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Molecular diagnosis of hereditary cystatin C amyloid angiopathy
1Department of Medical Genetics, Blood Bank, National University Hospital, Reykjavik, Iceland.
Insights
Hereditary cystatin C amyloid angiopathy (HCCAA) is a genetic disorder causing fatal brain hemorrhages. A specific gene mutation leads to amyloid buildup, detectable via DNA analysis for early diagnosis.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disorder.
- Amyloid deposition in cerebral arteries causes fatal brain hemorrhages before age 40.
- The disease results from a specific mutation in the cystatin C gene.
Purpose of the Study:
- To identify the genetic cause of HCCAA.
- To develop a molecular diagnostic method for HCCAA.
- To screen individuals and families for the HCCAA mutation.
Main Methods:
- DNA sequencing to identify the causative mutation in the cystatin C gene.
- Restriction fragment-length polymorphism (RFLP) analysis using AluI to detect the mutation.
- Screening of 191 individuals, including prenatal diagnosis.
Main Results:
- A T-->A point mutation at codon 68 in exon 2 of the cystatin C gene causes HCCAA.
- This mutation results in a leucine-->glutamine substitution.
- The mutation abolishes an AluI restriction site, enabling RFLP diagnosis.
- 36 individuals in nine Icelandic families were found to have the mutation.
Conclusions:
- A specific cystatin C gene mutation is responsible for HCCAA.
- AluI RFLP analysis provides a simple and accurate method for HCCAA diagnosis.
- The mutation is prevalent in Icelandic families, suggesting a common ancestor.
Abstract:
Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disorder characterized by the deposition of amyloid in most investigated tissues. The main component of the amyloid deposits is a variant of the cysteine proteinase inhibitor cystatin C, and the most serious consequence of the disease is that amyloid deposition in the cerebral arteries leads to a massive brain hemorrhage and death before 40 years of age. HCCAA has been shown to be caused by a T-->A point mutation in the codon for leucine at position 68 in exon 2 of the cystatin C gene, which results in a leucine-->glutamine amino acid substitution in the cystatin C molecule. Since the HCCAA-causing mutation abolishes an AluI restriction site in the cystatin C gene, analysis of this AluI restriction fragment-length polymorphism (RFLP) enables simple and accurate molecular diagnosis of HCCAA. One hundred ninety-one individuals have now been screened for the HCCAA causing mutation, including a fetus for prenatal diagnosis. Thirty-six individuals belonging to nine Icelandic families have been found to have the mutation and it is highly probable that these families descend from a common ancestor.