric zinc transporter YiiP.…”

Section: Journal Of Biological Chemistrymentioning

confidence: 99%

A Dominant Negative Heterozygous G87R Mutation in the Zinc Transporter, ZnT-2 (SLC30A2), Results in Transient Neonatal Zinc Deficiency

Lasry¹,

Seo²,

Ityel³

et al. 2012

Journal of Biological Chemistry

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“…GAD 65 kDa (GAD65), insulin, protein tyrosine phosphatase (IA-2), zinc transporter 8 (ZnT8) and several additional proteins have been identified as autoantigens based on antibody or T cell reactivity in sera from type 1 diabetes patients [7,8]. However, the paradigm of type 1 diabetes as a classical autoimmune disorder contains a paradox: none of the established autoantigens [9][10][11][12], with the possible exception of insulin, are exclusively expressed in the beta cells, thus failing to explain the selective immunemediated destruction of the beta cells-a fact that has been largely neglected by researchers in the field.…”

Section: Introductionmentioning

confidence: 99%

Do post-translational beta cell protein modifications trigger type 1 diabetes?

et al. 2013

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Type 1 diabetes is considered an autoimmune disease characterised by specific T cell-mediated destruction of the insulin-producing beta cells. Yet, except for insulin, no beta cell-specific antigens have been discovered. This may imply that the autoantigens in type 1 diabetes exist in modified forms capable of specifically triggering beta cell destruction. In other immune-mediated diseases, autoantigens targeted by the immune system have undergone post-translational modification (PTM), thereby creating tissue-specific neo-epitopes. In a similar manner, PTM of beta cell proteins might create beta cell-specific neo-epitopes. We suggest that the current paradigm of type 1 diabetes as a classical autoimmune disease should be reconsidered since the immune response may not be directed against native beta cell proteins. A modified model for the pathogenetic events taking place in islets leading to the T cell attack against beta cells is presented. In this model, PTM plays a prominent role in triggering beta cell destruction. We discuss literature of relevance and perform genetic and human islet gene expression analyses. Both direct and circumstantial support for the involvement of PTM in type 1 diabetes exists in the published literature. Furthermore, we report that cytokines change the expression levels of several genes encoding proteins involved in PTM processes in human islets, and that there are type 1 diabetes-associated polymorphisms in a number of these. In conclusion, data from the literature and presented experimental data support the notion that PTM of beta cell proteins may be involved in triggering beta cell destruction in type 1 diabetes. If the beta cell antigens recognised by the immune system foremost come from modified proteins rather than native ones, the concept of type 1 diabetes as a classical autoimmune disease is open for debate.

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Diabetes-linked zinc transporter ZnT8 is a homodimeric protein expressed by distinct rodent endocrine cell types in the pancreas and other glands

Cited by 88 publications

References 33 publications

Thyroid autoimmunity in relation to islet autoantibodies and HLA-DQ genotype in newly diagnosed type 1 diabetes in children and adolescents

Thyroid autoimmunity in relation to islet autoantibodies and HLA-DQ genotype in newly diagnosed type 1 diabetes in children and adolescents

A Dominant Negative Heterozygous G87R Mutation in the Zinc Transporter, ZnT-2 (SLC30A2), Results in Transient Neonatal Zinc Deficiency

Do post-translational beta cell protein modifications trigger type 1 diabetes?

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