LRPPRC

Chr 2AR

leucine rich pentatricopeptide repeat containing

ENSG00000138095 UniProt: P42704 OMIM: 607544

This protein localizes to mitochondria and is involved in transcriptional regulation of mitochondrial genes, though its precise function remains unclear. Mutations cause French-Canadian type Leigh syndrome (mitochondrial complex IV deficiency, nuclear type 5) through an autosomal recessive inheritance pattern. The pathogenic mechanism appears to be dominant negative.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

May play a role in RNA metabolism in both nuclei and mitochondria. In the nucleus binds to HNRPA1-associated poly(A) mRNAs and is part of nmRNP complexes at late stages of mRNA maturation which are possibly associated with nuclear mRNA export. Positively modulates nuclear export of mRNAs containing the EIF4E sensitivity element (4ESE) by binding simultaneously to both EIF4E and the 4ESE and acting as a platform for assembly for the RNA export complex (PubMed:19262567, PubMed:28325843). Also binds to exportin XPO1/CRM1 to engage the nuclear pore and traffic the bound mRNAs to the cytoplasm (PubMed:28325843). May bind mature mRNA in the nucleus outer membrane. In mitochondria binds to poly(A) mRNA. Plays a role in translation or stability of mitochondrially encoded cytochrome c oxidase (COX) subunits. May be involved in transcription regulation. Cooperates with PPARGC1A to regulate certain mitochondrially encoded genes and gluconeogenic genes and may regulate docking of PPARGC1A to transcription factors. Seems to be involved in the transcription regulation of the multidrug-related genes MDR1 and MVP. Part of a nuclear factor that binds to the invMED1 element of MDR1 and MVP gene promoters. Binds single-stranded DNA (By similarity). Required for maintaining mitochondrial potential (PubMed:23822101). Suppresses the initiation of basal levels of autophagy and mitophagy by sustaining BCL2 levels (PubMed:23822101)

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.531 OMIM phenotype

Clinical Summary— LRPPRC

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.53LOEUF

pLI 0.000

Z-score 5.00

OE 0.39 (0.29–0.53)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-1.93Z-score

OE missense 1.20 (1.14–1.27)

858 obs / 713.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.39 (0.29–0.53)

0≤0.351.4

Missense OE?1.20 (1.14–1.27)

0≤0.61.4

Synonymous OE?1.17

0≤1.21.6

LoF obs/exp: 31 / 78.9Missense obs/exp: 858 / 713.1Syn Z: -2.13

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveLRPPRC-related Leigh syndrome, French-Canadian typeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7034th %ile

GOF

0.5562th %ile

LOF

0.2288th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.