Mutations in MRPS2 Gene Linked to Mitochondrial Dysfunction for First Time, Case Report Shows

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by Alice Melão |

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New genetic mutations affecting the MRPS2 gene were identified as the cause of mitochondrial disorder in two unrelated children, a case report shows.

The study, “Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies,” is the first report implicating the MRPS2 gene in mitochondrial disease. It was published in The American Journal of Human Genetics.

Mitochondria are responsible for the production of the necessary molecular energy to sustain cells’ normal functions. This energy production process is carried out by the oxidative phosphorylation system (OXPHOS) that is encoded by specific mitochondrial genes.

Several genetic mutations affecting the mitochondrial genes have been linked to defective mitochondrial activity, leading to disorders with severe organ involvement and poor outcome. In addition to the altered metabolic pattern associated with these disorders, they may be linked to specific clinical features including early-onset heart problems, developmental abnormalities, low blood sugar, and Leigh syndrome, as well as short stature and abnormal body appearance.

The first child, a 5-year-old girl, had pronounced wrinkled skin since birth, particularly in the abdomen area and hands. Physical examination at birth revealed she had other minor abnormal body features, including low-set ears and eyes slanted slightly upward.

During her first year of life, she showed signs of motor and psychological developmental delay. At 3 years old, she developed progressive hearing loss, which initially required the use of a hearing aid but was later corrected with cochlear implants in both ears. This correction significantly improved her speech and development. A formal developmental assessment when she was 5 years, 10 months old revealed that her average developmental state was only at that of a child at the age of 2 years, 6 months.

Additional clinical evaluations showed she had no brain structure alterations that could explain her developmental delay. Blood analyses showed she was prone to reduced blood sugar levels, increased levels of liver enzymes, and overall altered metabolic biomarkers. Measurements of OXPHOS complex activities in the liver, muscle, and skin cells revealed a decrease in multiple enzyme complexes of the system.

The second reported case was an 11-year-old boy who had experienced several acute events of low blood sugar levels after overnight fasting since he was 18 months old. He started walking at 22 months old, and had delayed speech development due to severe deafness at 2 years old. Similar to the previous case, his speech improved significantly after the hearing loss was corrected.

His last assessment showed he had a normal physical appearance, with normal growth parameters, but he had a moderate intellectual disability. He also had frequent headache episodes and muscular weakness in his lower limbs, and complained of marked muscle pain when walking.

No physical brain alterations were detected by magnetic resonance imaging (MRI) scans, but several metabolic biomarkers were altered in a blood analysis. Determination of OXPHOS activity showed a decrease in multiple complexes in the liver and fibroblasts, and a complex IV deficiency in muscle cells.

The boy had two unaffected siblings and a third sibling who had died during pregnancy. The cause of death was unknown, and it was not possible to determine if it could be related to mitochondrial disease.

Genetic analysis was performed in both patients, and the only gene found to be potentially responsible for their symptoms was MRPS2. This gene provides instructions for making mitochondrial ribosomal proteins, which are involved in protein synthesis within the mitochondrion.

To further test the association between MRPS2 mutations and mitochondrial disease, the researchers conducted a series of experiments in cell line models. These confirmed that the children’s genetic mutations had the potential to promote OXPHOS dysfunction, leading to mitochondrial deficiency.

These two case reports demonstrate that mutations in MRPS2 “cause a recognizable” manifestation of mitochondrial disorder, with hearing loss, low blood sugar, altered cellular metabolism, developmental delay, and multiple-OXPHOS-complex dysfunction, the researchers said.

“The clinical recognition of these features should allow a targeted diagnostic approach to mitoribosomal protein deficiencies,” the researchers wrote.