HGNC Approved Gene Symbol: MRPL44
Cytogenetic location: 2q36.1 Genomic coordinates (GRCh38): 2:223,950,854-223,967,714 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q36.1 | Combined oxidative phosphorylation deficiency 16 | 615395 | Autosomal recessive | 3 |
Mitochondria have their own translation system for production of 13 inner membrane proteins essential for oxidative phosphorylation. MRPL44 is a component of the large subunit of the mitochondrial ribosome that is encoded by the nuclear genome (Koc et al., 2001).
By searching databases using bovine Mrpl44 as query, Koc et al. (2001) identified human MRPL44. They also identified MRPL44 homologs in mouse, Drosophila, C. elegans, and yeast, but not in E. coli or Arabidopsis. Mouse and human MRPL44 share 87% amino acid identity.
Gross (2017) mapped the MRPL44 gene to chromosome 2q36.1 based on an alignment of the MRPL44 sequence (GenBank BC012058) with the genomic sequence (GRCh38).
In 2 Finnish sisters with variable expression of combined oxidative phosphorylation deficiency-16 (COXPD16; 615395), Carroll et al. (2013) identified a homozygous mutation in the MRPL44 gene (L156R; 611849.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in several large control databases or in controls. Haplotype analysis indicated distant consanguinity in the family. One sister had hypertrophic cardiomyopathy resulting in death in infancy, whereas the other had infantile-onset hypertrophic cardiomyopathy, but was asymptomatic as a teenager. Both had hepatic steatosis. The first patient had a combined deficiency of respiratory complexes I and IV in heart and skeletal muscle, whereas the second had a decrease of complex IV in fibroblasts. Transduction of wildtype MRPL44 into patient fibroblasts corrected the COX defects and restored assembly of the large ribosomal subunit. The findings indicated that the MRPL44 mutation affected the respiratory chain in a tissue-specific manner, and suggested that MRPL44 is required for assembly and stability of the mitochondrial large ribosomal subunit.
In 2 unrelated patients with COXPD16, Friederich et al. (2021) identified compound heterozygous mutations in the MRPL44 gene (611849.0001-611849.0003). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. MRPL44 protein level was reduced and mitochondrial protein synthesis was decreased in fibroblasts from both patients compared to controls.
In 2 unrelated patients with COXPD16, Distelmaier et al. (2015) identified biallelic mutations in the MRPL44 gene. Patient 1 was homozygous for a previously identified missense mutation (L156R; 611849.0001), and patient 2 was compound heterozygous for L156R and a novel missense mutation (R78Q; 611849.0004). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing.
In 2 Finnish sisters with variable expression of combined oxidative phosphorylation deficiency-16 (COXPD16; 615395), Carroll et al. (2013) identified a homozygous c.467T-G transversion in the MRPL44 gene, resulting in a leu156-to-arg (L156R) substitution at a highly conserved residue in the RNase III-like domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in several large control databases or in 436 control chromosomes. Haplotype analysis indicated distant consanguinity in the family. One sister had hypertrophic cardiomyopathy resulting in death in infancy, whereas the other had infantile-onset hypertrophic cardiomyopathy, but was asymptomatic as a teenager. Both had hepatic steatosis. The first patient had a combined deficiency of respiratory complexes I and IV in heart and skeletal muscle, whereas the second had a decrease of complex IV in fibroblasts. Molecular modeling predicted that the mutation would impair correct folding, resulting in protein instability. Western blot analysis showed decreased levels of MRPL44 protein in the heart and skeletal muscle from the deceased sib and decreased amounts of protein in fibroblasts from the surviving sib. In vitro studies showed that the mutant protein affected the stability or assembly of COX subunits, although de novo synthesis of the polypeptides appeared to be unaffected. Patient fibroblasts had decreased amounts of assembled large ribosomal subunit and decreased levels of 16S rRNA, leading to complex IV deficiency. Transduction of wildtype MRPL44 into patient fibroblasts corrected the COX defects and restored assembly of the large ribosomal subunit. The findings indicated that the MRPL44 mutation affected the respiratory chain in a tissue-specific manner, and suggested that MRPL44 is required for assembly and stability of the mitochondrial large ribosomal subunit.
