Identification of a novel homozygous synthesis of cytochrome c oxidase 2 variant in siblings with early‐onset axonal Charcot‐Marie‐Tooth disease

Abstract

The synthesis of cytochrome c oxidase 2 (SCO 2 ) gene encodes for a mitochondrial located metallochaperone essential for the synthesis of the cytochrome c oxidase (COX) subunit 2. Recessive mutations in SCO 2 have been reported in several cases with fatal infantile cardioencephalomyopathy with COX deficiency and in only four cases with axonal neuropathy. Here, we identified a homozygous pathogenic variant (c.361G > C; p.[Gly121Arg]) in SCO 2 in two brothers with isolated axonal motor neuropathy. To address pathogenicity of the amino acid substitution, biochemical studies were performed and revealed increased level of the mutant SCO 2 -protein and dysregulation of COX subunits in leukocytes and moreover unraveled decrease of proteins involved in the manifestation of neuropathies. Hence, our combined data strengthen the concept of SCO 2 being causative for a very rare form of axonal neuropathy, expand its molecular genetic spectrum and provide first biochemical insights into the underlying pathophysiology.

Proteomic studies in VWA1‐related neuromyopathy allowed new pathophysiological insights and the definition of blood biomarkers

“…White blood cells isolated and purified from 7.5 mL freshly collected EDTA‐blood 11 derived from six VWA1 ‐patients: two siblings carrying the compound heterozygous c.62‐71dup and c.879del variants (family 1; see Table 1 ) and four relatives carrying the homozygous c.252del variant (family 2; see Table 1 ) in addition to a total of nine gender‐ and age‐matched controls (Figure 1C ). None of the control individuals presented with any sign of disease at the time of blood sampling.…”

“…Functional and biochemical research of neurological illnesses is often limited by the availability of appropriate biomaterial. Notably, patient‐derived white blood cells have been shown to represent suitable in vitro models to study the nature of rare neurological disorders overcoming the scarcity of tissues vulnerable in these diseases 10–12 . Thus, here in the context of the first biomarker study of VWA1 ‐related neuromyopathy, we investigated white blood cells to define marker proteins with pathophysiological relevance in skeletal muscle as a tissue clinically affected by the presence of pathogenic VWA1 ‐variants.…”

“…Notably, patient‐derived white blood cells have been shown to represent suitable in vitro models to study the nature of rare neurological disorders overcoming the scarcity of tissues vulnerable in these diseases. 10 , 11 , 12 Thus, here in the context of the first biomarker study of VWA1 ‐related neuromyopathy, we investigated white blood cells to define marker proteins with pathophysiological relevance in skeletal muscle as a tissue clinically affected by the presence of pathogenic VWA1 ‐variants. For that purpose, proteomic profiling was carried out on white blood cells derived from six VWA1 ‐patients of two unrelated families.…”

A Homozygous NDUFS6 Variant Associated with Neuropathy and Optic Atrophy

“…Mitochondrial diseases often present with fatal infantile phenotypes but over the last years some authors reported isolated axonal neuropathy phenotypes, e.g. for SCO2 [ 9 ] and MTATP6 [ 10 ].…”

Protein Transduction Domain-Mediated Delivery of Recombinant Proteins and In Vitro Transcribed mRNAs for Protein Replacement Therapy of Human Severe Genetic Mitochondrial Disorders: The Case of Sco2 Deficiency

“…Mutations in SCO2 are often reported in cases of COX deficiency and have been associated with severe phenotypes and different clinical outcomes, such as myopathies, cardiac hypertrophy, neuropathies, and Leigh syndrome [ 66 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 ]. Initially, mutations in SCO2 were found in three unrelated infants with fatal cardioencephalomyopathy and COX deficiency [ 66 ].…”