Functional characterization of two novel non-synonymous alterations in CD46 and a Q950H change in factor H found in atypical hemolytic uremic syndrome patients

Mohlin, Frida C.; Nilsson, Sara C.; Levart, Tanja Kersnik; Golubovic, Ema; Rusai, Krisztina; Müller-Sacherer, Thomas; Arbeiter, Klaus; Pállinger, Éva; Szarvas, Nóra; Csuka, Dorottya; Szilágyi, Ágnes; Villoutreix, Bruno O.; Prohászka, Zoltán; Blom, Anna M.

doi:10.1016/j.molimm.2015.02.013

Cited by 25 publications

(19 citation statements)

References 35 publications

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“…CR1 was ruled out as pathogenic following normal expression of the complement receptor 1 on erythrocytes with normal levels of C3dg on the RBC surface. The Q950H variant of Factor H is now known to impair factor H activity (10), providing a genetic explanation for the patient’s aHUS. As previously reported, most aHUS mutations show variable penetrance, providing explanation for why the proband’s father is unaffected (11).…”

Section: Resultsmentioning

confidence: 99%

Unexpected Findings in a Child with Atypical Hemolytic Uremic Syndrome: An Example of How Genomics Is Changing the Clinical Diagnostic Paradigm

et al. 2017

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CBL is a tumor suppressor gene on chromosome 11 encoding a multivalent adaptor protein with E3 ubiquitin ligase activity. Germline CBL mutations are dominant. Pathogenic de novo mutations result in a phenotype that overlaps Noonan syndrome (1). Some patients with CBL mutations go on to develop juvenile myelomonocytic leukemia (JMML), an aggressive malignancy that usually necessitates bone marrow transplantation. Using whole exome sequencing methods, we identified a known mutation in CBL in a 4-year-old Caucasian boy with atypical hemolytic uremic syndrome, moyamoya phenomenon, and dysmorphology consistent with a mild Noonan-like phenotype. Exome data revealed loss of heterozygosity across chromosome 11q consistent with JMML but in the absence of clinical leukemia. Our finding challenges conventional clinical diagnostics since we have identified a pathogenic variant in the CBL gene previously only ascertained in children presenting with leukemia. The increasing affordability of expansive sequencing is likely to increase the scope of clinical profiles observed for previously identified pathogenic variants and calls into question the interpretability and indications for clinical management.

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Section: Resultsmentioning

confidence: 99%

Unexpected Findings in a Child with Atypical Hemolytic Uremic Syndrome: An Example of How Genomics Is Changing the Clinical Diagnostic Paradigm

et al. 2017

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“…In order to screen for mutations, rare variations or risk polymorphisms in the coding regions of complement Factor H (CFH), Factor I (CFI), membrane cofactor protein (CD46), thrombomodulin (THBD), Factor B (CFB) and C3 (C3) ,the samples were analyzed bydirect bidirectional DNA sequencing following PCR amplification, as described formerly (Szilagyi et al, 2013). Previously recognized and functionally characterized missense [43][44][45][46][47], nonsense and splice site mutations were categorized as LPVs. Novel missense variations were considered as likely pathogenic if they were not found in international databases such as dbSNP (www.ncbi.nlm.nih.gov/snp), Exome Variant Server (NHLBI GO ExomeSequencing Project (ESP), Seattle, WA (http://evs.gs.washington.edu/ EVS/) and 1000Genomes Project phase 3 (http:// browser.1000genomes.org/index.html) or if their minor allele frequency was < 0.1% and CADD score ≥ 10.…”

Section: Genetic Analysismentioning

confidence: 99%

C4 nephritic factor in patients with immune-complex-mediated membranoproliferative glomerulonephritis and C3-glomerulopathy

Garam

Prohászka

Szilágyi

et al. 2019

Orphanet J Rare Dis

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Background: Acquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) as well. Less is known about the presence and role of C4nephritic factor(C4NeF) which may stabilize the classical pathway C3-convertase. Our aim was to examine the presence of C4NeF and its connection with clinical features and with other pathogenic factors. Results: One hunfe IC-MPGN/C3G patients were enrolled in the study. C4NeF activity was determined by hemolytic assay utilizing sensitized sheep erythrocytes. Seventeen patients were positive for C4NeF with lower prevalence of renal impairment and lower C4d level, and higher C3 nephritic factor (C3NeF) prevalence at time of diagnosis compared to C4NeF negative patients. Patients positive for both C3NeF and C4NeF had the lowest C3 levels and highest terminal pathway activation. End-stage renal disease did not develop in any of the C4NeF positive patients during follow-up period. Positivity to other complement autoantibodies (anti-C1q, anti-C3) was also linked to the presence of nephritic factors. Unsupervised, data-driven cluster analysis identified a group of patients with high prevalence of multiple complement autoantibodies, including C4NeF.

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“…CFH p.Gln950His, residing in SCR16, is associated with disease risk for aHUS with moderate effect on cofactor function. 40 CFH p.Asn1050Tyr, in SCR18, is a polymorphism reported various times in aHUS without functional analyses. [41][42][43] No information is available on CFH p.Gln1143Glu and its association with aHUS/C3G.…”

Section: Complement Fhmentioning

confidence: 99%

Genotype‐phenotype correlations of low‐frequency variants in the complement system in renal disease and age‐related macular degeneration

et al. 2018

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Genetic alterations in the complement system have been linked to a variety of diseases, including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), and age‐related macular degeneration (AMD). We performed sequence analysis of the complement genes complement factor H (CFH), complement factor I (CFI), and complement C3 (C3) in 866 aHUS/C3G and 697 AMD patients. In total, we identified 505 low‐frequency alleles, representing 121 unique variants, of which 51 are novel. CFH contained the largest number of unique low‐frequency variants (n = 64; 53%), followed by C3 (n = 32; 26%) and CFI (n = 25; 21%). A substantial number of variants were found in both patients groups (n = 48; 40%), while 41 (34%) variants were found only in aHUS/C3G and 32 (26%) variants were AMD specific. Genotype‐phenotype correlations between the disease groups identified a higher frequency of protein altering alleles in short consensus repeat 20 (SCR20) of factor H (FH), and in the serine protease domain of factor I (FI) in aHUS/C3G patients. In AMD, a higher frequency of protein‐altering alleles was observed in SCR3, SCR5, and SCR7 of FH, the SRCR domain of FI, and in the MG3 domain of C3. In conclusion, we observed a substantial overlap of variants between aHUS/C3G and AMD; however, there is a distinct clustering of variants within specific domains.

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Functional characterization of two novel non-synonymous alterations in CD46 and a Q950H change in factor H found in atypical hemolytic uremic syndrome patients

Cited by 25 publications

References 35 publications

Unexpected Findings in a Child with Atypical Hemolytic Uremic Syndrome: An Example of How Genomics Is Changing the Clinical Diagnostic Paradigm

Unexpected Findings in a Child with Atypical Hemolytic Uremic Syndrome: An Example of How Genomics Is Changing the Clinical Diagnostic Paradigm

C4 nephritic factor in patients with immune-complex-mediated membranoproliferative glomerulonephritis and C3-glomerulopathy

Genotype‐phenotype correlations of low‐frequency variants in the complement system in renal disease and age‐related macular degeneration

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