Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder (PEX6), metabolic disorders (CLPP, GGPS1), and mtDNA maintenance/translation disorders (LARS2, TFAM)

Tucker, Elena J.; Rius, Rocío; Jaillard, Sylvie; Bell, Katrina M.; Lamont, Phillipa; Travessa, André; Dupont, Juliette; Sampaio, Lurdes; Jérôme, D.; Vuillaumier‐Barrot, Sandrine; Whalen, Sandra; Isapof, Arnaud; Stojkovic, Tanya; Quijano‐Roy, Susana; Robevska, Gorjana; Bergen, Jocelyn van den; Hanna, Chloe; Simpson, Andrea; Ayers, Katie; Thorburn, David R.; Christodoulou, John; Touraine, Philippe; Sinclair, Andrew H.

doi:10.1007/s00439-020-02176-w

Cited by 34 publications

(37 citation statements)

References 45 publications

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“…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.…”

Section: Clppmentioning

confidence: 70%

“…1). Two unrelated individuals with Perrault syndrome were reported as homozygous for missense variants (R261H and N90S) of GGPS1 (Tucker et al 2020). The substitutions of GGPS1 associated with Perrault syndrome are not located in the catalytic domain and are suggested to alter interactions with predicted, although presently unreported, binding partners important for function of GGPS1 in ovaries, ears and muscle (Foley et al 2020).…”

Section: Ggps1mentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Clppmentioning

confidence: 70%

Section: Ggps1mentioning

confidence: 99%

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

et al. 2021

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“…Recently, a group of researchers identified a homozygous predicted pathogenic missense mutation in TFAM [NM_003201.3: c.694C>T,NP_003192.1: p.(Arg232Cys)]. Their data suggest that pathogenic TFAM variants and consequently, defects in mtDNA maintenance can be fatal (early-onset liver disease) and cause some rare genetic disorders, like Perrault syndrome [36].…”

Section: Plos Onementioning

confidence: 99%

Characterization of post-edited cells modified in the TFAM gene by CRISPR/Cas9 technology in the bovine model

et al. 2020

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Gene editing in large animal models for future applications in translational medicine and food production must be deeply investigated for an increase of knowledge. The mitochondrial transcription factor A (TFAM) is a member of the HMGB subfamily that binds to mtDNA promoters. This gene maintains mtDNA, and it is essential for the initiation of mtDNA transcription. Lately, we generated a new cell line through the disruption of the TFAM gene in bovine fibroblast cells by CRISPR/Cas 9 technology. We showed that the CRISPR/Cas9 design was efficient through the generation of heterozygous mutant clones. In this context, once this gene regulates the mtDNA replication specificity, the study aimed to determine if the post-edited cells are capable of in vitro maintenance and assess if they present changes in mtDNA copies and mitochondrial membrane potential after successive passages in culture. The post-edited cells were expanded in culture, and we performed a growth curve, doubling time, cell viability, mitochondrial DNA copy number, and mitochondrial membrane potential assays. The editing process did not make cell culture unfeasible, even though cell growth rate and viability were decreased compared to control since we observed the cells grow well when cultured in a medium supplemented with uridine and pyruvate. They also exhibited a classical fibroblastoid appearance. The RT-qPCR to determine the mtDNA copy number showed a decrease in the edited clones compared to the non-edited ones (control) in different cell passages. Cell staining with Mitotracker Green and red suggests a reduction in red fluorescence in the edited cells compared to the non-edited cells. Thus, through characterization, we demonstrated that the TFAM gene is critical to mitochondrial maintenance due to its interference in the stability of the mitochondrial DNA copy number in different cell passages and membrane potential confirming the decrease in mitochondrial activity in cells edited in heterozygosis.

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“…PRLTS is characterized by the presence of sensorineural HL in both males and females and ovarian dysfunction ranging from gonadal dysgenesis to POI in females. These are the two PRLTS cardinal features; however, in some individuals additional, usually neurological conditions (e.g., developmental delay, cognitive impairment, ataxia or sensory axonal neuropathy) have been also reported ( Table 3 ) [ 33 ]. Taking into account the heterogeneity of PRLTS phenotypic manifestations, in our opinion, it seems justified to recognize RMND1 as the seventh PRLTS gene, where renal involvement represents an additional characteristic finding and no neurological signs or symptoms are found (neither in the patient reported by Demain [ 6 ] nor in our patients).…”

Section: Discussionmentioning

confidence: 99%

Two Novel Pathogenic Variants Confirm RMND1 Causative Role in Perrault Syndrome with Renal Involvement

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et al. 2020

Genes

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RMND1 (required for meiotic nuclear division 1 homolog) pathogenic variants are known to cause combined oxidative phosphorylation deficiency (COXPD11), a severe multisystem disorder. In one patient, a homozygous RMND1 pathogenic variant, with an established role in COXPD11, was associated with a Perrault-like syndrome. We performed a thorough clinical investigation and applied a targeted multigene hearing loss panel to reveal the cause of hearing loss, ovarian dysfunction (two cardinal features of Perrault syndrome) and chronic kidney disease in two adult female siblings. Two compound heterozygous missense variants, c.583G>A (p.Gly195Arg) and c.818A>C (p.Tyr273Ser), not previously associated with disease, were identified in RMND1 in both patients, and their segregation with disease was confirmed in family members. The patients have no neurological or intellectual impairment, and nephrological evaluation predicts a benign course of kidney disease. Our study presents the mildest, so far reported, RMND1-related phenotype and delivers the first independent confirmation that RMND1 is causally involved in the development of Perrault syndrome with renal involvement. This highlights the importance of including RMND1 to the list of Perrault syndrome causative factors and provides new insight into the clinical manifestation of RMND1 deficiency.

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Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder (PEX6), metabolic disorders (CLPP, GGPS1), and mtDNA maintenance/translation disorders (LARS2, TFAM)

Cited by 34 publications

References 45 publications

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

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

Characterization of post-edited cells modified in the TFAM gene by CRISPR/Cas9 technology in the bovine model

Two Novel Pathogenic Variants Confirm RMND1 Causative Role in Perrault Syndrome with Renal Involvement

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