A variant in<i>MRPS14</i>(uS14m) causes perinatal hypertrophic cardiomyopathy with neonatal lactic acidosis, growth retardation, dysmorphic features and neurological involvement

Jackson, Christopher B.; Huemer, Martina; Bolognini, Ramona; Martin, Franck; Szinnai, Gabor; Donner, Birgit; Richter, Uwe; Battersby, Brendan J.; Nuoffer, Jean‐Marc; Suomalainen, Anu; Schaller, André

doi:10.1093/hmg/ddy374

Cited by 40 publications

(40 citation statements)

References 40 publications

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“…For example, fibroblasts provide an opportunity to study mitochondrial translation defects that underlie an OXPHOS deficiency using [ 35 S] labeled methionine and cysteine incorporation to assess nascent mitochondrial protein synthesis, and when mitoribosomal defects are suspected, sucrose gradients to analyze their assembly. These techniques recently revealed that homozygous MRPS14 variants diminished translation, but did not affect mitoribosomal assembly . An observable biochemical defect in patient fibroblasts also allows rescue experiments to be performed and, as stated earlier, these are crucial for functionally confirming the pathogenicity of novel variants in novel disease genes.…”

Section: Methods To Functionally Validate Pathogenicity and Dissect Mmentioning

confidence: 99%

“…The first to be described was a variant in MRPS16 encoding a subunit of the mitoribosome . Only one other mitoribosomal component ( MRPS22 ) was associated with disease before NGS was introduced, but since then pathogenic variants in MRPL3, MRPL44, MRPL12, MRPS7, MRPS23, MRPS34, MRPS2, MRPS14, MRPS28 and MRPS39 have been identified in patients. All were discovered by NGS methods with the exception of MRPL12 which was identified using microsatellite genotyping and Sanger sequencing .…”

Section: Introductionmentioning

confidence: 99%

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Recent advances in understanding the molecular genetic basis of mitochondrial disease

Thompson

Collier

Glasgow

et al. 2019

J of Inher Metab Disea

126

104

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Mitochondrial disease is hugely diverse with respect to associated clinical presentations and underlying genetic causes, with pathogenic variants in over 300 disease genes currently described. Approximately half of these have been discovered in the last decade due to the increasingly widespread application of next generation sequencing technologies, in particular unbiased, whole exome—and latterly, whole genome sequencing. These technologies allow more genetic data to be collected from patients with mitochondrial disorders, continually improving the diagnostic success rate in a clinical setting. Despite these significant advances, some patients still remain without a definitive genetic diagnosis. Large datasets containing many variants of unknown significance have become a major challenge with next generation sequencing strategies and these require significant functional validation to confirm pathogenicity. This interface between diagnostics and research is critical in continuing to expand the list of known pathogenic variants and concomitantly enhance our knowledge of mitochondrial biology. The increasing use of whole exome sequencing, whole genome sequencing and other “omics” techniques such as transcriptomics and proteomics will generate even more data and allow further interrogation and validation of genetic causes, including those outside of coding regions. This will improve diagnostic yields still further and emphasizes the integral role that functional assessment of variant causality plays in this process—the overarching focus of this review.

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Section: Methods To Functionally Validate Pathogenicity and Dissect Mmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Recent advances in understanding the molecular genetic basis of mitochondrial disease

Thompson

Collier

Glasgow

et al. 2019

J of Inher Metab Disea

126

104

View full text Add to dashboard Cite

show abstract

“…The fact that cultured cells are highly proliferative and display fast protein turnover underlines the need for animal models to obtain insights into regulatory mechanisms of mitochondrial translation in tissues (Bogenhagen et al., 2018, Ruzzenente et al., 2012). Moreover, as mutations in rRNAs and mitoribosomal proteins can cause severe tissue-specific human diseases, animal models will be crucial to understand the molecular consequences of disturbed mitochondrial translation (Hällberg and Larsson, 2014, Jackson et al., 2019). We therefore generated MitoRibo-Tag mice as a versatile tool to study mitoribosome composition and the mitoribosome-interactome in different mouse tissues in vivo .…”

Section: Introductionmentioning

confidence: 99%

MitoRibo-Tag Mice Provide a Tool for In Vivo Studies of Mitoribosome Composition

et al. 2019

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SummaryMitochondria harbor specialized ribosomes (mitoribosomes) necessary for the synthesis of key membrane proteins of the oxidative phosphorylation (OXPHOS) machinery located in the mitochondrial inner membrane. To date, no animal model exists to study mitoribosome composition and mitochondrial translation coordination in mammals in vivo. Here, we create MitoRibo-Tag mice as a tool enabling affinity purification and proteomics analyses of mitoribosomes and their interactome in different tissues. We also define the composition of an assembly intermediate formed in the absence of MTERF4, necessary for a late step in mitoribosomal biogenesis. We identify the orphan protein PUSL1, which interacts with a large subunit assembly intermediate, and demonstrate that it is an inner-membrane-associated mitochondrial matrix protein required for efficient mitochondrial translation. This work establishes MitoRibo-Tag mice as a powerful tool to study mitoribosomes in vivo, enabling future studies on the mitoribosome interactome under different physiological states, as well as in disease and aging.

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“…Although I have started with congenital lactic acidosis as the earliest onset mitochondrial disease, antenatal mitochondrial disease presentations are increasingly recognized. For example, prenatal presentation has been reported in some of the early‐onset CoQ 10 biosynthesis deficiency syndromes [12,13], defects of mitochondrial ribosomal proteins [14,15] and even in POLG disease [16].…”

Section: Clinical Complexity: Canonical Syndromic Presentations Of Chmentioning

confidence: 99%

Mitochondrial disease in children

Rahman

2020

J Intern Med

109

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A variant inMRPS14(uS14m) causes perinatal hypertrophic cardiomyopathy with neonatal lactic acidosis, growth retardation, dysmorphic features and neurological involvement

Cited by 40 publications

References 40 publications

Recent advances in understanding the molecular genetic basis of mitochondrial disease

Recent advances in understanding the molecular genetic basis of mitochondrial disease

MitoRibo-Tag Mice Provide a Tool for In Vivo Studies of Mitoribosome Composition

Mitochondrial disease in children

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