Expanding the genotypic spectrum of Perrault syndrome

Abstract

Perrault syndrome is a rare autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) in both sexes and primary ovarian insufficiency in 46, XX karyotype females. Biallelic variants in five genes are reported to be causative: HSD17B4, HARS2, LARS2, CLPP and C10orf2. Here we present eight families affected by Perrault syndrome. In five families we identified novel or previously reported variants in HSD17B4, LARS2, CLPP and C10orf2. The proband from each family was whole exome sequenced and variants confirmed by Sanger sequencing. A female was compound heterozygous for a known, p.(Gly16Ser) and novel, p.(Val82Phe) variant in D‐bifunctional protein (HSD17B4). A family was homozygous for mitochondrial leucyl aminocyl tRNA synthetase (mtLeuRS) (LARS2) p.(Thr522Asn), previously associated with Perrault syndrome. A further family was compound heterozygous for mtLeuRS, p.(Thr522Asn) and a novel variant, p.(Met117Ile). Affected individuals with LARS2 variants had low frequency SNHL, a feature previously described in Perrault syndrome. A female with significant neurological disability was compound heterozygous for p.(Arg323Gln) and p.(Asn399Ser) variants in Twinkle (C10orf2). A male was homozygous for a novel variant in CLPP, p.(Cys144Arg). In three families there were no putative pathogenic variants in these genes confirming additional disease‐causing genes remain unidentified. We have expanded the spectrum of disease‐causing variants associated with Perrault syndrome.

Selective Activation of Human Caseinolytic Protease P (ClpP)

“…A2,6-configuration of chlorine and fluorine (7)s howed almost no activity.Derivatives with only one halogen substituent at various positions (3,5,8,9)showed reduced activation potential. These results indicate that halogen substitutions at the benzyl moiety of D9 are essentially required to boost hClpP activity.A si tw as previously reported that simplified variants of ADEPs retain their activation potential as long as they keep the phenylalanine recognition motif, [22] we probed the benzodioxole part of D9 for tolerating structural modifications in as econd set of analogues (14)(15)(16)(17)(18)(19)(20). These results indicate that halogen substitutions at the benzyl moiety of D9 are essentially required to boost hClpP activity.A si tw as previously reported that simplified variants of ADEPs retain their activation potential as long as they keep the phenylalanine recognition motif, [22] we probed the benzodioxole part of D9 for tolerating structural modifications in as econd set of analogues (14)(15)(16)(17)(18)(19)(20).…”

“…[10,11] Furthermore,a lso small molecules were shown to exert conformational control. [16][17][18] Dissecting the molecular details of hClpPsc onformational activation will lead to abetter understanding of mitochondrial protein homeostasis and disease mechanisms. [12,13] Ad ifferent class of molecules, activators of self-compartmentalizing proteases (ACPs), also are thought to address the same pockets and thereby efficiently activate ClpP from Escherichia coli (EcClpP).…”

“…An unsubstituted benzyl group (6)a sw ell as ab enzyl group bearing electron-donating methoxy (12,13), methylenedioxy (10)a nd methyl (11) groups showed no activation effect. Fore xample,achange to am ethoxy-substituted benzyl (14)a nd extension of the carbon linker (15)w ere tolerated, however,i ntroduction of hydroxy (16), alkyl (17), dimethoxy (18), alkyne (19), or imidazole (20)g roups either reduced or abolished activity suggesting that both parts of D9 underlie constraints for stimulating hClpP peptidolysis. Fore xample,achange to am ethoxy-substituted benzyl (14)a nd extension of the carbon linker (15)w ere tolerated, however,i ntroduction of hydroxy (16), alkyl (17), dimethoxy (18), alkyne (19), or imidazole (20)g roups either reduced or abolished activity suggesting that both parts of D9 underlie constraints for stimulating hClpP peptidolysis.…”

Specific MRI Abnormalities Reveal Severe Perrault Syndrome due to CLPP Defects

“…Comparable symptoms have previously been reported in seven other families with CLPP defects (Table 2) (16, 21–24). Apart from the consistent involvement of SNHL, sex-related clinical features have been reported such as female ovarian dysgenesis and infertility due to azoospermia in males (15, 22). Our male patients were not tested for infertility.…”

Selektive Aktivierung der humanen caseinolytischen Protease P (ClpP)

“…[7][8][9] Ein Hauptmerkmal dieser Ausprägungen ist die Orientierung der zentralen E-Helix, die kritische Kontakte zwischen den Heptamer-Ringen in der tetradekameren, gestreckten Va riante bildet und direkt mit dem aktiven Zentrum verbunden ist. [16][17][18] Die Analyse der molekularen Details der hClpP-Funktion, sprich der konformationellen Aktivierung,k ann somit zu einem besseren Verständnis der mitochondrialen Proteinhomçostase und Krankheitsmechanismen führen. [10,11] Daneben kçnnen auch niedermolekulare Verbindungen konformationelle Kontrolle ausüben.…”