Hereditary cystatin C amyloid angiopathy: identification of the disease-causing mutation and specific diagnosis by polymerase chain reaction based analysis.
Hereditary cystatin C amyloid angiopathy (HCCAA) is a dominantly inherited disease characterized by amyloidosis, dementia and fatal cerebral hemorrhage of young adults. A method for rapid and simple diagnosis of HCCAA is described. It is based upon oligonucleotide-directed enzymatic amplification of a 275-bp genomic DNA segment containing exon 2 of the cystatin C gene from a blood sample, followed by digestion of the amplification product with AluI. Loss of an AluI recognition site in the amplified DNA segment from HCCAA patients results in a deviating band-pattern at agarose gel electrophoresis, compared with that obtained from normal subjects or unaffected HCCAA family members. In a population of 9 patients with manifest HCCAA, 14 patients with other causes of brain hemorrhage and 16 healthy individuals, the diagnostic procedure displayed a sensitivity and specificity for HCCAA of 100%. Amplified DNA segments from 4 HCCAA patients of four different families were analyzed by nucleotide sequencing; the HCCAA-causing mutation in all families was found to be a single T----A substitution in the codon for amino acid residue 68 of cystatin C.
Abrahamson
M
M
Department of Clinical Chemistry, University of Lund, University Hospital, Sweden.
Jonsdottir
S
S
Olafsson
I
I
Jensson
O
O
Grubb
A
A
D000595:Amino Acid Sequence; D001483:Base Sequence; D015139:Blotting, Southern; D016657:Cerebral Amyloid Angiopathy / Q000175:diagnosis / Q000235:genetics*; D002556:Cerebrospinal Fluid Proteins / Q000235:genetics*; D055316:Cystatin C; D015891:Cystatins / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009838:Oligodeoxyribonucleotides / Q000235:genetics; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length
C525030:CST3 protein, human; D002556:Cerebrospinal Fluid Proteins; D055316:Cystatin C; D015891:Cystatins; D009838:Oligodeoxyribonucleotides