GALT (9p13.3,Galaktoosi-1- fosfaatti-uridyylitransferaasi

https://www.ncbi.nlm.nih.gov/gene/2592
 GALT entsyymi katalysoi  toista askelta  Leloirin tiessä ( galaktoosiaineenvaihdunnan päätiessä) , jossa  tapahtuu sekä  UDP-glukoosin että  Gal-1-fosfaatin  muuttumiset UDP-galaktoosiksi ja Glc-1-fosfaatiksi ( yksisuuntaisesti) . Jos  Galaktoosi-1- fosfaatti ei pääse muuntumaan tässä kohtaa  glukoosin puolelle tai  aktivoitumaan  UDP-galaktoosiksi ( ja  myöhemmin UDP-glukoosiksi) , seuraa  galaktoosin pakkautumista siten,  että  ihmisellä havaitaan  klassista galaktosemiaa . Vastasyntyneillä  voi olla hengenvaarallista, jos dieetin laktoosi ei imeydy.  (Laktoosia  ihmiskeho  tarvitsee  rintamaidon tuotantoon  ja vstasyntyneen aivon ja keskushermoston kehittymiseen).   Galaktosemian  patofysiologiaa ei ole selkeästi määritelty. GALT. geenistä  on  kaksi transkriptivarianttia  jotka koodaavat eri isoformeja. Geeniä ilmenee pohjukaissuolessa, maksassa ja 25 muussa kudoksessa.
PubMed -geenireferaateissa mainitaan seuraavaa:
1992 laktosemian geneettinen tausta selvitettiin. Samana vuonna  havaittiin GALT entsyymissä mutaatioita  (missense mutations). Ihmisen Galaktoosi-1-fosfaatti-uridyltransferaasin geeni GALT  oli myös selvitetty.  Hereditäärisen dystonian  yleiskatsaus  1993.   Vuonna 1993 erotettiin klassinen galaktosemia ja  kliininen variantti.  Duarten variantti galaktosemiasta.
Vuonna 2007 oli olemassa GALT  mutaatioista  perustavat tietueet .
 Vuonna 2017 havaittiin  Equadorista uusi GALT- mutaatio, joka johtaa galaktosemiaan. Myös Kreikassa todettiin kaksi uutta mutaatiota.  2018 on julkaistu tietoa kroatialasväestössä  esiintyvästä  klassisesta  galaktosemiasta.
Tähän mennessä on julkaistu tietoa yli 300  GALT mutaatiosta, jotka assosioituvat tautiin. 
Näissä viitteissä ei ole tästä geenistä  näkyvää yhteyttä  diabeettisuuteen. 

• Summary: Galactose-1-phosphate uridyl transferase (GALT) catalyzes the second step of the Leloir pathway of galactose metabolism, namely the conversion of UDP-glucose + galactose-1-phosphate to glucose-1-phosphate + UDP-galactose. The absence of this enzyme results in classic galactosemia in humans and can be fatal in the newborn period if lactose is not removed from the diet. The pathophysiology of galactosemia has not been clearly defined. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
•  Expression  Ubiquitous expression in duodenum (RPKM 23.8), liver (RPKM 21.4) and 25 other tissues See more

