Raznolikost fenotipova uzrokovanih mutacijom gena CACNA1

master's thesis

• Title (english): Phenotypic diversity in patients with CACNA1 gene mutation
• Author: Vana Vukić
• Mentor: Nina Barišić (mentor)
• Committee member: Irena Senečić-Čala (predsjednik povjerenstva)
• Committee member: Marija Jelušić (član povjerenstva)
• Committee member: Nina Barišić (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Pediatrics); Zagreb
• Defense date and country: 2020-07-17, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Pediatrics
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Neurology

Abstract

Kalcijevi kanali regulirani naponom široko su rasprostranjeni u središnjem živčanom sustavu gdje posreduju utok iona kalcija u stanicu u odgovoru na depolarizaciju. To omogućuje egzocitozu neurotransmitera, regulaciju ekspresije gena i brojne druge fiziološke funkcije. α - podjedinica tvori senzor napona i poru kanala kroz koju ulaze kalcijevi ioni. Poznato je 10 različitih α - podjedinica kodirano CACNA1 genima. Mutacije CACNA1 implicirane su u razvoju brojnih neuroloških poremećaja. Mutacije CACNA1A gena, koji kodira α - podjedinicu P/Q - tipa kalcijevog kanala, dosada su pokazale najveću raznolikost fenotipa. Uzrokuju familijarnu hemiplegičnu migrenu tip 1, vrstu migrene s aurom karakteriziranom hemiplegijom. Epizodička ataksija tip 2 i spinocerebelarna ataksija tip 6 bolesti su koje poglavito oslikavaju zahvaćenost cerebeluma, što nije neuobičajeno budući da su P/Q - kanali tamo široko rasprostranjeni. Epizodička ataksija karakterizirana je povremenim simptomima poremećaja cerebelarne funkcije na početku bolesti, no s vremenom simptomi postaju trajno prisutni, a bolest progresivna. Spinocerebelarna ataksija je sporo progresivna bolest, koja se, u većini slučajeva, javlja u srednjoj do starijoj životnoj dobi. Dostignuća molekularne tehnologije omogućila su identifikaciju ostalih fenotipova. Otkrivena je povezanost mutacija CACNA1A gena s razvojem epileptičke encefalopatije, što je u ovom radu dodatno naglašeno prikazom dvoje pacijenata s tom dijagnozom. Refraktorne epilepsije, zastoj u razvoju i ostali neuropsihijatrijski poremećaji najčešće su posljedica de novo mutacija. Osim CACNA1A, de novo mutacije ostalih CACNA1 gena povezane su s ekspresijom sličnih fenotipova i ukratko prikazane.

Abstract (english)

Voltage-gated calcium channels are expressed abundantly throughout the central nervous system. They mediate calcium influx in cells in response to membrane depolarization. This step is crucial for neurotransmitter exocytosis, regulation of gene expression, and other physiological functions. 10 CACNA1 genes code for alpha subunits that incorporate the voltage sensor and channel pore. CACNA1 encodes the alpha subunit of P/Q - calcium channel. Mutations of many of CACNA1 genes cause neurological disorders. CACNA1A gene mutations hold the greatest phenotypic diversity. Hemiplegia in the aura phase defines familial hemiplegic migraine type 1. Cerebellar dysfunction, as a consequence of high P/Q - channel expression in cerebellum, is best represented by episodic ataxia type 2 and spinocerebellar ataxia type 6. Episodes of cerebellar dysfunction characterize the beginning of episodic ataxia, but symptoms progress and become permanent in the later course of the disease. Spinocerebellar ataxia begins at an older age and progresses slowly. Advances in molecular technology provided the establishment of more phenotypes. A correlation between epileptic encephalopathy and CACNA1A mutations has been observed. This paper presents two patients with the disease and confirms the association. De novo mutations are usually the cause of refractory epilepsy, developmental delay, and various neuropsychiatric disorders. De novo mutations in other CACNA1 genes give rise to similar phenotypes.

• Keywords: ataksija; CACNA1; CACNA1A; cerebelum; epileptička encefalopatija
• Keywords (english): ataxia; CACNA1; CACNA1A; cerebellum; epileptic encephalopathy
• Language: croatian
• URN:NBN: urn:nbn:hr:105:115338
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2021-08-27 09:09:24