In 2 unrelated patients with COXPD16, Friederich et al. (2021) identified compound heterozygous mutations in the MRPL44 gene. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Patient 1 had the c.467T-G transversion (c.467T-G, NM_022915.3), resulting in L156R, and a c.481_484delinsTC mutation (618849.0002), predicted to result in a frameshift and premature termination (Thr161SerfsTer2). MRPL44 protein level, assessed by Western blot analysis, was reduced in patient heart, muscle, and fibroblasts; an additional higher molecular weight band was also present, possibly indicating retention of a mitochondrial leader peptide. Testing of respiratory chain enzyme activity in heart tissue showed a profound decrease in complex IV, a strong decrease in complex I, and a mild decrease in complex II-III. Skeletal muscle showed an increase in complex II and citrate synthase activity, and mild decreases in complexes I and IV. Complex I was also shown to be incompletely assembled in heart. Fibroblasts from the patient showed decreased synthesis of mitochondrial proteins. Patient 2 had the L156R mutation and a c.467T-C transition, resulting in a leu156-to-pro (L156P; 618849.0003) substitution. MRPL44 protein level, assessed by Western blot analysis, was reduced in fibroblasts; an additional higher molecular weight band was also present. Testing of respiratory chain enzyme activity in skeletal muscle showed a severe deficiency of complex IV activity and deficiencies of complexes I, II, and V. Fibroblasts from the patient showed decreased synthesis of mitochondrial proteins.
In 2 unrelated patients with COXPD16, Distelmaier et al. (2015) identified the L156R mutation. The mutation was present in homozygous state in patient 2 and in compound heterozygous state with another missense mutation (R78Q; 611849.0004) in patient 1. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The parents of patient 2 were heterozygous for the L146R variant, which was present in the ExAC database at an allele frequency of 8/122,890. The R78Q variant was present in the ExAC database at an allele frequency of 1/122,890. Biochemical analysis of cardiac tissue from patient 2 demonstrated severe reduction in complex IV and moderate deficiency of complex I of the mitochondrial respiratory chain. Biochemical analysis of skin fibroblasts from patient 1 demonstrated a deficiency of complex IV of the mitochondrial respiratory chain.
For discussion of the c.481_484delinsTC mutation (c.481-484delinsTC, NM_022915.3) in the MRPL44 gene, predicted to result in a frameshift and premature termination (Thr161SerfsTer2), that was found in compound heterozygous state in a patient with combined oxidative phosphorylation deficiency-16 (COXPD16; 615395) by Friederich et al. (2021), see 618849.0001.
For discussion of the c.467T-C transition (c.467T-C, NM_022915.3) in the MRPL44 gene, resulting in a leu156-to-pro (L156P) substitution, that was found in compound heterozygous state in a patient with combined oxidative phosphorylation deficiency-16 (COXPD16; 615395) by Friederich et al. (2021), see 618849.0001.
For discussion of the c.233G-A transition in the MRPL44 gene, resulting in an arg78-to-gln (R78Q) substitution, that was found in compound heterozygous state in a patient with combined oxidative phosphorylation deficiency-16 (COXPD16; 615395) by Distelmaier et al. (2015), see 618849.0001.
Carroll, C. J., Isohanni, P., Poyhonen, R., Euro, L., Richter, U., Brilhante, V., Gotz, A., Lahtinen, T., Paetau, A., Pihko, H., Battersby, B. J., Tyynismaa, H., Suomalainen, A. Whole-exome sequencing identifies a mutation in the mitochondrial ribosome protein MRPL44 to underlie mitochondrial infantile cardiomyopathy. J. Med. Genet. 50: 151-59, 2013. [PubMed: 23315540] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101375]
Distelmaier, F., Haack, T. B., Catarino, C. B., Gallenmuller, C., Rodenburg, R. J., Strom, T. M., Baertling, F., Meitinger, T., Mayatepek, E., Prokisch, H., Klopstock, T. MRPL44 mutations cause a slowly progressive multisystem disease with childhood-onset hypertrophic cardiomyopathy. Neurogenetics 16: 319-23, 2015. [PubMed: 25797485] [Full Text: https://doi.org/10.1007/s10048-015-0444-2]
Friederich, M. W., Geddes, G. C., Wortmann, S. B., Punnoose, A., Wartchow, E., Knight, K. M., Prokisch, H., Creadon-Swindell, G., Mayr, J. A., Van Hove, J. L. K. Pathogenic variants in MRPL44 cause infantile cardiomyopathy due to a mitochondrial translation defect. Molec. Genet. Metab. 133: 362-371, 2021. [PubMed: 34140213] [Full Text: https://doi.org/10.1016/j.ymgme.2021.06.001]
Gross, M. B. Personal Communication. Baltimore, Md. 10/31/2017.
Koc, E. C., Burkhart, W., Blackburn, K., Moyer, M. B., Schlatzer, D. M., Moseley, A., Spremulli, L. L. The large subunit of the mammalian mitochondrial ribosome: analysis of the complement of ribosomal proteins present. J. Biol. Chem. 276: 43958-43969, 2001. [PubMed: 11551941] [Full Text: https://doi.org/10.1074/jbc.M106510200]