Combined Oxidative Phosphorylation Deficiency 38

A number sign (#) is used with this entry because of evidence that combined oxidative phosphorylation deficiency-38 (COXPD38) is caused by homozygous mutation in the MRPS14 gene (611978) on chromosome 1q23. One such patient has been reported.

For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Clinical Features

Jackson et al. (2019) reported a 5-year-old girl, born of distantly related Turkish parents, with a complex phenotype consistent with a mitochondrial disorder. She was noted on prenatal ultrasound to have hypertrophic cardiomyopathy with mildly impaired left ventricular contractility. Soon after birth, she had respiratory insufficiency and increased serum lactate, and she later showed hypotonia, failure to thrive, global developmental delay, and Wolff-Parkinson-White syndrome. In the first 2 years of life, she experienced acute deterioration during infections, but her condition later stabilized, and she demonstrated catch-up growth and learned to walk and talk at 3.5 years of age. At age 5, she had a broad-based gait and some mild dysmorphic features, including retroverted low-set ears, midface hypoplasia, hypertelorism, and flat nasal bridge. Analysis of skeletal muscle tissue showed an isolated decrease in the activity of mitochondrial complex IV to approximately 44% of control values. However, immunoblot analysis of patient fibroblasts showed a combined deficiency of assembled oxidative phosphorylation complexes, with complexes I and IV barely detectable, and complexes III and V markedly decreased. There was also a decrease in base-level oxygen consumption, with deficient ADP-dependent and slightly decreased complex IV-dependent respiration activity. Mitochondrial morphology was partially distorted. The family had a history of repeated miscarriages. The patient's father had had a single episode of rhabdomyolysis and variable abnormal creatine kinase levels, suggesting a possible partial dominant effect.

Inheritance

The transmission pattern of COXPD38 in the family reported by Jackson et al. (2019) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a 5-year-old girl, born of distantly related Turkish parents, with COXPD38, Jackson et al. (2019) identified a homozygous missense mutation in the MRPS14 gene (R108C; 611978.0001). The mutation, which was found by targeted exome sequencing of nuclear genes encoding proteins with mitochondrial function, was confirmed by Sanger sequencing and segregated with the disorder in the family. The variant was not found in the ExAC or gnomAD databases. Steady-state levels of small and large mitochondrial ribosomal subunits were intact and similar to controls. The mutant MRPS14 protein was stable, but was demonstrated to impair mitochondrial translation in patient fibroblasts; the defect could be rescued by expression of wildtype MRPS14. The findings indicated that the mutation impaired the function of mitochondrial ribosomes during translation elongation or mitochondrial mRNA recruitment, rather than affecting the assembly of mitochondrial ribosomes.