RESEARCH PROJECTS
GMPPB VARIANT IDENTIFIED IN 3 CONSANGUINEOUS IRANIAN FAMILIES WITH LIMB-GIRDLE MUSCULAR DYSTROPHY THROUGH WHOLE-EXOME SEQUENCING
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Dystroglycanopathies make up a subset of muscular dystrophies, which result from the hypoglycosylation of the alpha subunit of the dystroglycan complex thus reducing the laminin binding affinity of the overall dystrophin-glycoprotein complex. Dystroglycanopathies present with a wide spectrum of clinical manifestations, where phenotypes range from congenial muscular dystrophy with brain and eye abnormalities to adult onset limb-girdle muscular dystrophy without any additional abnormalities. Currently there are 18 genes which have been associated with dystroglycanopathy and upon whole-exome sequencing and variant prioritization of 3 individuals from 3 separate consanguineous families of Iranian origin, a single variant in one of these known genes was identified in all 3 families. GDP – mannose pyrophosphorylase B (GMPPB) is a transferase protein involved in the production of dolichol phosphate mannose, a substrate required for the creation of O-mannosylated glycans. Further diagnostic weight of the GMPPB variant (c.C3308T:p.P103L) was gained by co-segregation analysis and homozygosity mapping. The pathogenicity of this variant was also discerned through application of guidelines for interpretation of sequence variants proposed by the College of Medical Genetics and Genomics in conjunction with signal-to-noise analysis of the primary structure of GMPPB. It was concluded that the GMPPB variant, c.C308T:p.P103L, found in all 3 families was ‘likely pathogenic’.
AN EXPLORATION OF NONSENSE INDUCED TRANSCRIPTIONAL COMPENSATION AS AN EXPLANATION FOR GENETIC ROBUSTNESS IN THE HUMAN POPULATION
Nonsense induced transcriptional compensation (NITC) is an intriguing mechanism by which organisms may achieve genetic robustness. To date, this mechanism has not been studied in the context of human genetics and increased understanding would aid future therapeutics. General trends in Loss of Function (LoF) tolerance and gene sequence similarity was first studied. This revealed that overall, genes with more LoF tolerance show significantly higher redundancy in the human genome with more regions of sequence similarity and by extension functional similarity which persisted after filtering data for essential genes. Following this, gene expression data was utilized to establish the presence of the NITC mechanism in humans and to subsequently characterise it. This association study identified a single significant association between a LoF mutation in PSG9 and the downregulation of PSG5 with substantial sequence similarity. Both genes are members of the same gene family and the LoF mutation was not located in a regulatory region however, the association was identified in an incongruent tissue. Lowering the threshold for significance revealed a further 17 associations, however these associations lacked matching gene ontologies between gene pairs. Overall, the findings presented here present a case for further investigation into NITC in humans.