Glykotoxisuuden tiet

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920740/
19.6. 2019 Tässä artikkelissa on kuva glykotoksisuuden teistä ja mainittu ( DM vihkossa on kartta ja kuva).

• polyolitie
• urinihappotie
• hexosaminitie
• proteinkinaasi C-tie
• AGE-tie. 

GLIS3 (ZNZ515) assosioitunut diabetes

ZNF family GLIS

GLIS3 , ZNF515 (9p24.2) , NDH

7.6. 2019 suomennosta M. Cassandrin artikkelista.

"On useita raportteja ZNF- perheen osallistumisesta diabeteksen kehittymiseen.

Esimerkkinä on GLIS3 (C2H2-tyyppinen transkriptiofaktori, Krüppelin kaltaisen rakenteen omaava ZNF-proteiini), jota ilmenee vahvasti haiman beetasoluissa. GLIS3-geenin mutaatioita on tunnistettu ihmisen neonataalidiabeteksessa ja kongenitaalisessa hypotyreoidismissa (NDH). Ihmisen GLIS3-mutaatio johtaa C-terminaalisesti lyhentyneeseen proteiiniin, mutta ei ole selvitetty, millä tavalla tämä mutaatio johtaa neonataalidiabetekseen. GLIS3 moduloi insuliinin ilmentymistä sekä suoralla että epäsuoralla mekanismilla sitoutumalla INS- promoottoriin tai moduloimalla toisien, beetasoluun rikastuneiden transkriptiofaktoreiden aktiivisuutta kuten MafA, Nkx6-1 ja Pax6: 

• INS (11p15.5)  https://www.ncbi.nlm.nih.gov/gene/3630

• MafA https://www.ncbi.nlm.nih.gov/gene/389692 Also known as INSDM; hMafA; RIPE3b1Summary MAFA is a transcription factor that binds RIPE3b, a conserved enhancer element that regulates pancreatic beta cell-specific expression of the insulin gene (INS; MIM 176730) (Olbrot et al., 2002 [PubMed 12011435]).[supplied by OMIM, Mar 2008]

• Nkx6-1 https://www.ncbi.nlm.nih.gov/gene/4825 Also known as NKX6A; NKX6.1 Summary In the pancreas, NKX6.1 is required for the development of beta cells and is a potent bifunctional transcription regulator that binds to AT-rich sequences within the promoter region of target genes Iype et al. (2004) [PubMed 15056733].[supplied by OMIM, Mar 2008] Preferred Names homeobox protein Nkx-6.1 Names NK homeo box, family 6, member A NK homeobox, family 6, A ,NK6 transcription factor homolog A ,NK6 transcription factor related, locus 1, homeobox protein NK-6 homolog

• Pax6. https://www.ncbi.nlm.nih.gov/gene/5080 Also known as AN; AN2; FVH1; MGDA; WAGR; ASGD5; D11S812E Summary This gene encodes paired box protein Pax-6, one of many human homologs of the Drosophila melanogaster gene prd. In addition to a conserved paired box domain, a hallmark feature of this gene family, the encoded protein also contains a homeobox domain. Both domains are known to bind DNA and function as regulators of gene transcription. Activity of this protein is key in the development of neural tissues, particularly the eye. This gene is regulated by multiple enhancers located up to hundreds of kilobases distant from this locus. Mutations in this gene or in the enhancer regions can cause ocular disorders such as aniridia and Peter's anomaly. Use of alternate promoters and alternative splicing results in multiple transcript variants encoding different isoforms. Interestingly, inclusion of a particular alternate coding exon has been shown to increase the length of the paired box domain and alter its DNA binding specificity. Consequently, isoforms that carry the shorter paired box domain regulate a different set of genes compared to the isoforms carrying the longer paired box domain. [provided by RefSeq, Mar 2019] Expression Broad expression in brain (RPKM 3.5), stomach (RPKM 2.6) and 15 other tissues See more Orthologs mouse all Preferred Names paired box protein Pax-6 Names: aniridia type II protein, oculorhombin, paired box homeotic gene-6
  

"Muutamia vuosia siten on saatu kehitettyä GLIS3-vajeinen hiirimalli (GLIS3-/-) ja se ilmentää korkeita verensokeripitoisuuksia, haimadefektejä ja keskoiskuolleisuutta. Nämä fenotyypit muistuttavat ihmisen neonataalidiabetesta, jota aiheutuu GLS3 mutaatioista. Tämä hiirimalli voisi olla hyvin hyödyllinen tutkittaessa terapeuttisia sovelluksia ihmisen diabetekseen. On alettu tunnistaa GLS3-mutaatioista johtuvia uusia kliinisiä manifestaatioita neonataalidiabetesta potevilla ihmisillä: on tunnistettu luustodeformaatioihin ja murtumiin assosioituvaa osteopeniaa, molemminpuolista sensorineuraalia kuuroutta ja exogeenisen haiman vikatoimintaa. Näitä kliinisiä piirteitä ei ole aiemmin kuvattu, mikä osoittaa GLIS3-mutaatiofenotyypin suurta vaihtelevaisuutta ottaen huomioon että erilaiset geneettiset mutaatiot johtavat kudosspesifisen Glis3 mRNA:n ilmenemiseen”.

