Genomic profiling of pediatric patients with liver glycogenosis: genotype-phenotype correlation and functional characterization of novel variants

[A. G. Skakić]

129 listova

Molekularna biologija eukariota - Molekularna genetika / Molecular biology of eukaryotes - Molecular genetics

Bolesti koje nastaju usled naslednog enzimskog poremećaja u sintezi ili razgradnji glikogena i koje primarno pogađaju jetru i bubrege, nazivaju se hepatične glikogenoze. Glikogenoza tip I (GSD tip I) je jedan od najčešćih oblika i zauzima posebno mesto u grupi ovih bolesti zbog prepoznatljivog kliničkog fenotipa koji jasno odražava složenu patofoziologiju poremećaja u metabolizmu glikogena. GSD tip Ia razvija se usled deficitarne aktivnosti enzima glukozo-6-fosfataze α (G6Paza-α ili G6PC), a GSD tip Ib nastaje kao posledica deficijencije transportera glukozo-6-fosfat translokaze (G6PT ili SLC37A4) koja se nalazi na membrani endoplazmatičnog retikuluma (ER). U jetri, bubrezima i mukozi creva, G6Paza-α i G6PT formiraju funkcionalni kompleks koji učestvuje u održavanju homeostaze glukoze u krvi između obroka. Ukoliko je ovaj proces narušen, dolazi do nakupljanja glikogena u jetri, bubrezima i intestinalnoj mukozi i razvoja hipoglikemije, hiperlaktatemije, hiperlipidemije, hiperurikemije, i hepatonefromegalije. Ove metaboličke abnormalnosti rezultiraju dugoročnim komplikacijama bubrežnih bolesti i hepatocelularnih adenoma/karcinoma, čiji su molekularni mehanizmi slabo istraženi. Kod pacijenata obolelih od GSD tip Ib dodatno se javlјaju neutropenija i disfunkcija neutrofila i makrofaga, pa zbog toga ovi pacijenti razvijaju rekurentne bakterijske infekcije, neretko praćene simptomima inflamatorne bolesti creva slične Kronovoj bolesti. Uzimajući u obzir patofiziološke posledice metaboličkog stresa kod pacijenata obolelih od GSD tip Ib, od velikog interesa su adaptivni odgovori i molekularni mehanizmi koje ćelije aktiviraju pod takvim uslovima. Poznato je da poremećaj homeostaze ER-a, nastalog kao posledica gubitka intraćelijske produkcije glukoze, dovodi do hronične aktivacije „odgovora nesavijenih proteina” (UPR) čime doprinosi patogenezi mnogih bolesti. Stres ER-a je impliciran u mnogim hroničnim bolestima, ali se vrlo malo zna o hroničnom stresu ER-a uzrokovanog nedostatkom G6PT. Osim GSD tip I, postoji još šest hepatičnih GSD (tipovi 0, III, IV, VI, IX i XI), kao i desetine tipova GSD koje pogađaju skeletne mišiće, srce i druge organe. Pošto su posledice bolesti ozbilјne i ireverzibilne, molekularno-genetičko testiranje je od presudne važnosti za precizno postavlјanje dijagnoze i što raniju primenu adekvatne terapije...

Hepatic glycogen storage diseases (GSD) are inherited disorders of glycogen synthesis or degradation, which primarily affect the liver and kidneys. GSD type I is one of the most common types and takes a special place in the group of these diseases due to a recognizable clinical phenotype that clearly reflects the complex pathophysiology of disorders in glycogen metabolism. GSD type Ia and type Ib are due to a deficiency of an enzyme glucose-6-phosphatase α (G6Pase-α or G6PC) and endoplasmic reticulum (ER) glucose-6-phosphate translocase (G6PT or SLC37A4), respectively. G6Pase-α and G6PT form a functional complex on the ER membrane, that maintenance the blood glucose homeostasis between the meals, and its deficiency results in excessive accumulation of glycogen in the liver, kidney, and intestinal mucosa, leading to the hypoglycemia, hyperlactatemia, hyperlipidemia, hyperuricemia, and hepathonephromegaly. These metabolic abnormalities result in long-term complications of kidney diseases and hepatocellular adenomas/carcinoma, whose molecular mechanisms are poorly understood. Patients with GSD type Ib, also develop neutropenia and dysfunction of neutrophils and macrophages followed by recurrent bacterial infections, and symptoms of inflammatory bowel disease like Crohn’s disease. Considering the pathophysiological consequences of this metabolic stress, the adaptive responses and molecular markers which cells activate under such conditions are of great interest. It is known that disturbance of ER homeostasis, resulting from a loss of intracellular glucose production, leads to the chronic activation of the unfolded protein response (UPR), which contributes to the pathogenesis of many diseases. ER stress is implicated in many chronic diseases, but little is known how the UPR corresponds to the chronic ER stress caused by a deficiency of G6PT. Besides GSD type I, there are six additional hepatic GSD types (0, III, IV, VI, IX and XI), as well as dozens of GSD forms that affect skeletal muscles, heart and other organs. Since the consequences of the disease are serious and irreversible, molecular-genetic testing is crucial for precise diagnosis and applying the appropriate therapy as early as possible...

Hepatične glikogenoze, gen SLC37A4, sekvenciranje nove generacije, genotip-fenotip korelacija, tehnologija CRISPR/Cas9, stres endoplazmatičnog retikuluma, apoptoza

Hepatic glycogenosis, SLC37A4 gene, Next Generation Sequencing, genotype- phenotype correlations, CRISPR/Cas9 technology, endoplasmic reticulum stress, apoptosis

616-053.2:575.113.1:[616.36-008.6:612.122]:[575.21:575.22](043.3)

Tekst