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Case Reports
. 2020 Sep 8;11(9):1060.
doi: 10.3390/genes11091060.

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

Dominika Oziębło  1   2 , Joanna Pazik  3 , Iwona Stępniak  1 , Henryk Skarżyński  4 , Monika Ołdak  1
Affiliations
Case Reports

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

Dominika Oziębło et al. Genes (Basel). .

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.

Keywords: COXPD11 (combined oxidative phosphorylation deficiency); Perrault syndrome; RMND1 (required for meiotic nuclear division 1 homolog); hearing loss; mitochondria; ovarian dysfunction; renal disease.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Pedigree and audiological data of the investigated family. (A) Pedigree showing affected family members (proband II.2, proband’s sister II.6) and the identified RMND1 variants. (B) Pure tone audiometry results of the proband (left panel) and her sister (right panel) at the age of 32.
Figure 2
Figure 2
Genetic data of the investigated family. (A) Results of next-generation sequencing (NGS) and Sanger sequencing showing c.583G>A transition (p.Gly195Arg) and c.818A>C transversion (p.Tyr273Ser) in the RMND1 gene. (B) Multiple protein sequence alignment of selected RMND1 regions among different species.
Figure 3
Figure 3
Schematic representation of RMND1 gene and protein organization. Gene and protein structure is depicted based on the canonical transcript NM_017909.4 and reference protein sequence NP_060379.2. Previously reported RMND1 pathogenic variants involved in development of combined oxidative phosphorylation deficiency (COXPD11) are written in black. Variants identified in this study are shown in red. Bolded are variants involved in the development of Perrault syndrome (PRLTS) with renal involvement. Abbreviations: MLS, mitochondrial localization sequence; DUF155, domain of unknown function; CC, coiled-coil; TM, transmembrane.
See this image and copyright information in PMC

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