Browsing by Author "Humalajoki, Mari"

Primary human complement deficiencies are rare conditions, which affect the functions of the immune defense. Central complement component C3 deficiencies manifest in early childhood mostly as recurring bacterial infections. The severity of the infections showcases the importance of the human complement system in antimicrobial defense and overall immunity. Overall, there are only about 30 reported cases of total C3 deficiency worldwide. This study introduces two Finnish siblings with no detectable C3 in the plasma of either the proband or their sibling. Primary C3 deficiency was suspected in the proband (elder sibling) due to the relapses of severe pneumococcal infections (meningitis, sepsis, pneumonia) under the age of two. We set out to study the genetic basis of the deficiency. The proband's C3 gene was sequenced and results validated with Whole Genome Sequencing. C3 protein deficiency was confirmed via immunoblotting of serum and peripheral blood mononuclear cell lysate samples. Comprehensive clinical data was obtained from patient physicians. In genetic studies, we observed 1) a maternal truncation at exon 9 of the human C3 gene and 2) a paternal indel disrupting a splice site motif at exon 29. Together, they create compound heterozygosity resulting in total C3 deficiency. Total C3 deficiency was confirmed by the lack of C3 protein by immunoblotting of plasma and of blood mononuclear cell lysates. Compound heterozygosity in the patients lead to a complete deficiency of mature, functional C3. The lack of C3 in serum was first described in Pekkarinen et al. (2013) and now confirmed through immunoblotting. Also, no intracellular C3 was detected in similar experiments. The complete lack of C3 in the patient does not corroborate extracellular or intracellular C3 being obligatory for life.