New CD46 gene mutation identifier in a young child with recurrent aHUS | A very rare mutation “prepares” the girl to develop the disease

new mutation in CD46 recurring gene atypical hemolytic syndrome (aHUS) was identified in a 13-month-old girl, according to a case report from Denmark.

As described in the report, the mutation affected the activity of the complement cascade – a part of the immune system known to drive aHUS.

the study, “A novel homozygous CD46 variant with C-isoform expression affects C3b inactivation in atypical hemolytic syndrome.“in European Journal of Immunology.

Suggestions for reading

A very rare mutation affects levels of the CD46 protein in cells

A rare disease, characterized by hemolytic anemia, or destruction of red blood cells, low levels of platelets, and the formation of blood clots in small blood vessels.

The The condition arises Through problems with the functioning of the complement system – a group of more than 50 proteins that are part of the body’s immune defenses – often due to mutations in genes associated with supplementation.

The CD46 The gene contains instructions for producing a cell membrane protein, called CD46, which protects cells from injury by complement activation. It interacts with complement factor I, and mediates the inactivation of C3b/C4b complement proteins.

Currently, more than 60 CD46 Gene mutations are associated with aHUS. These genetic variants are found in 10-15% of all pediatric cases of acquired immunodeficiency syndrome. CD46-related susceptibility to aHUS is often associated with dominant mutations, which means that only one copy of the mutated genes is required for disease progression.

A team led by researchers at Aarhus University has identified a new species CD46 Mutation in both gene copies, one inherited from each parent, in a young child with recurrent aHUS.

The girl was diagnosed with AHUS when she was 13 months old. I was hospitalized after a few days of tiredness and dark urine. Blood tests showed high levels of creatinine, an indicator of poor kidney function, very low platelet count (thrombocytopenia), along with too much acid in her blood (metabolic acidosis) and anemia.

Doctors suspected HUS and ordered genetic tests to look for possible causative mutations. These tests identified a previously unreported mutation, called c.602C>T, in both copies of CD46 gene, which was considered very rare.

Further tests also revealed that the mutation was present in a single copy of CD46 Jane is her parents. No other family member has been diagnosed with AHUS or experienced similar symptoms, including the baby’s little older brother.

The girl had episodes of flares, or worsening episodes of the disease, during follow-up: one when she was 21 months old and one when she was about 3 years old.

She was taken to the hospital and treated Soliris (eculizumab), a monoclonal antibody that binds to the complement system protein C5, preventing the system from being overactive.

The researchers performed further analyzes to understand how the mutation affects CD46 protein and the complement system. They found that the mutation led to a marked decrease in CD46 levels in blood cells.

Additional tests evaluated the ability of C3b to bind to CD46 in cells bearing normal CD46 Gene versus cells that carry the mutated gene. In cells affected by the mutation CD46 The binding of the C3b gene to the cell membrane was significantly reduced. In fact, other studies showed that the mutation was related to a specific protein variant, called the isoform, which binds significantly to a lower amount of C3b than the other isoforms.

in select file CD46 The mutation ‘that predisposes the development of aHUS,’ this study ‘contributes[s] To understand how a defect in CD46 integrity and expression causes disruption of the complement system and the development of the AHUS system.”