A known pathogenic variant in the essential mitochondrial translation gene <i>RMND1</i> causes a Perrault‐like syndrome with renal defects

Demain, Leigh A.M.; Antunes, Diana; O’Sullivan, James; Bhaskhar, S.S.; O’Keefe, Raymond T.; Newman, William G.

doi:10.1111/cge.13255

Cited by 15 publications

(13 citation statements)

References 6 publications

(9 reference statements)

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“…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: 75%

“…Our clinical and genetic investigation shows that a combination of HL, ovarian dysfunction, and CKD constitutes a milder end of the RMND1 -related phenotypic spectrum. Presence of the three clinical features can be defined as Perrault-like syndrome [ 6 ], PRLTS with renal involvement or just PRLTS with a respective consecutive number, according to the nomenclature used by OMIM (Online Mendelian Inheritance in Man, ), where subsequent numbers are assigned to a syndrome in order to distinguish the causative gene. 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.…”

Section: Discussionmentioning

confidence: 99%

“…It was manifested by cystic dysplasia, renal tubular acidosis (persistent hyponatremia and hyperkalemia), end stage renal failure with subsequent kidney transplantation, anemia, proteinuria or CKD at different stages. The single, so far described, patient with PRLTS and RMND1 homozygous pathogenic variant [ 6 ] had distal renal tubular acidosis with hyperchloremic metabolic acidosis, a normal anion gap, mildly elevated uric acid, low urine citrate levels, normal calcium levels, and a normal renal ultrasound. CKD was mentioned, but exact kidney function has not been given.…”

Section: Discussionmentioning

confidence: 99%

“…Ovarian dysfunction (ovarian atrophy and hypergonadotropic hypogonadism) as a consequence of RMND1 pathogenic variants has been previously reported only once in a patient described by Demain et al [ 6 ] and in none of the approximately 40 patients with OXPHOS deficiency. This could be explained by the early, prepubertal age at which the majority of children were investigated [ 4 , 5 , 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…The individual reported by Demain et al suffered from sensorineural hearing loss (HL) and primary ovarian insufficiency (POI), defining clinical features of PRLTS, in addition to renal dysfunction and short stature. The phenotype was delineated based on exome sequencing data from a single patient [ 6 ]. Considering the absence of another reported disease-causing variant, a doubt may arise as to whether RMND1 is related to PRLTS development.…”

Section: Introductionmentioning

confidence: 99%

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

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Stępniak

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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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

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Pazik

Stępniak

et al. 2020

Genes

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The ever wider clinical spectrum of RMND1-related disorders and limitedness of phenotype-based classifications

et al. 2023

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RMND1 has been identified as a mitochondriopathy-associated gene less than 12 years ago. The most common phenotype related to this gene is an early onset, severe form of encephalomyopathy that leads to death in a medium time of three years after birth. However, milder and later onset presentations have been reported in some individuals, including two in whom the mitochondriopathy was identified at ~ 40 years of age, and the early onset presentations have been the object of no reports in those who survived beyond age 10. It is thus unclear how lethal RMND1-related conditions really are. We herein describe the oldest case to have been identified hitherto with this condition, i.e., that of a white female who was 61 at the time of diagnosis but was still active in her everyday life. The gene defect identified was nonetheless associated with many manifestations including ovarian insufficiency and sensorineural hearing loss (two features of what is currently designated as Perrault syndrome) as well as chronic renal failure, asymptomatic myopathy, leukopenia, and a few others. In our opinion, this case is of great translational interest for at least three reasons. First, it hints towards the possibility of near-normal life expectancies in some if not many individuals with RMND1 insufficiency. Second, it underlines the wide clinical spectrum associated with this gene. Third, it brings us to question the use of eponyms and syndromic features to identify the true etiology of multisystemic phenotypes. Key messages RMND1-related conditions typically manifest at an early age with a progressive and lethal form of encephalomyopathy. More benign presentations have been described with some being categorized as Perrault syndrome but none have been diagnosed after the age of 45. The clinical spectrum and presenting age of RMND1-related mitochondriopathies are probably much more varied than implied in the current literature. The case reported in this manuscript illustrates the limitedness of phenotype-based classifications of genetic disorders to identify the defect at cause.

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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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A known pathogenic variant in the essential mitochondrial translation gene RMND1 causes a Perrault‐like syndrome with renal defects

Cited by 15 publications

References 6 publications

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

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

The ever wider clinical spectrum of RMND1-related disorders and limitedness of phenotype-based classifications

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

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