Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54

Thomas B. Smith; Alessandro Rea; Huw B. Thomas; Kyle Thompson; Monika Oláhová; Reza Maroofian; Mina Zamani; Langping He; Saeid Sadeghian; Hamid Galehdari; Nava Shaul Lotan; Tal Gilboa; Kristin C. Herman; Thomas J. McCorvie; Wyatt W. Yue; Henry Houlden; Robert W. Taylor; William G. Newman; Raymond T. O’Keefe

doi:10.1038/s41431-023-01437-2

Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54

Thomas B. Smith, Alessandro Rea, Huw B. Thomas, Kyle Thompson, Monika Oláhová, Reza Maroofian, Mina Zamani, Langping He, Saeid Sadeghian, Hamid Galehdari, Nava Shaul Lotan, Tal Gilboa, Kristin C. Herman, Thomas J. McCorvie, Wyatt W. Yue, Henry Houlden, Robert W. Taylor, William G. Newman^*, Raymond T. O’Keefe

^*Corresponding author for this work

Applied Sciences Department

Research output: Contribution to journal › Article › peer-review

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Abstract

Biallelic hypomorphic variants in PRORP have been recently described as causing the autosomal recessive disorder combined oxidative phosphorylation deficiency type 54 (COXPD54). COXPD54 encompasses a phenotypic spectrum of sensorineural hearing loss and ovarian insufficiency (Perrault syndrome) to leukodystrophy. Here, we report three additional families with homozygous missense PRORP variants with pleiotropic phenotypes. Each missense variant altered a highly conserved residue within the metallonuclease domain. In vitro mitochondrial tRNA processing assays with recombinant TRMT10C, SDR5C1 and PRORP indicated two COXPD54-associated PRORP variants, c.1159A>G (p.Thr387Ala) and c.1241C>T (p.Ala414Val), decreased pre-tRNA^Ile cleavage, consistent with both variants impacting tRNA processing. No significant decrease in tRNA processing was observed with PRORP c.1093T>C (p.Tyr365His), which was identified in an individual with leukodystrophy. These data provide independent evidence that PRORP variants are associated with COXPD54 and that the assessment of 5′ leader mitochondrial tRNA processing is a valuable assay for the functional analysis and clinical interpretation of novel PRORP variants.

Original language	English
Pages (from-to)	1190-1194
Number of pages	5
Journal	European Journal of Human Genetics
Volume	31
Issue number	10
Early online date	9 Aug 2023
DOIs	https://doi.org/10.1038/s41431-023-01437-2
Publication status	Published - 1 Oct 2023

Keywords

Female
Humans
Genotype
Hearing Loss, Sensorineural/genetics
Homozygote
Mitochondrial Diseases/genetics
RNA, Transfer
Ribonuclease P/genetics

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Smith, T. B., Rea, A., Thomas, H. B., Thompson, K., Oláhová, M., Maroofian, R., Zamani, M., He, L., Sadeghian, S., Galehdari, H., Lotan, N. S., Gilboa, T., Herman, K. C., McCorvie, T. J., Yue, W. W., Houlden, H., Taylor, R. W., Newman, W. G., & O’Keefe, R. T. (2023). Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54. European Journal of Human Genetics, 31(10), 1190-1194. https://doi.org/10.1038/s41431-023-01437-2

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title = "Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54",

abstract = "Biallelic hypomorphic variants in PRORP have been recently described as causing the autosomal recessive disorder combined oxidative phosphorylation deficiency type 54 (COXPD54). COXPD54 encompasses a phenotypic spectrum of sensorineural hearing loss and ovarian insufficiency (Perrault syndrome) to leukodystrophy. Here, we report three additional families with homozygous missense PRORP variants with pleiotropic phenotypes. Each missense variant altered a highly conserved residue within the metallonuclease domain. In vitro mitochondrial tRNA processing assays with recombinant TRMT10C, SDR5C1 and PRORP indicated two COXPD54-associated PRORP variants, c.1159A>G (p.Thr387Ala) and c.1241C>T (p.Ala414Val), decreased pre-tRNAIle cleavage, consistent with both variants impacting tRNA processing. No significant decrease in tRNA processing was observed with PRORP c.1093T>C (p.Tyr365His), which was identified in an individual with leukodystrophy. These data provide independent evidence that PRORP variants are associated with COXPD54 and that the assessment of 5′ leader mitochondrial tRNA processing is a valuable assay for the functional analysis and clinical interpretation of novel PRORP variants.",

keywords = "Female, Humans, Genotype, Hearing Loss, Sensorineural/genetics, Homozygote, Mitochondrial Diseases/genetics, RNA, Transfer, Ribonuclease P/genetics",

author = "Smith, {Thomas B.} and Alessandro Rea and Thomas, {Huw B.} and Kyle Thompson and Monika Ol{\'a}hov{\'a} and Reza Maroofian and Mina Zamani and Langping He and Saeid Sadeghian and Hamid Galehdari and Lotan, {Nava Shaul} and Tal Gilboa and Herman, {Kristin C.} and McCorvie, {Thomas J.} and Yue, {Wyatt W.} and Henry Houlden and Taylor, {Robert W.} and Newman, {William G.} and O{\textquoteright}Keefe, {Raymond T.}",

