Characterising the genetic basis of Perrault syndrome

Abstract

Perrault syndrome is a rare autosomal recessive condition characterised by bilateral sensorineural hearing loss with variable age of onset in both sexes and ovarian dysfunction in females who have a 46,XX karyotype. Neurological features including ataxia, neuropathy, intellectual disability and leukoencephalopathy have also been recorded in 40% of affected individuals. Perrault syndrome is a genetically heterogeneous condition as it is caused by biallelic hypomorphic variants in eight confirmed genes: HSD17B4, HARS2, LARS2, CLPP, TWNK, ERAL1, GGPS1 and RMND1. Work in our laboratory has revealed potential association with five additional genes: GPN2, DAP3, NOP14, MRPL49 and PRORP. Most genes discovered in association with Perrault syndrome have functions linked to the mitochondrial translation pathway. In my thesis I present data on the genetic and functional characterisation of nine families affected by Perrault syndrome with biallielic variants in GPN2 (three families), DAP3 (two families) and PRORP (four families). Evidence of the implication of GPN2 in Perrault syndrome and of its involvement in mitochondria is revealed here for the first time. The novel implication of DAP3 in Perrault syndrome and the relevance of GTPase activity of DAP3 in relation to the development of Perrault syndrome is discussed. The functional effect of variants in PRORP identified in patients with Perrault syndrome on mitochondrial tRNA processing is presented. The characterisation of the genetic basis of Perrault syndrome is expanded with evidence supporting the characterisation of three novel genes and providing an insight into the pathogenic mechanisms in mitochondria leading to hearing loss and infertility.

Date of Award	1 Aug 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Raymond O'Keefe (Supervisor) & William Newman (Supervisor)