HCCAA in leelandie families
The HCCAA-causing mutation has been found in
nine leelandie families originating in the west and
south of leeland but the descendants are now
scattered over most of the country ( l, 20, 21). In
seven pedigrees, transmission Iines through two
ormore family branches extend back from affected
members ascertained in the last 70 years to
progenitors bom 150-200 years ago
(1).
Since the
same mutation has been found in all HCCAA
patients available to study, it is highly probable
that all affected descend from a common ancestor
who initially transmitted this mutant gene to all
nine HCCAA families known to date.
RFLP analysis ofthree polymophic restriction
sites at 3' end of the cystatio C gene in families
withHCCAA
RFLP analysis of three polymorphic restriction
sites has been performed in all nine HCCAA
families. These three polymorphic restriction
sites are located 1.4, 4.1 , and 16 kb downstreamof
the cystatin C gene and detected by
Pst/, Sac/
and
EcoRI,
respectively (22).
Haplotype analysis has shown that all patients
available for study share an RFLP haplotype with
1.9-kb
Pst/,
2.7-kb
Sac/,
and 21-kb
EcoRI
fragments, which is also the most common
haplotype in the normal leelandie population. An
exception was found in one family which has an
RFLP haplotype with 2.6-kb
Pst/,
2.7-kb
Sac/,
and 21-kb
EcoRI
fragments instead (20). This
suggests that the HCCAA-causing mutation has
occurred in a common ancestor with the most
common haplotype in leeland and a crossover has
occurred between the mutated cystatin Cgene and
the Pstl restfiction site in this exceptional family .
Unknown pathophysiologicmechanism behind
HCCAA
It is not known how the T->A mutation in the
cystatin Cgene, resulting in a leucine-> gJutamine
amino acid substitution in the cystatin Cmolecule,
is related to the deposition of the amyloid fibrils in
HCCAA patients. The substitution of one amino
acid probably changes the physicochemical
properties of cystatin C resulting in lower
extracellular solubility or intracellular deposition
because of impeded processing and transport out
Klinisk kemi
i
Norden 2, /993
of cystatin C producing cells (23). It is also
possible that the amino acid substitution affects
the cysteine proteinase inhibitory properties of
cystatin
c.
studies of the physicochemical and
cysteine proteinase inhibitory properties of the
mutated cystatin C as well as its intracellular
transport will be crucial for understanding the
pathophysiologic mechanisms behind HCCAA
and, thus, for finding possible remedies for the
disease.
References
l.
Jensson O, Gudmundsson G, Amason A, Blöndal H,
Petursdottir I, Thorsteinsson L, Grubb A, Lötberg H, Cohen
D, Frangione B. Hereditary cystalin C ("(-trace) amyloid
angiopathy of the CNS eausing cerebral hemorrhage. Acta
Neuro! Scand 1987; 76: 102-114.
2. Arnason
A.
Apoplexie und ihre vererbung. Acta Psychiatr
Neuro! Suppll935; 7: 1-180.
3. Gudmundsson G, Hallgrimsson J, Jonasson TA, Bjamason
O. Hereditary cerebral ha:morrhage with amyloidosis. Brain
1972;95: 387-404.
4. Cohen DH, Feiner H, Jensson O, Frangione B. Amyloid
fibril in hereditary cerebral hemorrhage with amyloidosis
(HCHWA) is related to the gastroenteropancreatic neuroen–
docfine protein, ganuna trace. J Exp Med 1983; 158: 623-
628.
5.
GrubbA, Löfberg H. Human "(-trace, abasic microprotein:
Amino acid sequence and presence in the adenohypophysis.
Proc Natl Acad Sci USA 1982; 79: 3024-3027.
6. Barrett AJ, Davies ME, Grubb A. The place of human g–
trace (cystatin C) amongst the cysteine proteinase inhibitors.
Biochem Biophys Res Commun 1984; 120: 631-636.
7. Abrahamson M, Barrett AJ, Salvesen G, GrubbA. Isola–
tion of six cysteine proteinase inhibitors from human urine.
Their physiocochemical and enzyme kinetic properties and
concentrations in biological fluids. J Bio! Chem 1986; 261:
11282-11289.
8. Ghiso
J,
Jensson O, Frangione B. Amyloid fibrils
in
hereditary cerebral hemorrhage with amyloidosis of
leelandie type is a variant of "(-trace basic protein (cystatin
C). Proc Natl Acad Sci USA 1986; 83: 2974-2978.
9. Lötberg H, Grubb AO, Nilsson EK, Jensson O, Gud–
mundsson G, Blöndal H, Amason A, Thorsteinsson
L.
Immu–
nohistochemical characterization of the amyloid deposits and
quantitation of pertinent cerebrospinal fluid proteins in here–
ditary cerebral hernorrhage with amy1oidosis. Stroke 1987;
18: 431-440.
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