FAMILIAL ATYPICAL HEMOLYTIC UREMIC SYNDROME
WITH POSITIVE p.S1191L (c.3572C>T) MUTATION ON
THE CFH GENE: A SINGLE-CENTER EXPERIENCE
Ersoy Dursun F1,*, Yesil G2, Sasak G3, Dursin H4
*Corresponding Author: Dr. Fadime Ersoy Dursun, Hematoloji Bilim Dalı, Istanbul Medeniyet Universitesi
Tıp Fakultesi, Dr. Erkin Cad. No. 6, 34722 Kadıköy, Istanbul, Turkiye. Tel.: +90-536-838-5101.
Fax: +90-216-606-5210. E-mail: drfadimeersoy@yahoo.com.tr
page: 81
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INTRODUCTION
Hemolytic uremic syndrome (HUS) is a type of
thrombotic microangiopathy (TMA) characterized by
thrombo-cytopenia, acute kidney injury (AKI), and microangiopathic
hemolytic anemia [1-3]. Atypical HUS
(aHUS) comprises around 5.0-10.0% of all HUS cases
and frequently leads to irreversible kidney injury, often
with a worse prognosis [1,2,4]. Atypical HUS is a disease
complex characterized by the uncontrolled over-activation
of the alternative pathway of the complement system.
Activation has been linked to mutations in complement
factors in 50.0-60.0% of cases [3]. Atypical HUS cases
can be categorized as sporadic or familial. Familial aHUS
requires diagnosing at least two aHUS cases in the same
family over the past 6 months. Twenty percent of all aHUS
patients are familial aHUS cases [5].
Genetic disorders such as gene mutations, rare variants,
and risk haplotypes in familial aHUS and sporadic
aHUS cases and developmental anomalies such as factor
H against autoantibodies are found in 70.0% of patients
[6]. The regulator of complement activation gene cluster
on human chromosome 1q32 spans over a total of 21.45
cM and contains more than 60 gene codes, 15 of which
are complement regulators. This code plays a vital role
for both soluble and transmembrane proteins in regulating
complement activity. These complement genes are arranged in tandem within two groups. Gene mutations
usually occur in complementary genes such as factor H
(CFH), factor I (CFI), factor B (CFB), complement 3 (C3)
and membrane cofactor protein (MCP or CD46). Although
not all these gene mutations are detectable in the aHUS,
they are the most frequently detected ones.
Data obtained from familial studies demonstrate that,
due to a high level of incomplete penetrance of aHUS,
50.0% of persons carrying CFH or MCP mutations do not
develop the disease. The genes for CFH and five CFHrelated
proteins, CFHR1, CFHR2, CFHR3, CFHR4 and
CFHR5, lie in a centromeric 360 kb segment [7-11]. Gene
mutations and related proteins encoded by these genes
play an important role in the course of the disease. Genetic
studies in these patients do not include large series [12].
Venables et al. [13] previously showed, in a family with
aHUS that non allelic homologous recombination results
in the formation of a hybrid gene derived from exons 1-21
of CFH and exons 5-6 of CFHR1. The protein product of
this hybrid gene is identical to the aHUS associated CFH
mutant S1191L/V1197A, which arises through gene conversion
[14]. We present a study on an aHUS patient where
genetic screening was performed on family members to
diagnose familial aHUS due to family history of chronic
renal failure (CRF).
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