Mitochondrial Complex Iii Deficiency, Nuclear Type 7

A number sign (#) is used with this entry because of evidence that mitochondrial complex III deficiency nuclear type 7 (MC3DN7) is caused by homozygous mutation in the UQCC2 gene (614461) on chromosome 6p21.

For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).

Clinical Features

Tucker et al. (2013) reported a boy, born of consanguineous Lebanese parents, with mitochondrial complex III deficiency. He presented in the neonatal period with severe metabolic acidosis, increased serum and CSF lactate, and evidence of renal tubular acidosis. He had mild dysmorphic features, including synophrys, epicanthal folds, upslanting palpebral fissures, depressed nasal bridge, and flattened nose. He also had unilateral undescended testis and unilateral postaxial polydactyly. His otherwise unaffected father had a similar facial appearance and a history of cleft palate. The child showed delayed psychomotor development with lack of meaningful speech, and later developed autistic features and aggressive behavior. He had infrequent seizures and mild sensorineural hearing loss. Laboratory studies showed markedly decreased complex III deficiency in skeletal muscle (9% of controls) and skin fibroblasts (5% of controls), with less severe secondary decreases in complexes I and IV.

Feichtinger et al. (2017) reported a female infant, born of consanguineous Turkish parents, with MC3DN7. She was born prematurely at 32 weeks' gestation due to a pregnancy complicated by intrauterine growth retardation and oligohydramnios. She presented with respiratory distress syndrome and developed seizures in the first weeks of life that progressed to status epilepticus. Laboratory findings included profound lactic acidosis and increased urinary pyruvate. She died at age 33 days. Dysmorphic features and physical examination were unremarkable, although she had brain imaging signs of general hypoxemic encephalopathy. Analysis of patient muscle showed decreased levels and activities of mitochondrial complex III, with secondary decreases in complex I.

Inheritance

The transmission pattern of MC3DN7 in the family reported by Tucker et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a boy, born of consanguineous Lebanese parents, with MC3DN7, Tucker et al. (2013) identified a homozygous splice site mutation in the UQCC2 gene (614461.0001), resulting in a severe loss of UQCC2 protein. Western blot analysis showed no detectable UQCC2, and complex III activity was severely decreased in patient muscle (9% of controls) and skin fibroblasts (5% of controls). Transduction of wildtype UQCC2 into patient cells resulted in the restoration of complex III assembly and activity.

In a female infant, born of consanguineous Turkish parents, with MC3DN7, Feichtinger et al. (2017) identified 2 homozygous missense mutations in the UQCC2 gene (R8P and L10F; 614461.0002). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in the 1000 Genomes Project or ExAC databases. The patient's unaffected mother was heterozygous for the mutations. Both mutations occurred at highly conserved residues. Analysis of patient cells showed almost complete loss of the UQCC2 protein, and immunoblot analysis showed a severe reduction of complex III with secondary reduction of complex I. Enzymatic activity of both complex III and I was variably decreased in patient muscle, but not in fibroblasts, suggesting tissue specificity.