note = "Funding information: This study was supported by the Medical Research Council (MR/W019027/1), the Royal National Institute for the Deaf/Masonic Charitable Foundation (S60_Newman) and the NIHR Manchester Biomedical Research Centre (NIHR 203308). RWT is supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Mitochondrial Disease Patient Cohort (UK) (G0800674), the Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Lily Foundation, Mito Foundation, the Pathological Society, the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. MO is funded by Mito Foundation, The Lily Foundation and The Pathological Society.",

year = "2023",

month = oct,

day = "1",

doi = "10.1038/s41431-023-01437-2",

language = "English",

volume = "31",

pages = "1190--1194",

journal = "European Journal of Human Genetics",

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publisher = "Nature Publishing Group",

number = "10",

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Smith, TB, Rea, A, Thomas, HB, Thompson, K, Oláhová, M, Maroofian, R, Zamani, M, He, L, Sadeghian, S, Galehdari, H, Lotan, NS, Gilboa, T, Herman, KC, McCorvie, TJ, Yue, WW, Houlden, H, Taylor, RW, Newman, WG & O’Keefe, RT 2023, 'Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54', European Journal of Human Genetics, vol. 31, no. 10, pp. 1190-1194. https://doi.org/10.1038/s41431-023-01437-2

TY - JOUR

T1 - Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54

AU - Smith, Thomas B.

AU - Rea, Alessandro

AU - Thomas, Huw B.

AU - Thompson, Kyle

AU - Oláhová, Monika

AU - Maroofian, Reza

AU - Zamani, Mina

AU - He, Langping

AU - Sadeghian, Saeid

AU - Galehdari, Hamid

AU - Lotan, Nava Shaul

AU - Gilboa, Tal

AU - Herman, Kristin C.

AU - McCorvie, Thomas J.

AU - Yue, Wyatt W.

AU - Houlden, Henry

AU - Taylor, Robert W.

AU - Newman, William G.

AU - O’Keefe, Raymond T.

N1 - Funding information: This study was supported by the Medical Research Council (MR/W019027/1), the Royal National Institute for the Deaf/Masonic Charitable Foundation (S60_Newman) and the NIHR Manchester Biomedical Research Centre (NIHR 203308). RWT is supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Mitochondrial Disease Patient Cohort (UK) (G0800674), the Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Lily Foundation, Mito Foundation, the Pathological Society, the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. MO is funded by Mito Foundation, The Lily Foundation and The Pathological Society.

PY - 2023/10/1

Y1 - 2023/10/1

N2 - Biallelic hypomorphic variants in PRORP have been recently described as causing the autosomal recessive disorder combined oxidative phosphorylation deficiency type 54 (COXPD54). COXPD54 encompasses a phenotypic spectrum of sensorineural hearing loss and ovarian insufficiency (Perrault syndrome) to leukodystrophy. Here, we report three additional families with homozygous missense PRORP variants with pleiotropic phenotypes. Each missense variant altered a highly conserved residue within the metallonuclease domain. In vitro mitochondrial tRNA processing assays with recombinant TRMT10C, SDR5C1 and PRORP indicated two COXPD54-associated PRORP variants, c.1159A>G (p.Thr387Ala) and c.1241C>T (p.Ala414Val), decreased pre-tRNAIle cleavage, consistent with both variants impacting tRNA processing. No significant decrease in tRNA processing was observed with PRORP c.1093T>C (p.Tyr365His), which was identified in an individual with leukodystrophy. These data provide independent evidence that PRORP variants are associated with COXPD54 and that the assessment of 5′ leader mitochondrial tRNA processing is a valuable assay for the functional analysis and clinical interpretation of novel PRORP variants.

AB - Biallelic hypomorphic variants in PRORP have been recently described as causing the autosomal recessive disorder combined oxidative phosphorylation deficiency type 54 (COXPD54). COXPD54 encompasses a phenotypic spectrum of sensorineural hearing loss and ovarian insufficiency (Perrault syndrome) to leukodystrophy. Here, we report three additional families with homozygous missense PRORP variants with pleiotropic phenotypes. Each missense variant altered a highly conserved residue within the metallonuclease domain. In vitro mitochondrial tRNA processing assays with recombinant TRMT10C, SDR5C1 and PRORP indicated two COXPD54-associated PRORP variants, c.1159A>G (p.Thr387Ala) and c.1241C>T (p.Ala414Val), decreased pre-tRNAIle cleavage, consistent with both variants impacting tRNA processing. No significant decrease in tRNA processing was observed with PRORP c.1093T>C (p.Tyr365His), which was identified in an individual with leukodystrophy. These data provide independent evidence that PRORP variants are associated with COXPD54 and that the assessment of 5′ leader mitochondrial tRNA processing is a valuable assay for the functional analysis and clinical interpretation of novel PRORP variants.

KW - Female

KW - Humans

KW - Genotype

KW - Hearing Loss, Sensorineural/genetics

KW - Homozygote

KW - Mitochondrial Diseases/genetics

KW - RNA, Transfer

KW - Ribonuclease P/genetics

UR - http://www.scopus.com/inward/record.url?scp=85167361207&partnerID=8YFLogxK

U2 - 10.1038/s41431-023-01437-2

DO - 10.1038/s41431-023-01437-2

M3 - Article

C2 - 37558808

AN - SCOPUS:85167361207

SN - 1018-4813

VL - 31

SP - 1190

EP - 1194

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 10

ER -

Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54

Abstract

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