Muuta lähdetietoa GLIS3 -geenistä PubMed Geenitietueesta.

GLIS3 (9p24.2) , ZNF515 , NDH https://www.ncbi.nlm.nih.gov/gene/169792

Also known as NDH; ZNF515 .Summary This gene is a member of the GLI-similar zinc finger protein family and encodes a nuclear protein with five C2H2-type zinc finger domains. This protein functions as both a repressor and activator of transcription and is specifically involved in the development of pancreatic beta cells, the thyroid, eye, liver and kidney. Mutations in this gene have been associated with neonatal diabetes and congenital hypothyroidism (NDH). Alternatively spliced variants that encode different protein isoforms have been described but the full-length nature of only two have been determined. [provided by RefSeq, Jul 2008] Expression Biased expression in thyroid (RPKM 8.8), gall bladder (RPKM 2.6) and 13 other tissues See more

Preferred Names : zinc finger protein GLIS3

Names: GLI-similar 3

OK/KNS-cl.4

zinc finger protein 515

Related articles in PubMed

1. Discovery of a drug candidate for GLIS3-associated diabetes. Amin S, et al. Nat Commun, 2018 Jul 11. PMID 29992946, Free PMC Article
   GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes, reflecting a key function for this gene in pancreatic β-cell biology. Previous attempts to recapitulate disease-relevant phenotypes in GLIS3^-/- β-like cells have been unsuccessful. Here, we develop a "minimal component" protocol to generate late-stage pancreatic progenitors (PP2) that differentiate to mono-hormonal glucose-responding β-like (PP2-β) cells. Using this differentiation platform, we discover that GLIS3^-/- hESCs show impaired differentiation, with significant death of PP2 and PP2-β cells, without impacting the total endocrine pool. Furthermore, we perform a high-content chemical screen and identify a drug candidate that rescues mutant GLIS3-associated β-cell death both in vitro and in vivo. Finally, we discovered that loss of GLIS3 causes β-cell death, by activating the TGFβ pathway. This study establishes an optimized directed differentiation protocol for modeling human β-cell disease and identifies a drug candidate for treating a broad range of GLIS3-associated diabetic patients.
2. Polymorphism of the GLIS3 gene in a Caucasian population and among individuals with carbohydrate metabolism disorders in Russia. Shakhtshneider EV, et al. BMC Res Notes, 2018 Apr 2. PMID 29606121, Free PMC Article
3. A novel variant in GLIS3 is associated with osteoarthritis. Casalone E, et al. Ann Rheum Dis, 2018 Apr. PMID 29436472, Free PMC Article
4. The role of GLIS3 in thyroid disease as part of a multisystem disorder. Dimitri P. Best Pract Res Clin Endocrinol Metab, 2017 Mar. PMID 28648506
5. GLIS3 rs7020673 and rs10758593 polymorphisms interact in the susceptibility for type 1 diabetes mellitus. Duarte GCK, et al. Acta Diabetol, 2017 Sep. PMID 28597135

See all (43) citations in PubMed

GeneRIFs: Gene References Into Functions

1. The SNP rs3753841 in COL11A1, rs1258267 in CHAT and rs736893 in GLIS3 are associated with PACG in northern Chinese people, and the association of genetic markers manifests a tendency of ethnic diversity. Larger population-based studies are warranted to reveal additional primary angle-closure glaucoma loci and ethnic aspects of primary angle-closure glaucoma.
2. We detect a genome-wide significant association at rs10116772 with knee and/or hip total joint replacement; for allele A, an intronic variant in GLIS3, which is expressed in cartilage of osteoarthritis patients.We identify a novel susceptibility locus for OA that has been previously implicated in diabetes and glycaemic traits.
3. Data show that loss of zinc finger protein GLIS3 (GLIS3) causes beta-cell death.
4. Data did not show any associations of GLI similar 3 protein (GLIS3) gene polymorphisms rs806052, rs143051164, and rs149840771 with carbohydrate metabolism disorders among patients with maturity onset diabetes of the young (MODY) and type 2 diabetes mellitus (DM2) in Russia.
5. Individually the rs7020673 and rs10758593 SNPs are not significantly associated with T1DM but seem to interact in the predisposition for this disease.
6. Replication of lead type 2 diabetes mellitus SNPs in GLIS3, KCNK16, and ZFAND3 was observed in American Indians. Sex-specific T2DM signals in GLIS3 and ZFAND3, which are distinct from the East Asian GWAS signals, were also identified.
7. Given the role of GLIS3 in transcriptional activation and repression during embryogenesis, in humans, GLIS3 mutations present with multisystem involvement that also includes renal cystic dysplasia, progressive liver fibrosis and osteopenia. Thyroid findings in GLIS3 patients include thyroid aplasia, diminished colloid with interstitial fibrosis at post-mortem.[review]
8. GLIS3 polymorphism is not associated with Dermatomyositis /Polymyositis in the Chinese Han population
9. we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations and report the emergence of a distinct, probably recognizable facial gestalt in this group which evolves with age.
10. It may play a role in a number of physiological processes controlled by Glis3.