IDENTIFYING GENETIC VARIANTS IMPLICATED IN PERRAULT SYNDROME FOR IMPROVED HEARING LOSS DIAGNOSIS AND THERAPEUTICS

UoM administered thesis: Phd

Abstract

Perrault syndrome is a rare autosomal recessive condition characterised by sensorineural hearing loss affecting both sexes and premature ovarian insufficiency in 46, XX females. Some affected individuals present with neurological features such as ataxia, neuropathies and intellectual disability. To date six genes which cause Perrault syndrome have been identified; HSD17B4, HARS2, LARS2, CLPP, C10orf2 and ERAL1. In many cases the genetic cause of Perrault syndrome is unknown. We used whole exome sequencing to identify the genetic basis of Perrault syndrome in nine affected families. In six families we identified variants in known Perrault syndrome genes and highlighted a genotype-phenotype link between the variant LARS2 c.1565C>A p.(T522N) and low frequency sensorineural hearing loss. We also found marfanoid habitus in Perrault syndrome is not genotype specific. In three families we identified putative pathogenic variants in three novel Perrault syndrome genes; PRORP, NOP14 and DAP3. Investigation of novel Perrault genes revealed a defect of mitochondrial translation is the likely pathogenic mechanism in the case of Perrault syndrome caused by variants in PRORP, but data from a patient with Perrault syndrome caused by DAP3 showed that this is unlikely to be the mechanism in all cases. PRORP is a subunit of mitochondrial RNase P, a mitochondrial tRNA processing complex. The variant in the affected family, PRORP p.A485V, reduced mitochondrial tRNA processing by 40% resulting in accumulation of unprocessed RNA transcripts and a defect of mitochondrial translation in patient fibroblasts. DAP3 is an essential subunit of the mitochondrial ribosome. In the proband with the variant DAP3 p.C395Y, which is in trans to a large deletion, there was no defect of mitochondrial translation seen in fibroblasts. The variant DAP3 p.C395Y likely affects a non-ribosomal role of DAP3 indicating a different Perrault Syndrome pathology to that of Perrault syndrome caused by defects of PRORP. NOP14 localises to the nucleolus and functions in ribosome biogenesis but our data suggests NOP14 may have a mitochondrial function. Haploinsufficiency of NOP14 in yeast causes the slow loss of mitochondria and we saw a distinct non-nucleolar localisation of Nop14 in the mouse organ of Corti. Perrault syndrome shows large genetic and phenotypic heterogeneity. We have identified three novel Perrault syndrome genes and shed some light on the molecular pathology of Perrault syndrome.

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Original languageEnglish
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Award date31 Dec 2017