Abstract. An increasing cause of end-stage renal disease
is the pathological lesion focal and segmental glomeru-
losclerosis (FSGS). FSGS is characterized by proteinuria
and frequently nephrotic syndrome with ensuing renal
failure. The etiology remains unknown in the majority of
individuals. The idiopathic form of FSGS is most com-
mon; however, secondary forms of FSGS do exist. There
is a form of FSGS that is fulminant that frequently recurs
after renal transplantation with an estimated frequency of
approximately 30%, suggesting that the pathogenesis is
not solely a result of intrinsic kidney disease. Recently,
hereditary forms of the disease were recognized as well as
those associated with other congenital syndromes. Known
genetic causes of the hereditary form of this disease have
been suggested to account for upwards of 18% of cases.
This review will address recent discoveries of the genetic
mechanisms of hereditary FSGS and the current interpre-
tations of their interactions at the slit diaphragm.
Keywords. Familial focal segmental glomerulosclerosis, familial nephropathy, genetics, kidney; hereditary, TRPC6,
podocin, nephrin, ACTN4.
Introduction
End-stage renal disease (ESRD) is a substantial cause of
morbidity and mortality worldwide. A recent review of
the available data suggests that focal and segmental glo-
merulosclerosis (FSGS) is a considerable cause of ESRD,
accounting for up to 20% of dialysis patients [1, 2]. FSGS
has been reported in all ethnicities; however, it accounts
for 50% of unexplained nephrotic syndrome in blacks [3].
The diagnosis of FSGS requires the presence of areas of
glomerular sclerosis and tuft collapse that are both focal
(some glomeruli are affected but not all) and segmental (a
segment of the glomerulus is affected). The clinical hall-
marks include proteinuria, nephrotic syndrome and fre-
quently the progressive loss of renal function. Segmental
hyalinosis, glomerular deposits that are positive for im-
munoglobulin M and/or C3 by immunofluorescence mi-
croscopy as well as epithelial cell foot process effacement
by electron microscopy are often seen but not required to
make the diagnosis.
While the idiopathic form of FSGS is most common,
secondary FSGS can occur in association with reflux
nephropathy, obesity, HIV infection and sickle cell dis-
order as well as other medical conditions [4–6]. Recently,
autosomal dominant and recessive forms of FSGS have
been described as well as those associated with congeni-
tal syndromes [5, 7–16]. It is now thought that perhaps
up to 18% of FSGS cases are due to familial disease [17].
Substantial progress has been made over the last decade
by advances in molecular genetics technology and map-
ping, including high-throughput genotyping for genomic
screening, that provide powerful tools for the analysis of
renal diseases [7]. These insights have promoted addi-
tional understanding of the biologic basis of FSGS and
podocyte structure, and function through the identifica-
tion and understanding of genetic mutations associated
with various familial forms.
The etiology of FSGS remains unknown in a majority of
cases. There is an estimated
recurrence rate of FSGS in
Human Genome & Diseases: Review
Focal and segmental glomerulosclerosis
N. Daskalakis
a, b
and M. P. Winn
a, b,
*
a
Duke University Medical Center, Duke Box 2903, Durham, North Carolina 27705 (USA), Fax: +1 919 684 0920,
e-mail: michelle.winn@duke.edu
b
Center for Human Genetics, Duke University Medical Center, Durham, North Carolina 27710 (USA)
Received 17 April 2006; received after revision 23 May 2006; accepted 6 July 2006
Online First 4 September 2006
* Corresponding author.
Cell. Mol. Life Sci. 63 (2006) 2506–2511
1420-682X/06/212506-6
DOI 10.1007/s00018-006-6171-y
© Birkhäuser Verlag, Basel, 2006
Cellular and Molecular Life Sciences