Genetic basis of hereditary persistence of fetal haemoglobin

This thesis investigated the extent to which genetic factors underlie the variations observed in fetal haemoglobin (HbF) levels. This is important as it is known that an elevated HbF level can ameliorate the symptoms of many of the haemoglobinopathies. The frequency and range of hereditary persistence of fetal haemoglobin (HPFH) in the UK population was determined which was otherwise unknown. All 4 categories of deletion mutations were identified and demonstrated the high frequency of deletional HPFH in UK patients. Four potentially novel deletions were identified and 2 fully characterised. One novel deletion was the first reported case of a large b0-thalassaemia deletion mutation in the Afghan population. Mutations in the g-globin gene promoters were identified as a frequent (21% of patients) cause of non-deletion HPFH in the UK. The majority of mutations being in white British individuals with elevated HbF levels only, probably arisen independently through genetic drift. The strongest association with the three polymorphisms and HbF expression was seen in b-thalassaemia trait subjects with the XmnI-HBG2 polymorphism. The SNPs in BCL11A and HBS1L-MYB failed to show statistical correlations with HbF. Heterozygosity for ten novel mutations in the KLF1 gene were indentified in patients with a high HbF indicating that a single altered KLF1 allele can elevate HbF. The identification of a KLF1 mutation in an individual with a particularly mild form of sickle cell disease could provide in-vivo evidence that controlled reduction of KLF1 expression could be an effective treatment for sickle cell disease. Finally, the finding that Asian Indian newborns undergo haemoglobin switching earlier than other ethnic groups was investigated. Birth weight, gestation and chromosomal abnormalities were not responsible and the frequency of the 4.9kb g-thalassaemia deletion mutation was determined to be low.

Grantor dc:publisher

Oxford Brookes University

Year dc:date

2013

Author dc:creator

• Gallienne, A

Statement dc:rights

• All rights reserved

Language dc:language

en

Repository record dc:identifier

https://radar.brookes.ac.uk/radar/items/91191227-5bd3-4e2b-9f8b-8998677e0439/1/

OAI identifier oai:identifier

tle:91191227-5bd3-4e2b-9f8b-8998677e0439:d6bd9758-527a-46cd-bfe2-c433766e8fca:1