Combined Oxidative Phosphorylation Deficiency 34

A number sign (#) is used with this entry because of evidence that combined oxidative phosphorylation deficiency-34 (COXPD34) is caused by homozygous mutation in the MRPS7 gene (611974) on chromosome 17q25. One such family has been reported.

Description

COXPD34 is an autosomal recessive disorder resulting from a defect in mitochondrial function. The phenotype is variable, but may include congenital sensorineural deafness, increased serum lactate, and hepatic and renal dysfunction. Neurologic function is relatively preserved (summary by Menezes et al., 2015).

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

Clinical Features

Menezes et al. (2015) reported 2 sisters, born of unrelated Australian parents, with congenital sensorineural deafness apparent from birth. The older sister presented at age 13 months with recurrent vomiting, failure to thrive, hypoglycemia, hepatomegaly, and increased serum lactate after surgery. Liver biopsy at age 2 years showed steatosis and mild fibrosis. She had severe deficiencies of mitochondrial complexes I, III, and IV in liver, mild complex III deficiency in skeletal muscle, and deficiencies of complexes I and IV in fibroblasts. At age 14 years, she presented with liver failure, pancytopenia, and renal dysfunction that progressed to acute fatal encephalopathy associated with a cerebral infarct. The proband's younger sister had a less severe clinical course. She had congenital deafness, intermittent hypoglycemia and increased serum lactate early in life, and mild learning difficulties, primary hypogonadism, and primary adrenal failure during the teenage years. At age 17.5 years, she was generally well without hepatomegaly or signs of liver dysfunction, but there was mild renal insufficiency. Renal biopsy showed many atrophic renal tubules with protein casts and giant mitochondria. Muscle and liver showed similar deficiencies in mitochondrial respiratory chain activities as her sister. The older sister (patient 1) had previously been reported by Freckmann et al. (1997), who demonstrated the defect in mitochondrial respiratory chain activity and noted that the features were suggestive of a defect in fatty acid oxidation.

Inheritance

The transmission pattern of COXPD34 in the family reported by Menezes et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs with COXPD34, Menezes et al. (2015) identified a homozygous missense mutation in the MRPS7 gene (M184V; 611974.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Fibroblasts derived from 1 of the patients showed decreased levels of MRPS7 mRNA and protein, as well as decreased ATP production (80% of controls), decreased complex I activity (7.3% of controls), decreased complex IV activity (58.5% of controls), decreased mitochondrial protein synthesis (54% of controls), decreased 12S rRNA, and fragmentation of the mitochondrial network. These defects could be rescued by expression of wildtype MRPS7. The findings indicated that MRPS7 is an important component of the mitochondrial ribosome and plays a role in mitochondrial translation and functioning of the OXPHOS system.