Molecular Biology of Hereditary Cystatin C
Amyloid Angiopathy in leeland
Sif Jonsdottir
1
and Astridur Palsdottir
2
Department ofMedical Genetics, The Blood Bank, National University Hospital,
IS-101 Reykjavik, leeland
1
Present address: Immunogenetics unit, Department ofPathology, National University Hospital, IS-/0/ Reykjavik leeland
2
Present address: Genetics Laboratory, Institute of Biology, University of Iceland, Grensasvegur 12, IS-108 Reykjavik,
leeland
Address correspondence to: Sif Jonsdottir, Immunogenetics unit, Department of Pathology, National
University Hospital, House #14, IS-101 Reykjavik, lceland.
Tel.: 354-1-601956, Fax.: 354-1-601519
INTRODUCTION
The main purpose ofthis short review is to describe
the advances made in recent years in elucidating
the nature of hereditary cystatio C amyloid
angiopathy (HCCAA) occurring in lcelanders.
The research groups in the Blood Bank in leeland
and in the Department of Clinical Chemistry at the
University ofLund in Sweden have been studying
this disease and recently devised a simple
diagnostic test for HCCAA by the methods of
molecular genetics.
We have submitted a minireview on molecular
diagnosis of HCCAA for publication in the jour–
nal, BiochemicalMedicine andMetabolic Biology,
which is now in press. This review is presented
here with a few modifications.
Hereditary cystatio C amyloid angiopathy
(HCCAA), previously called hereditary cerebral
hernorrhage with amyloidosis, is an autosomal
dominant disorder characterized by amyloidosis
and fatal cerebral hernorrhage of young non–
hypertensive adults. The clinical manifestations
ofHCCAA range from dying immediately or after
few days or weeks following the first stroke to
living for many years crippled by multiple strokes
eausing paralysis, dementia and behavioral
changes; but death usually occurs before the age
of 40 years
(1).
HCCAA was first described in 1935 by Ami
Amason. He described a few leelandie families
with a high incidence of cerebral hernorrhage and
concluded that a hereditary form of the disease
was present in these farnilies (2). Later it was
demonstrated that of the disease was due to the
Klinisk kemi i Norden 2, 1993
deposition of amyloid in the cerebral arteries (3).
The main fibrillar components of the amyloid
deposits have been found to consist of a variant of
the basic microprotein cystatio C (originally called
y-trace) (4), a cysteine proteinase inhibitor, which
in its native state consists of 120 arnino acids and
has awidespread distribution in human body fluids
(5-7). The amyloid protein differs from normal
cystatio C in two respects. The first l
O
arnino
acids are missing from the arnino terminal and
there is an amino acid substitution (glutarnine for
leucine) at positon 68 of the normal cystatio C (8).
Later studies have shown thatcystatin C amyloid
deposits in HCCAA patients not only occur in the
arterles of the brain, but also in other tissues such
as lymph nodes, spleen, salivary glands, seminal
vesicles and skin (9-11 ). No clinical symptoms
are associated with the presence of amyloid in
organs outside the brain
(l).
HCCAA is also characterized by an abnormally
low level of cystatio C in the cerebrospinal fluid
(CSF) or approximately one third of the mean
value found in healthy control subjects (12 ).
HCCAA is the only human disorder known to
be eaused by selective deposition of cystatio C
amyloid fibrils.
Cystatio C gene
and
HCCAA
The human cystatio C gene has been sequenced
entirely andassigned to chromosome 20 at 20p12
(13-15). The gene is approximately 4.5 kb in
length and contains 3 exons (13).
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