Table 2.
Results of genetic investigations in 14 women with aHUS
| Patient | Gene | Alteration in Protein | Domain | In Silico Predictions on Possible Functional Effect | Minor Allele Frequencya | Functional Effect | Risk Haplotype | Copy Number of CFH, CFHR1,-R2, -R3, and -R5 |
|---|---|---|---|---|---|---|---|---|
| A.1 | CFI | p.G342E | serine protease | probably damaging,1 damaging,2 deleterious,3 disease causing4 | 0% | not characterized42 | het CFH H3 | no alteration |
| CD46 | p.D257Vfsa42 | SCR4 | disease causing4 | 0% | FS causing, damaging43 | |||
| A.2 | CFI | p.I416L | serine protease | benign,1 tolerated,2 neutral,3 disease causing4 | 0.01%–1.29% | quantitative Factor I Deficiency42,44–47 | none | het dele CFHR1,-R3 |
| B.1 | none | na | na | na | na | het CFH c.-331C>T | het dele CFHR1,-R3 | |
| B.2 | none | na | na | na | na | hom CFH H3 | no alteration | |
| B.3 | CD46 | p.E234K | SCR4 | benign,1 tolerated,2 neutral,3 poly4 | 0% | not characterized7 | het CFH H3 | no alteration |
| B.4 | C3 | p.D61N | MG1 | probably damaging,1 tolerated,2 neutral,3 poly4 | 0% | not characterizedb | het CFH H3 | no alteration |
| B.5 | CD46 | p.A353V | TM | benign,1 tolerated,2 neutral,3 poly4 | 0.29%–1.73% | deficient cell surface control of AP48–52 | none | no alteration |
| C.1 | C3 | p.K104E | MG1 | benign,1 tolerated,2 neutral,3 poly4 | 0% | not characterized | het CFH H3 | no alteration |
| C3 | p.D1457H | MG8 | probably damaging,1 damaging,2 deleterious,3 poly4 | 0.34% | not characterized | |||
| C.2 | THBD | p.E560Q | probably damaging,1 tolerated,2 neutral,3 disease causing4 | 0.01%–0.02% | not characterized | het CFH H3 | no alteration | |
| C.3 | none | na | na | na | na | het CFH H3/H8 | na | |
| C.4 | CFHR5 | p.E163Rfsa34 | SCR3 | disease causing4 | 0.09%–0.30% | FS causing, damaging53,54 | none | no alteration |
| C.5 | none | None | na | na | na | na | hom CFH H3 | no alteration |
| C.6 | CFH | p.N516K | SCR9 | probably damaging,1 tolerated,2 deleterious,3 poly4 | 0.02%–0.04% | not characterized42,44,48,55 | het CFH H3 hom p.E936D | no alteration |
| C.7 | CFH | p.D748Nfsa10 | SCR13 | disease causing4 | 0% | FS causing, damaging | het CFH H3 | |
| CD46 | p.A353V | TM | benign,1 tolerated,2 neutral,3 poly4 | 0.29%–1.73% | deficient cell surface control of AP48–52 | no alteration |
CFH, complement factor H; CFHR1–5, CFH related protein 1–5; CFI, complement factor I; het, heterogeneous; CD46, cluster of differentiation 46; SCR, short consensus repeat; FS, frameshift; dele, deletion; na, not applicable; hom, homogenous; poly, polymorphism; MG, macroglobulin; TM, transmembrane; AP, alternative pathway; THBD, thrombomodulin.
Minor allele frequency was included on the basis of the Exome Sequencing (http://evs.gs.washington.edu/EVS/) and 1000 Genomes Projects (reported by dbSNP https://www.ncbi.nlm.nih.gov/SNP/); for patient C.3 only CFH was analyzed and CFH c.-331C>T was not included (CFH-H3/H8); CFHR5 was sequenced only in patients C.4 and C.5.
p.K65Q at a near site affects the C3 binding to factor H and membrane cofactor protein.