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

Dominika Oziębło,Joanna Pazik,Iwona Stępniak,Monika Ołdak,Henryk Skarżyński

doi:10.3390/genes11091060

Abstract

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.

Highlights

RMND1 is a nuclear gene that encodes a protein needed for proper functioning of mitochondria
The major clinical features of the proband, a 44-year old female, and her sister, a 36-year old female, were severe-to-profound bilateral sensorineural hearing loss (HL) (Figure 1B) and ovarian dysfunction accompanied by chronic kidney disease (CKD) that developed in the fourth decade of life
Laboratory findings on renal involvement, blood lactate concentration and core parameters of venous acid-base balance are given in Table 1, as shown by eGFR and UACR both patients were in stage

Summary

Introduction

RMND1 (required for meiotic nuclear division 1 homolog) is a nuclear gene that encodes a protein needed for proper functioning of mitochondria. The data on its exact role are still limited, it has been shown that the RMND1 protein belongs to a large mitochondrial inner membrane complex that supports translation of the mtDNA-encoded polypeptides [1,2], all of which represent essential structural components of the oxidative phosphorylation (OXPHOS) complexes. Genes 2020, 11, x FOR PEER REVIEW with combined oxidative phosphorylation deficiency (COXPD11; MIM #614922), a severe recessive condition characterized the presenceby of the lacticpresence acidosis,ofdeafness, renal and liver dysfunction, central recessive conditionby characterized lactic acidosis, deafness, renal and liver nervous system and muscle involvement with an onset at birthwith or early infancy [4,5]. Dysfunction, central nervous system and muscle involvement an onset at birth or early infancy In. 2018, a different clinical presentation consistent with a diagnosis of Perrault syndrome (PRLTS).

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