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
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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
- Discovery of a drug candidate for GLIS3-associated diabetes. Amin S, et al. Nat Commun, 2018 Jul 11. PMID 29992946, Free PMC ArticleGLIS3 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.
- 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
- A novel variant in GLIS3 is associated with osteoarthritis. Casalone E, et al. Ann Rheum Dis, 2018 Apr. PMID 29436472, Free PMC Article
- 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
- GLIS3 rs7020673 and rs10758593 polymorphisms interact in the susceptibility for type 1 diabetes mellitus. Duarte GCK, et al. Acta Diabetol, 2017 Sep. PMID 28597135
