Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54.
Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54.
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DOI：
10.1038/s41431-023-01437-2
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发表时间：
2023-10
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影响因子：
--
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PRORP中的双等位基因亚型变体最近被描述为引起常染色体隐性遗传疾病结合氧化磷酸化缺陷型54（COXPD 54）。COXPD 54包括感音神经性听力损失和卵巢功能不全（Perrault综合征）至脑白质营养不良的表型谱。在这里，我们报告了三个额外的家庭与纯合子错义PRORP变异与多效性表型。每个错义变体改变了金属核酸酶结构域内的高度保守残基。用重组TRMT 10 C、SDR 5C 1和PRORP进行的体外线粒体tRNA加工测定表明，两种COXPD 54相关的PRORP变体c.1159A>G（p.Thr387Ala）和c.1241C>T（p.Ala414Val）减少了前-tRNAIle切割，这与影响tRNA加工的两种变体一致。在脑白质营养不良的个体中鉴定的PRORP c.1093T>C（p.Tyr365His）中未观察到tRNA加工的显著减少。这些数据提供了独立的证据，证明PRORP变体与COXPD 54相关，并且5′前导线粒体tRNA加工的评估对于新型PRORP变体的功能分析和临床解释是有价值的测定。
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.
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影响因子：
9.8
作者：
Hochberg I;Demain LAM;Richer J;Thompson K;Urquhart JE;Rea A;Pagarkar W;Rodríguez-Palmero A;Schlüter A;Verdura E;Pujol A;Quijada-Fraile P;Amberger A;Deutschmann AJ;Demetz S;Gillespie M;Belyantseva IA;McMillan HJ;Barzik M;Beaman GM;Motha R;Ng KY;O'Sullivan J;Williams SG;Bhaskar SS;Lawrence IR;Jenkinson EM;Zambonin JL;Blumenfeld Z;Yalonetsky S;Oerum S;Rossmanith W;Genomics England Research Consortium;Yue WW;Zschocke J;Munro KJ;Battersby BJ;Friedman TB;Taylor RW;O'Keefe RT;Newman WG
通讯作者：
Newman WG
影响因子：
2.9
作者：
Mohsen, AA;Anderson, BD;Vockley, J
通讯作者：
Vockley, J
影响因子：
9.8
作者：
Ensenauer, R;Vockley, J;Matern, D
通讯作者：
Matern, D
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
DOI：
10.1056/nejmsr1406261
发表时间：
2015-06-04
期刊：
The New England journal of medicine
影响因子：
--
作者：
Rehm HL;Berg JS;Brooks LD;Bustamante CD;Evans JP;Landrum MJ;Ledbetter DH;Maglott DR;Martin CL;Nussbaum RL;Plon SE;Ramos EM;Sherry ST;Watson MS;ClinGen
通讯作者：
ClinGen