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1.Nephmadness tweetorial ahead!

So now that #Nephmadness is here, it’s time for a #tweetorial to convince you why you should be voting for genetic C3 glomerulopathy (C3G) not only to beat acquired causes of C3G, but to make a run for the championship.
Firstly, what percentage of C3G is thought to be due to an underlying genetic predisposition?
3.Those of you who have chosen 20% are correct! The remainder are due to acquired causes (more on this below). Before we start, it’s important to have a quick overview of C3G. C3G comprises two diseases, dense deposit disease (DDD) and C3 glomerulonephritis (C3GN).
These are caused by excessive activation of the alternative pathway within the fluid phase (where the fluid phase is defined as those complement interactions which occur within the serum as opposed to the cell surface, the other major site of complement activity) which...
... result in the abnormal deposition of C3 within the glomerular basement membrane (GBM) and clinical features of the disease (proteinuria, creatinine rise and haematuria).
5.C3 activation is spontaneous within the serum and along with factor B self-forms its own C3 convertase.
This activation is normally tightly controlled by regulatory proteins such as Factor H which promote the decay of C3 convertases within both the fluid and cell surface phase.
Up to 80% of C3G cases will have an acquired cause, most commonly an auto-antibody called C3 nephritic factor (C3NeF). C3NeF stabilizes C3 convertase causing increased C3 deposition. Other causes include C5/C4 nephritic factors, or antibodies to Factor H/I.
Genetic causes of C3G occur in the genes for:

1. C3 (which subsequently resists degradation)

2. Factor B (required for the formation of the C3 convertase)

3. Factor H and Factor I.

4. Complement Factor H Related Protein 5 (CFHR5, an enhancer of complement activation)
The spectrum of potential mutations is complex. For example, in Factor H there are type I mutations with low levels of circulating protein, and type II mutations with normal Factor H levels but a presumed functional deficiency due to alterations of the C3 binding site.
The fluid phase is where most of the abnormalities with C3G are thought to occur given mutations within the Factor H gene cluster around its fluid phase C3 binding site and not around its cell surface binding site domain.
However, the CFHR proteins variants appear to disrupt this paradigm by causing abnormal cell surface C3 regulation.
The CFHR mutations (with CFHR1, 2, and 5 being the most common, often as fusion products between their genes, ie CFHR1-CFHR1) cause abnormal duplication of their normal dimerization domains which lead to increased binding avidity.
This increased avidity allows these mutant proteins to out-compete Factor H for surface C3, particularly along the glycocalyx of the GBM where they preferentially bind causing increased deposition of C3 fragments.
Factor H mutations formed the basis of the first animal models of C3G (simple Factor H knockout leads to uncontrolled C3 activation and features of C3G on biopsy). Despite this such mutations are surprisingly found in only a minority of patients.
Curiously, mutations in both Factor H and I described in a series of C3G patients may be identical to those seen in complement-mediated HUS.
It is unclear why some mutations drive complement-mediated HUS and some drive C3G, although it seems likely that mutations in the alternative pathway complement genes alone may not be sufficient to cause the disease phenotype.
This article provides a fantastic review of C3G.
Those with C3G may carry a number of variants in complement-mediated genes and indeed variable penetrance has been noted in families of those with C3G, perhaps due to differing haplotypes affecting specific complement protein levels.
We must also consider that C3G is in fact two diseases as described above (DDD and C3GN) and it is unclear what genetic abnormalities drive one over the other.
Patients with familial C3G appear to more commonly have C3GN, with rearrangements of the Complement Factor H gene or CFHR fusion genes being the most commonly described abnormalities.
If you identify a case of C3G, what other investigations should be ordered?
It is indeed all of the above! The minimum recommended set of genes to test (which also interestingly overlaps with complement-mediated HUS) is CFH, CD46, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE.
... Although it should be noted that only variants in C3, CFH or CFB deficiency, or CFHR fusion proteins are currently sufficiently characterised to make a clear genetic diagnosis at this time.
The Kidney Disease Improving Global Outcomes (KDIGO) meeting report is an invaluable source of information for the workup and management of C3G.
Testing for C3NeF is also important and whilst most cases of C3G occur within the paediatric population, adult cases are well recognized and may be associated with an underlying monoclonal gammopathy (which curiously may block Factor H activity) which needs to be excluded
Thus ends this marathon tweetorial about genetic C3G. After reading the above and some of the fascinating nuances that we are only just beginning to understand about genetic C3G how could you possibly vote anything else? Cheers everyone!
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