4.3.2. Mutations in Complex IV Structural Subunits

In the past two decades, pathogenic mutations that result in COX deficiency have been identified in the structural subunits *COX4*, *COX5A*, *COX6A*, *COX6B*, *COX7B*, *COX8*, and *NDUFA4* (Table 5). With the exception of *COX7B*, patients with described mutations in structural COX subunits are born to consanguineous parents and therefore carry homozygous mutant alleles. Clinical phenotypes include, among others, Leigh or Leigh-like syndrome, encephalopathy, myopathy, and anemia.

Interestingly, *COX7B* is located in the X chromosome and is the only X-linked subunit of COX. Different heterozygous mutations in *COX7B* have been described in patients presenting with microphthalmia with linear skin lesions (MLS), a neurocutaneous X-linked dominant male-lethal disorder [136]. In addition to *COX7B*, MLS has also been associated with mutations in *HCCS*, the holocytochrome *c*-type synthase, and in *NDUFB11*, a subunit of Complex I. Somatic mosaicism and the degree of X chromosome inactivation in different tissues could explain the variability of additional clinical phenotypes that accompany MLS, such as developmental delay, abnormalities of the central nervous system, short stature, cardiac defects, and several ocular anomalies [137]. Indeed, the majority of MLS patients have severe skewing of X chromosome inactivation, probably because during embryonic development, respiratory competent cells multiply faster and outgrow cells harboring mutations in these structural genes [137].
