Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia

Abstract

We describe a novel autosomal recessive form of mitochondrial disease in a child with short stature, poor weight gain, and mild dysmorphic features with highly suspected Fanconi anemia due to a mutation in COX4I1 gene. Whole Exome Sequencing was performed then followed by Sanger confirmation, identified a K101N mutation in COX4I1, segregating with the disease. This nuclear gene encodes the common isoform of cytochrome c oxidase (COX) subunit 4 (COX 4-1), an integral regulatory part of COX (respiratory chain complex IV) the terminal electron acceptor of the mitochondrial respiratory chain. The patient's fibroblasts disclosed decreased COX activity, impaired ATP production, elevated ROS production, decreased expression of COX4I1 mRNA and undetectable (COX4) protein. COX activity and ATP production were restored by lentiviral transfection with the wild-type gene. Our results demonstrate the first human mutation in the COX4I1 gene linked to diseases and confirm its role in the pathogenesis. Thus COX4I1 mutations should be considered in any patient with features suggestive of this diagnosis.

Melatonin suppresses senescence‐derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L–mitophagy pathway

“…Mutation in the human COX4I1 gene induces short stature, poor weight gain, and chromosomal breaks (Abu‐Libdeh et al, ). Furthermore, low COX4I1 expression is associated with impaired ATP production and elevated ROS (Abu‐Libdeh et al, ). A recent study has indicated that a COX4I1‐HSP70 complex contributes to the formation of COX, leading to the maintenance of the mitochondrial membrane potential (Bottinger et al, ).…”

“…A clinical study has shown that the defective production of COX causes myopathy and Leigh syndrome (Pillai et al, 2019). Mutation in the human COX4I1 gene induces short stature, poor weight gain, and chromosomal breaks (Abu-Libdeh et al, 2017). Furthermore, low COX4I1 expression is associated with impaired ATP production and elevated ROS (Abu-Libdeh et al, 2017).…”

“…Mutation in the human COX4I1 gene induces short stature, poor weight gain, and chromosomal breaks (Abu-Libdeh et al, 2017). Furthermore, low COX4I1 expression is associated with impaired ATP production and elevated ROS (Abu-Libdeh et al, 2017).…”

Strategies for fighting mitochondrial diseases

“…Finally, NAC and ascorbate were shown to decrease ROS production in fibroblasts with a mutation in COX4‐1 subunit [46].…”

Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures

“…Biallelic variants in COX4I1 (OMIM: 123864) have been previously described in a patient who presented with short stature, poor weight gain, dysmorphic features and features of Fanconi anemia (Abu‐Libdeh et al, ). COX4I1 , located at 16q24.1, encodes the subunit IV isoform 1, the principal isoform for COX‐IV subunit of cytochrome c oxidase (COX) or complex IV in human beings and other vertebrates.…”