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. 2025 Jan 20;10(4):1274-1278.
doi: 10.1016/j.ekir.2025.01.019. eCollection 2025 Apr.

Genetic Terminal Complement Deficiency in Israeli Bedouins With Kidney Failure

Guy Chowers  1   2   3 , Dror Ben-Ruby  2   3 , Danit Atias-Varon  1   3 , Omer Shlomovitz  1   2   3 , Keren Slabodnik-Kaner  1   3 , Maayan Kagan  1   2   3 , Shany Avayou  3 , Elvira Romanjuk  4   5 , Boris Rogachev  4   5 , Yosef S Haviv  4   5 , Ohad S Birk  5   6 , Noam Hadar  5 , Younes Bathish  7   8 , Iris Barshack  2   9 , Alexander Volkov  2   9 , Camila Avivi  9 , Anna Pavlovsky  9 , Orly Haskin  2   10 , Amos J Simon  11   12 , Efrat Glick-Saar  12   13 , Alina Ostrovsky  11 , Mawada Assi  11 , Ruth Schreiber  5   14 , Dana Levin  3 , Yoram Yagil  5   15   16 , Mohammad Awawdeh  8   17 , Karl Skorecki  8   18   19 , Dan Dominissini  2   11   12   13 , Alla Shnaider  4   5 , Asaf Vivante  1   2   3   20
Affiliations

Genetic Terminal Complement Deficiency in Israeli Bedouins With Kidney Failure

Guy Chowers et al. Kidney Int Rep. .
No abstract available

Keywords: chronic kidney diseases; complement; ethnic minorities; exome sequencing; kidney failure; terminal complement complex.

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Figures

Figure 1
Figure 1
Identification of variants in C8A and C8B in 3 Israeli Bedouin individuals with kidney failure. (a) Exon structure of human C8A and C8B cDNA and domain structure of complement factor 8 alpha and beta chains (C8A and C8B). Nucleotide and protein changes are highlighted by red lines. Both variants were located in the MACPF domain. This domain is crucial for target membrane insertion and the formation of a transmembrane channel that disrupts the cell, causing lysis. ATG and TGA/TAG stop codons are indicated. (b) 3D model of C8A with and without the truncating variant. The model was generated the SWISS-MODEL. The N terminus upstream of the early stop codon at residue 210 is shown in blue. The C terminus, downstream of the early stop codon, is shown in red. (c) Western blot of serum from patients with deficits in terminal complement proteins. When probing the C8B chain, in addition to the anticipated protein absence in the case of the C8B variant, the 2 cases with the C8A variant showed reduced protein levels. The label in each lane indicates the affected gene in each patient, including 1 healthy, unrelated individual as a control (labeled WT). C6 was used as the loading control. (d) Proteomic analysis of the MAC components showing aberrant MAC formation. Complexes were analyzed following in vitro complement activation and pull-down of C6 containing complexes using co-IP. Each sample was compared to the average protein levels of controls. Whereas complete C5b-9 MAC were formed in controls, very low levels of C8 and C9 were detected in the cases. (e) Normal complement cascade and suggested pathological mechanisms leading to kidney disease. Abnormal C8 or C9 proteins result in the inability of C9 monomers to connect to the forming MAC and the absence of intact membranes penetrating pores. The resulting partial MAC, lacking C9 and some C8 chains, may lead to complement deposition in the glomeruli, either by itself as protein aggregates or as a part of immune complexes. co-IP, coimmunoprecipitation; EGF, epidermal growth factor like domain; LDLR, low density lipoprotein receptor class A domain; MAC, membrane attack complex; MACPF, membrane attack complex/perforin domain; TSP1, thrombospondin 1 domain.
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References

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