• Preferred Names

  galactose-1-phosphate uridylyltransferase

  Names

  UDP-glucose--hexose-1-phosphate uridylyltransferase

  gal-1-P uridylyltransferase

  galactose-1-phosphate uridyl transferase

  NP_000146.2

  • EC 2.7.7.12

  NP_001245261.1

  • EC 2.7.7.12

   
•  https://www.ncbi.nlm.nih.gov/pubmed/27005423
• Classic galactosemia is a potentially lethal disease caused by the dysfunction of galactose 1-phosphate uridylyltransferase (GALT). Over 300 disease-associated GALT mutations have been reported, with the majority being missense changes, although a better understanding of their underlying molecular effects has been hindered by the lack of structural information for the human enzyme. Here, we present the 1.9 Å resolution crystal structure of human GALT (hGALT) ternary complex, revealing a homodimer arrangement that contains a covalent uridylylated intermediate and glucose-1-phosphate in the active site, as well as a structural zinc-binding site, per monomer. hGALT reveals significant structural differences from bacterial GALT homologues in metal ligation and dimer interactions, and therefore is a model for understanding the molecular consequences of disease mutations. Both uridylylation and zinc binding influence the stability and aggregation tendency of hGALT. This has implications for disease-associated variants where p.Gln188Arg, the most commonly detected, increases the rate of aggregation in the absence of zinc likely due to its reduced ability to form the uridylylated intermediate. As such our structure serves as a template in the future design of pharmacological chaperone therapies and opens new concepts about the roles of metal binding and activity in protein misfolding by disease-associated mutants.
• 
  

ORIGIN      
        1 msrsgtdpqq rqqaseadaa aatfrandhq hirynplqde wvlvsahrmk rpwqgqvepq
       61 llktvprhdp lnplcpgair angevnpqyd stflfdndfp alqpdapspg psdhplfqak
      121 sargvckvmc fhpwsdvtlp lmsvpeirav vdawasvtee lgaqypwvqi fenkgammgc
      181 snphphcqvw assflpdiaq reersqqayk sqhgepllme ysrqellrke rlvltsehwl
      241 vlvpfwatwp yqtlllprrh vrrlpeltpa erddlasimk klltkydnlf etsfpysmgw
      301 hgaptgseag anwnhwqlha hyyppllrsa tvrkfmvgye mlaqaqrdlt peqaaerlra
      361 lpevhyhlgq kdretatia
//

 

Related articles in PubMed

1. Molecular basis and clinical presentation of classic galactosemia in a Croatian population. Ramadža DP, et al. J Pediatr Endocrinol Metab, 2018 Jan 26. PMID 29252199
2. Mutational analysis of GALT gene in Greek patients with galactosaemia: identification of two novel mutations and clinical evaluation. Schulpis KH, et al. Scand J Clin Lab Invest, 2017 Oct. PMID 28644047
3. A novel splicing mutation in GALT gene causing Galactosemia in Ecuadorian family. De Lucca M, et al. Clin Chim Acta, 2017 Jul. PMID 28450132
4. Genetic and functional studies reveal a novel noncoding variant in GALT associated with a false positive newborn screening result for galactosemia. Liu Y, et al. Clin Chim Acta, 2015 Jun 15. PMID 25920691, Free PMC Article
5. Clinical and molecular spectra in galactosemic patients from neonatal screening in northeastern Italy: structural and functional characterization of new variations in the galactose-1-phosphate uridyltransferase (GALT) gene. Viggiano E, et al. Gene, 2015 Apr 1. PMID 25592817

See all (115) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into Functions

1. GALT mutation is associated with galactosemia.
2. The mutational spectrum of the GALT gene in Greek galactosemia patients is presented for the first time.
3. novel splicing mutation in GALT gene causing Galactosemia in Ecuadorian family
4. 17 VUS (37%; 7 in ACADM, 9 in GALT, and 1 in PAH) were reclassified from uncertain (6 to benign or likely benign and 11 to pathogenic or likely pathogenic). We identified common types of missing information that would have helped make a definitive classification and categorized this information by ease and cost to obtain
5. we present the 1.9 A resolution crystal structure of human GALT (hGALT) ternary complex, revealing a homodimer arrangement that contains a covalent uridylylated intermediate and glucose-1-phosphate in the active site, as well as a structural zinc-binding site, per monomer
6. A novel noncoding homozygous GALT variant associated with asymptomatic galactosemia has been described in an infant of consanguineous heterozygous parents.
7. Mutation activates a cryptic donor splice site, inducing an aberrant splicing of the GALT pre-mRNA, which in turn leads to a frameshift with inclusion of a premature stop codon.
8. GALT activity in red blood cells of patients with galactosaemia
9. Novel missense mutations identified in Italian galactosemic patients.
10. In Korean population, novel GALT mutations were identified in the galactosemia patients different from those of other populations.

Submit: New GeneRIF Correction See all GeneRIFs (48)