https://www.um.edu.mt/library/oar/handle/123456789/31664 Sun, 05 Apr 2026 02:26:33 GMT 2026-04-05T02:26:33Z https://www.um.edu.mt/library/oar/handle/123456789/39642 Title: IFNGRI and TNFAIP3 in a Maltese family with a highly penetrant form of osteoporosis Abstract: Osteoporosis is a metabolic bone disease with a strong genetic component. It is characterised by decreased bone mineral density (BMD), deterioration of the micro architecture of bone and an increased susceptibility to fractures. In the last decade, much research using different approaches such as linkage and association, has been devoted to understand the genetic mechanism behind this complex trait. In this study, a linkage approach was taken. Suggestive linkage to chromosome 6q23-4 was reported from a genome-wide scan performed in a Maltese family with a history of osteoporosis. In this study, fine-mapping was carried by the use of additional microsatellite markers. Multipoint linkage analysis assuming dominant and recessive modes of inheritance with variable penetrance was performed. This revealed suggestive evidence linkage to a marker at 6q23-24, where a peak multipoint parametric LOD score of 1.91 and a non-parametric LOD score (NPL) of 7.06 were obtained under a dominant mode of inheritance with 90% penetrance and a phenocopy rate of 1 % by Easylinkage v5.05 using GENEHUNTER v2.1. Following fine-mapping, the putative susceptibility region was reduced from 20cM to that of 7cM. Based on the knowledge of bone physiology, interferon gamma receptor 1 (IFNGRl) and tumour necrosis factor alpha-induced protein factor 3 (TNFAIP3) were the two candidate genes sequenced. Both genes are located approximately I cM away from the indicated marker. A number of sequence variants were identified in IFNGRl, amongst which a novel non-synonymous sequence variant in exon 7, resulting in the amino acid change from valine to leucine at codon 289 (V289L). Sequencing of TNF AIP3 exons did not result in the identification of any sequence variants. Description: M.SC.PATHOLOGY Tue, 01 Jan 2008 00:00:00 GMT https://www.um.edu.mt/library/oar/handle/123456789/39642 2008-01-01T00:00:00Z https://www.um.edu.mt/library/oar/handle/123456789/38722 Title: Heroin addiction and associative learning Abstract: Associative Learning as a dysfunctional cognitive domain has been thoroughly investigated in disorders involving a hyperdopaminergic pathway. Kamin Blocking and Latent Inhibition tests have been used as operational tools to test associative learning in a sample of sixty male participants with ages ranging between sixteen and forty. Thirty nine of these were former heroin addicted individuals while the rest of the cohort were non-using controls. The heroin addicted group was further subdivided into individuals in Methadone Maintenance Programme (n=19) and Abstinent Abuser (n=20). The heroin addicted cohort displayed less Kamin blocking than the education-matched control group while in the Latent Inhibition test no such differences were apparent. Depressive symptoms were more evident in the MMP group while age of first use of heroin and family association of substance abuse did seem to correlate with the degree of blocking. Key words: heroin addiction, methadone maintenance, abstinence, depression, Kamin Blocking, latent Inhibition. Description: M.SC.PATHOLOGY Tue, 01 Jan 2008 00:00:00 GMT https://www.um.edu.mt/library/oar/handle/123456789/38722 2008-01-01T00:00:00Z https://www.um.edu.mt/library/oar/handle/123456789/34818 Title: Cognition in sepiapterin reductase deficiency Abstract: The title of this research is 'Cognition in Sepiapterin Reductase Deficiency'. The aim of this study is to explore the cognitive impairments found in individuals with Sepiapterin Reductase Deficiency (SRD). Using a quantitative approach, four cognitive tests were administered to seven SRD individuals along with seven age and gender-matched participants from a normal sample. The research question is 'What, if any, are the cognitive deficits found in an SRD sample?' The factors taken into consideration were: reasoning, spatial ability, memory, latent inhibition, kamin blocking and attention/concentration. The results obtained show that there is a significant difference in global non-verbal cognitive abilities when comparing the two groups. There is also a significant difference in the groups' results with regard to attention and concentration. The most important results that emerge from this study are the covert problems being faced by individuals with SRD. As such, these should be tackled by addressing all the effects of the disorder and not only the motor difficulties. Key Words: Sepiapterin Reductase Deficiency, Reasoning, Spatial Ability, Memory, Latent Inhibition, Kamin Blocking, Attention/Concentration. Description: M.SC.PATHOLOGY Tue, 01 Jan 2008 00:00:00 GMT https://www.um.edu.mt/library/oar/handle/123456789/34818 2008-01-01T00:00:00Z https://www.um.edu.mt/library/oar/handle/123456789/34219 Title: Sequencing of genes in two Maltese families with severe osteoporosis Abstract: Osteoporosis is a complex disease involving multiple genes, each contributing to the increased susceptibility of an individual to the disease. Following a genome-wide scan in two Maltese families with a high incidence of osteoporosis, chromosomal loci Sp 14, Sq34 and 11p12 were identified as areas of suggestive linkage (Vidal, 2007). Fine mapping at Sp14 was performed using 6 additional markers (D5S2054, D5S635, D5S1953, D5S208, D5S1486, D5S1954). Marker D5S1486 showed evidence of linkage with a non- parametric LOD (NPL) score of 4.41 (p= 0.0098) and a parametric LOD (pLOD) score of 1.98 for the dominant mode of inheritance. Searching the genome map at this region did not result in the identification of any plausible candidate genes which could be influencing bone physiology significantly. Fine mapping at 5q34 in one family (Family 1) showed evidence of linkage to marker D5S1960 with a NPL of 7.33 (p= 0.0005) and a pLOD score of 2.79 for the recessive mode of inheritance. Sequencing of the Msx2 gene located at 5q34- q35 did not reveal the presence of any causative variants. Fine mapping of chromosomal region 11p12 in the same family showed evidence of linkage to marker DllS4102 with a NPL score of 6.26 (p= 0.0078) and a pLOD score of 1.92 for the dominant mode of inheritance. Sequencing of exons and exon- intron boundaries of the EXT2 gene located at lip 12- P 11 did not result in the identification of any variants. The 11p12 region also showed evidence of linkage in Family 2 members to a marker D11S1392, with a NPL score of 5.86 (p= 0.0156) and a pLOD score of 1.77 for the dominant mode of inheritance. Sequencing of the CD44 gene found at position 11 p 13 identified three variants in intronic regions, one variant in exon 8, one in exon 9, two in exon 10 and one in exon 12. The most significant variant found was a synonymous G/A transition (rsll033026) in exon 9. This variant was found to be co-segregating with the marker haplotype in Family 2 members. It may be hypothesised that the G/ A synonymous transition in CD44 could result in altered binding of CD44 to its major ligand in bone OPN and thus to altered osteoclast activity. Functional studies may help shed light on the effect of the G/ A transition in CD44 on osteoporosis in this Maltese family. Description: M.SC.PATHOLOGY Tue, 01 Jan 2008 00:00:00 GMT https://www.um.edu.mt/library/oar/handle/123456789/34219 2008-01-01T00:00:00Z