Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome

Abstract

Perrault syndrome is a genetically heterogeneous recessive disorder characterized by ovarian dysgenesis and sensorineural hearing loss. In a nonconsanguineous family with five affected siblings, linkage analysis and genomic sequencing revealed the genetic basis of Perrault syndrome to be compound heterozygosity for mutations in the mitochondrial histidyl tRNA synthetase HARS2 at two highly conserved amino acids, L200V and V368L. The nucleotide substitution creating HARS2 p.L200V also created an alternate splice leading to deletion of 12 codons from the HARS2 message. Affected family members thus carried three mutant HARS2 transcripts. Aminoacylation activity of HARS2 p.V368L and HARS2 p.L200V was reduced and the deletion mutant was not stably expressed in mammalian mitochondria. In yeast, lethality of deletion of the single essential histydyl tRNA synthetase HTS1 was fully rescued by wild-type HTS1 and by HTS1 p.L198V (orthologous to HARS2 p.L200V), partially rescued by HTS1 p.V381L (orthologous to HARS2 p.V368L), and not rescued by the deletion mutant. In Caenorhabditis elegans, reduced expression by RNAi of the single essential histydyl tRNA synthetase hars-1 severely compromised fertility. Together, these data suggest that Perrault syndrome in this family was caused by reduction of HARS2 activity. These results implicate aberrations of mitochondrial translation in mammalian gonadal dysgenesis. More generally, the relationship between HARS2 and Perrault syndrome illustrates how causality may be demonstrated for extremely rare inherited mutations in essential, highly conserved genes.

LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure

“…In some cases, overlapping clinical features have been observed from mutations in different genes. For instance, mutations in HARS2 and LARS2 are both associated with sensorineural hearing loss and progressive ovarian failure (OMIM 614926) (Pierce et al 2011;Pierce et al 2013). However, in other cases, different mutations in the same gene result in distinct phenotypes.…”

Perrault Sendromunun genetik patogenezi

“…Although HSD17B4, mitochondrial histidyl tRNA synthetase (HARS2) and EIF2B should be examined in other cases, it may be time to classify PS type II under the leukodystrophies. The report of Pierce et al (8), represents a valuable contribution, because recent findings in genetic research have suggested that a large number of genetic disorders are highly related in the genotypical root. For example; Alstrom syndrome has begun to be classsified as a ciliopathy (10).…”

“…Long term follow up is very important, since some clinical manifestations appear later in life. Pierce et al (8) evaluated the sisters MK and LK, whose clinical manifestations had been thoroughly described previously by Fiumara et al (13) and Mc Carthy and Opitz (14). Therefore, these sisters are the only cases who have such a detailed clinical history, multidiciplinary approach and long term follow up.…”

“…Previously, partial deficiency of the mitochondrial enzyme cytochrome c oxidase and muscle coenzyme Q10 (CoQ10) deficiency was reported in cases with PS (4,5). Recently, mutations in 17 beta-hydroxysteroid dehydrogenase type 4 (also known as D-bifunctional protein (HSD17B4/DBP)) which is also involved in Zellweger syndrome, one of three leukodystrophies and mitochondrial histidyl tRNA synthetase (HARS2) also implicated, in the leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL), have been proposed as the genetic causes of PS (6)(7)(8). The "ovarioleukodystrophies" comprise a group of rare leukodystrophies associated with POI.…”

Challenges of Bringing Next Generation Sequencing Technologies to Clinical Molecular Diagnostic Laboratories

“…The NGS technology has been used to discover many novel genes that cause mitochondrial related disorders on research bases [1,[9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. It is now time to bring this technology to clinical diagnosis.…”