Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Apr;141(3-4):805-819.
doi: 10.1007/s00439-021-02319-7. Epub 2021 Aug 2.

New insights into Perrault syndrome, a clinically and genetically heterogeneous disorder

Affiliations
Review

New insights into Perrault syndrome, a clinically and genetically heterogeneous disorder

Rabia Faridi et al. Hum Genet. 2022 Apr.

Abstract

Hearing loss and impaired fertility are common human disorders each with multiple genetic causes. Sometimes deafness and impaired fertility, which are the hallmarks of Perrault syndrome, co-occur in a person. Perrault syndrome is inherited as an autosomal recessive disorder characterized by bilateral mild to severe childhood sensorineural hearing loss with variable age of onset in both sexes and ovarian dysfunction in females who have a 46, XX karyotype. Since the initial clinical description of Perrault syndrome 70 years ago, the phenotype of some subjects may additionally involve developmental delay, intellectual deficit and other neurological disabilities, which can vary in severity in part dependent upon the genetic variants and the gene involved. Here, we review the molecular genetics and clinical phenotype of Perrault syndrome and focus on supporting evidence for the eight genes (CLPP, ERAL1, GGPS1, HARS2, HSD17B4, LARS2, RMND1, TWNK) associated with Perrault syndrome. Variants of these eight genes only account for approximately half of the individuals with clinical features of Perrault syndrome where the molecular genetic base remains under investigation. Additional environmental etiologies and novel Perrault disease-associated genes remain to be identified to account for unresolved cases. We also report a new genetic variant of CLPP, computational structural insight about CLPP and single cell RNAseq data for eight reported Perrault syndrome genes suggesting a common cellular pathophysiology for this disorder. Some unanswered questions are raised to kindle future research about Perrault syndrome.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest None to declare.

Figures

Fig. 1
Fig. 1
The eight genes to date reported to be associated with Perrault syndrome, their pathogenic variants and locations in the exons or introns of these genes. There are two published deletions of CLPP that are in compound heterozygosity with amino acid substitutions. Deletion 1 was reported to be in trans to p.G162S while deletion 2 was in trans to p.P142L (Theunissen et al. 2016). For HARS2, # indicates variants that are associated with sensorineural hearing loss (Supplementary Table 1 for all reported variants and references). The ## for a variant of HSD17B4 indicates an association with premature ovarian failure while D/PS indicates variants associated with d-bifunctional protein deficiency/Perrault syndrome Type 1. The p.R663W variant of LARS2 was previously associated with Intellectual Disability (Cherot et al. 2018) although the same variant was reported for Perrault syndrome (Tucker et al. 2020). The homozygous N238S variant of RMND1 is associated with a Perrault-like syndrome with renal defects. Interestingly, the same variant in compound heterozygosity with p.Gln189* or c.613G > T is associated with a more severe phenotype that also includes chronic kidney disease, dilated cardiomyopathy, neurological involvement, neonatal lactic acidosis and deafness (Broenen et al. 2019; Gupta et al. 2016; Janer et al. 2015; Ravn et al. 2016; Shayota et al. 2019)
Fig. 2
Fig. 2
Structural models of amino acid substitutions of CLPP protein associated with Perrault syndrome. a Human CLPP X-ray structure without a ligand bound (apo) and with ONC201 bound (CLPP ring1) superimposed on the CLPP-CLPX complex formed by two CLPP rings and one heptamer of CLPX. ONC201 is shown as sticks in mustard color and the CLPP heptamer corresponding to the apo structure. CLPP and CLPX are represented as cartoon where the superimposed apo CLPP (ring 1) is highlighted in a different color per protomer, while the remainder CLPP heptamer (ring2) and the CLPX pentamer (corresponding to the CLPP-CLPX structure) are gray and red colored. The C-alphas of the residues mutated in Perrault syndrome are shown as spheres only in one of the CLPP protomers (green) where the residues in or close to the CLPX binding site are dark-green colored. b Structural comparison of the interacting networks where C86, T135, C144 G162 and Y229 participate in the WT and the corresponding modelled variant. As before, the model of each mutant was structurally superimposed on the CLPP-CLPX complex. The interactions between residues are shown as dashed lines and the residues participating in each interacting network are shown as sticks
Fig. 3
Fig. 3
Cochlear localization of Perrault syndrome genes using single-cell and single-nucleus RNA-Seq datasets to pinpoint the possible cell types associated with deafness in this genetically heterogenous disorder. Single-cell RNA-Seq datasets from the P7 mouse organ of Corti (Kolla et al. 2020) and P25–27 mouse spiral ganglion neurons (Shrestha et al. 2018) along with a published P30 adult mouse stria vascularis single-nucleus RNA-seq dataset (Gu et al. 2020) were utilized to identify Perrault gene expression levels in the cell types of the inner ear. Heatmaps display Perrault syndrome-associated genes along the vertical axis and cell types are grouped along the horizontal axis. Expression is in normalized counts scaled from 0 to 1. Higher expression of a gene of interest is indicated by an increasing darker purple color. a Heatmap of Perrault syndrome gene expression among P30 stria vascularis cell types including marginal, intermediate, basal, spindle, root, and Reissner’s membrane cells, as well as macrophages. Note the low level of expression of these genes across the stria vascularis. b Heatmap of Perrault syndrome gene expression among cell types in the P7 organ of Corti including inner hair cells (IHC), outer hair cells (OHC), pillar cells, and Deiters cells. Note the low level of expression of Clpp in these cell types in the organ of Corti. c Heatmap of Perrault syndrome gene expression among type 1 (1A, 1B, and 1C) and type 2 spiral ganglion neurons (SGN). Note that the prominent expression of these Perrault syndrome-associated genes across all SGN types suggests the hypothesis that the hearing loss for variants of the majority of Perrault syndrome genes is related to dysfunctional SGNs

Similar articles

Cited by

References

    1. Bae JW et al. (2019) Ras-related proteins (Rab) are key proteins related to male fertility following a unique activation mechanism. Reprod Biol 19:356–362. 10.1016/j.repbio.2019.10.001 - DOI - PubMed
    1. Baes M, Huyghe S, Carmeliet P, Declercq PE, Collen D, Mannaerts GP, Van Veldhoven PP (2000) Inactivation of the peroxisomal multifunctional protein-2 in mice impedes the degradation of not only 2-methyl-branched fatty acids and bile acid intermediates but also of very long chain fatty acids. J Biol Chem 275:16329–16336. 10.1074/jbc.M001994200 - DOI - PubMed
    1. Ben-Yosef T et al. (2003) Claudin 14 knockout mice, a model for autosomal recessive deafness DFNB29, are deaf due to cochlear hair cell degeneration. Hum Mol Genet 12:2049–2061. 10.1093/hmg/ddg210 - DOI - PubMed
    1. Bonner ER, Waszak SM, Grotzer MA, Mueller S, Nazarian J (2020) Mechanisms of imipridones in targeting mitochondrial metabolism in cancer cells. Neuro Oncol. 10.1093/neuonc/noaa283 - DOI - PMC - PubMed
    1. Brodie EJ, Zhan H, Saiyed T, Truscott KN, Dougan DA (2018) Perrault syndrome type 3 caused by diverse molecular defects in CLPP. Sci Rep 8:12862. 10.1038/s41598-018-30311-1 - DOI - PMC - PubMed

Supplementary concepts

LinkOut - more resources