MRPL3-Related Combined Oxidative Phosphorylation Deficiency via the MRPL3 Gene

Combined oxidative phosphorylation (OXPHOS) deficiency is a multi-systemic disorder characterized by reduced activity of two or more mitochondrial respiratory chain enzyme complexes. Pathogenic variants in over 30 different genes, primarily mitochondrial translation factors, have been linked to this disease.

MRPL3-associated combined OXPHOS deficiency has been described in only one family to date (Galmiche et al. 2011). All four patients presented at approximately five to six months of age with severe cardiomyopathy, lactic acidosis, failure to thrive, and psychomotor delay. Hypotrophy, hepatomegaly, and dyspnea were also noted in some of the affected individuals.

Combined oxidative phosphorylation (OXPHOS) deficiency is an autosomal recessive, X-linked, or maternally inherited disease. Pathogenic variants in over 30 different nuclear and mitochondrial genes have been reported as causative for this disorder. The majority of these genes encode for members of the mitochondrial translation apparatus or the mitochondrial tRNAs or rRNAs.

Nuclear genes associated with autosomal recessive inheritance of combined OXPHOS deficiency include: AARS2, ATP5A1, BOLA3, C12orf65, EARS2, ELAC2, FARS2, GFER, GFM1, GTPBP3, ISCU, LYRM4, MARS2, MRPL3, MRPL44, MRPS16, MRPS22, MTFMT, MTO1, NARS2, NFU1, PARS2, PNPT1, PUS1, RMND1, SERAC1, SFXN4, TARS2, TRMT5, TSFM, TUFM, VARS2, and YARS2.

AIFM1 is the only gene associated with X-linked recessive inheritance of this disease.

Additionally, pathogenic defects in any of the mitochondrial-encoded tRNA genes (22 total) or rRNA genes (2 total) are expected to result in combined oxidative phosphorylation deficiency (Smits et al. 2010).

The nuclear MRPL3 gene, consisting of 10 exons, encodes for a subunit of the mitochondrial large ribosome (Ou et al. 1987; Kenmochi et al. 2001). One missense change (c.950C>G) has been reported for MRPL3-related combined oxidative phosphorylation deficiency (Galmiche et al. 2011). In all four patients described, this missense variant was likely coupled with a large deletion (<255 bp) on the opposite allele, but the exact endpoints of this deletion were not determined.

MRPL3-associated combined oxidative phosphorylation (OXPHOS) deficiency has been described in only four individuals to date (Galmiche et al. 2011). Although we cannot precisely estimate clinical sensitivity at this time, pathogenic variants in MRPL3 appear to be a rare cause of combined OXPHOS deficiency.

This test provides full coverage of all coding exons of the MRPL3 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).