O55
COMPLEMENT FACTOR H RELATED PROTEIN 5 (CFHR5) NEPHROPATHY: AN
ENDEMIC CAUSE OF RENAL DISEASE IN CYPRUS
Gale, D1,6, de Jorge, E2, Cook, T3, Martinez-Barricarte, R4, Hadjisavvas, A5, McLean, A6, Pusey,
C6, Pierides, A7, Athanasiou, Y8, Voskarides, K9, Deltas, C9, Palmer, A6, Frémeaux-Bacchi, V10,
de Cordoba, S4, Maxwell, P1,Pickering, M2
1
Division of Medicine, University College, London, 2Rheumatology Section, 3Department of
Histopathology, and 6Imperial College Kidney and Transplant Institute, Imperial College,
London, 4Centro de Investigaciones Biológicas (CSIC), Madrid, Spain, 5Department of Electron
Microscopy and Pathology, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus, 7
Department of Nephrology, Hippocrateon Hospital, Cyprus, 8 Department of Nephrology,
Nicosia General Hospital, Cyprus, 9Department of Biological Science, University of Cyprus,
Nicosia, Cyprus, 10Service d’Immunologie Biologique, Hôpital Européen Georges Pompidou,
Paris, France
We report a novel familial disease, endemic in Cyprus, in which microscopic and synpharyngitic
macroscopic haematuria and renal impairment are transmitted as an autosomal dominant trait. Renal
biopsy in affected individuals demonstrates mesangiocapillary glomerulonephritis with glomerular
deposition of C3 but not immunoglobulins, suggesting a defect of complement alternative pathway
regulation. Serum levels of complement C3 and C4 were normal in all affected individuals studied.
A genome-wide linkage study in 11 individuals with the disease from two ostensibly unrelated
families from the mountainous Troodos region of Cyprus demonstrated linkage (with LOD 3.4) to the
Complement Factor H/Complement Factor H Related (CFHR) 1-5 gene cluster and a shared 8.4cM
haplotype spanning this locus.
An in-frame duplication of exons 2 and 3 of CFHR5 was identified by multiplex ligation-dependent
probe amplification analysis and its extent confirmed by Southern blotting. The allele cosegregated
with the disease in both pedigrees and was present in one out of 1015 Cypriot controls. The mutation
was also identified in 18 further affected individuals (including 5% of a group of 84 Cypriot patients
with chronic or end stage kidney disease of unknown cause) from 9 additional families, all of Cypriot
descent but not all with known ancestry in the Troodos region. These individuals were all resident in
either London or Cyprus. Haplotype analysis indicated that the most recent common ancestor of 5 of
the families lived approximately 16 generations (~400 years) ago.
The mutant CFHR5 protein was detected in the serum of affected individuals by Western blotting and
demonstrated reduced affinity for heparin and complement-lysed erythrocytes. In addition,
recombinant mutant protein exhibited reduced affinity for heparin and glomerular C3 when compared
with the recombinant wild type protein.
This disease, which we designate ‘CFHR5 Nephropathy,’ accounts for a significant proportion of
renal disease in Cypriot patients and implicates CFHR5 as an important regulator of complement
within the kidney in humans, suggesting that it may have therapeutic potential in diseases associated
with complement deposition.