Mutation in the cystatin C gene causes hereditary brain hemorrhage.
Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disorder leading to massive brain hemorrhage and death in young adults (Jensson et al., 1987). A variant of a potent inhibitor of cysteine proteinases, cystatin C (Barrett et al., 1984), is deposited as amyloid fibrils in the cerebral arteries of the patients (Ghiso et al., 1986). We have used the full length cystatin C cDNA probe (Abrahamson et al., 1987) to demonstrate a mutation in the codon for leucine at position 68, which abolishes an Alu I restriction site in cystatin C gene of the HCCAA patients. The Alu I marker has been used to show that this mutation is transmitted only in the affected members in all eight families investigated, proving that the mutated cystatin C gene causes HCCAA. This DNA marker will be useful for the diagnosis of HCCAA in patients, asymptomatic affected individuals and also for pre-natal diagnosis. HCCAA is the first human disorder known to be caused by an abnormal gene for a cysteine proteinase inhibitor.
Palsdottir
A
A
Blood Bank, National Hospital, University of Iceland, Reykjavik.
Abrahamson
M
M
Thorsteinsson
L
L
Arnason
A
A
Olafsson
I
I
Grubb
A
A
Jensson
O
O
D000686:Amyloidosis / Q000235:genetics* / Q000503:physiopathology; D002543:Cerebral Hemorrhage / Q000209:etiology* / Q000235:genetics; D055316:Cystatin C; D015891:Cystatins / Q000235:genetics* / Q000378:metabolism; D015342:DNA Probes; D005819:Genetic Markers; D006801:Humans; D007055:Iceland; D009154:Mutation; D011110:Polymorphism, Genetic
C525030:CST3 protein, human; D055316:Cystatin C; D015891:Cystatins; D015342:DNA Probes; D005819:Genetic Markers