Impact of genetic background and molecular mechanisms on Prader-Willi syndrome phenotype

master's thesis

• Title (croatian): Utjecaj genotipa i molekularnih mehanizama na fenotip Prader-Willijevog sindroma
• Author: Patrick Michael Galvano
• Mentor: Mario Ćuk (mentor)
• Committee member: Mario Ćuk (predsjednik povjerenstva)
• Committee member: Danko Milošević (član povjerenstva)
• Committee member: Marija Jelušić (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

Abstract

Prader-Willi syndrome (PWS) is a complex disorder with a vast variable clinical presentation, resulting from the loss of paternally inherited genes on chromosome 15q11-q13. The loss of expression of one or more genes located within the PWS critical region results in the various phenotypes. PWS can occur via three different distinct genetic mechanisms including paternal deletion of the 15q11-q13, maternal uniparental disomy (mUPD), or imprinting defects. Although there are some clinical symptoms that are shared among PWS patients, the overall complexity of the syndrome results in unique clinical presentations, emphasizing the importance of genetic diagnosis and counseling, where individual based therapy can be implemented. DNA methylation status was first confirmed, followed by the identification of one of the three molecular mechanisms. Individuals who suffered from paternal deletions shared common symptoms like low birth weight, lower IQ, hypopigmentation and maladaptive behaviours. The type of PWS deletion (type I or II) also impacts the clinical presentation, with type I patients having a more severe presentation and acquiring speech later than those with type II. Individuals with mUPD tend to present with lower birth length, various sleep disorders, psychosis and Autism Spectrum Disorder (ASD). In addition, the average maternal age in the mUDP patients was higher than those with deletions. No single gene mutation has been shown to contribute to PWS or related to any exclusive symptoms. Although some genes like MKRN3, MAGEL2, NDN do not address the full spectrum of symptoms, others have noted that SNORD116 located within the SNURF-SNRPN complex has become a critical candidate for PWS due to its role in growth
retardation and neuroendocrine disturbances leading to hyperphagia and obesity. The broad spectrum of PWS observed in patients and the absence of a clear genotype-phenotype relationship, implies that various genes involved, have an intensified effect on the various phenotypes when lost.

Abstract (croatian)

Prader-Willijev sindrom (PWS) je složen poremećaj s promjenjivom kliničkom slikom, koji nastaje kao posljedica gubitka funkcije očevih gena na kromosomu 15q11-q13. Gubitak ekspresije jednog ili više gena smještenih unutar PWS kritične regije rezultira rpojavom različitih fenotipova. PWS se može pojaviti putem tri različita genetska mehanizma, uključujući deleciju očevih gena u određenoj regiji kromosoma 15q11-q13, majčinsku uniparentalnu disomiju (mUPD) ili defekt genomskog upisa. Iako postoje neki klinički simptomi koji su jednaki među pacijentima sa PWS-om ukupna složenost sindroma rezultira jedinstvenom kliničkom slikom naglašavajući važnost genetske dijagnoze i savjetovanja, nakon kojih se može provesti individualna terapija. Prvo se potvrđuje status metilacije DNA, a zatim slijedi identifikacija jednog od tri molekularna mehanizma. Pojedinci koji pate od delecije DNA oca dijele uobičajene simptome poput niske tjelesne težine, nižeg IQ-a, hipopigmentacije i neprilagođenog ponašanja. Tip delecije (tip I ili II) također utječe na kliničku prezentaciju, gdje pacijenti s tipom I imaju jače izraženu kliničku sliku i kasnije usvajaju govor od onih s tipom II. Pojedinci s mUPD-om pretežito imaju manju porođajnu dužinu, razne poremećaje spavanja, psihozu i poremećaje iz spektra autizma (ASD). Prosječna dob majke u mUDP bolesnika je viša od one s deletacijama. Dokazano je da nijedna specifična mutacija ne uzrokuje PWS ili je povezana s bilo kojim isključivim simptomima. Iako se neki geni poput MKRN3, MAGEL2, NDN ne bave čitavim spektrom simptoma, primjećeno da je SNORD116 smješten u kompleksu SNURF-SNRPN postao kritični kandidat za PWS zbog njegove uloge u usporavanju rasta i poremećaja neuroendokrinog poremećaja koji dovode do hiperfagije i pretilosti. Široki spektar simptoma koji se nalazi u PWS-u i odsutnost jasnog odnosa genotip-fenotip podrazumijeva da različiti geni, kada nisu izraženi, imaju akumulativni učinak na različite fenotipove.

• Keywords: Prader-Willi syndrome; genotype; phenotype; maternal uniparental disomy
• Keywords (croatian): Prader-Willijev sindrom; genotip; fenotip; majčinska uniparentalna disomija
• Language: english
• URN:NBN: urn:nbn:hr:105:512794
• Study programme: Title: Medicine (in English language); 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: 2021-10-05 10:10:05