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Two-tiered DNA-based diagnosis of transthyretin amyloidosis reveals two novel point mutations

Peripheral Neuropathy Laboratory, Department of Neurology (Dr. S. Ii, S. Minnerath, and Drs. K. Ii and Dyck), and Department of Biochemistry and Molecular Biology (Drs. S. Ii and Sommer), Mayo Clinic and Mayo Foundation, Rochester, MN.

We analyzed 11 consecutive unrelated cases of polyneuropathy due to transthyretin amyloidosis. Direct sequencing of the promoter region, exons, and splice junctions revealed that each patient was heterozygous for a mutation: six patients had valine 30 substituted by methionine (V³⁰ M; Portuguese-Japanese type), one had threonine 60 substituted by alanine (T⁶⁰ A; Appalachian type), and two had serine 77 substituted by tyrosine (S⁷⁷ Y; Illinois type). In addition, two patients had previously undescribed mutations: phenylalanine 33 substituted by leucine (F³³ L) and phenylalanine 64 substituted by leucine (F⁶⁴ L). From present information, the probands of these novel mutations do not exhibit any pathology that clearly distinguishes them from individuals with the other mutations. The mutations extend the range of mutations associated with amyloidotic polyneuropathy. In our 11 patients, the different mutations did not seem to correlate with distinct clinical phenotypes. We developed PASA assays (PCR amplification of specific alleles) for each of the five mutations. PAS A can be used by any diagnostic laboratory that can perform PCR to rapidly detect any of the known mutations. The minority of samples with an undescribed mutation can be sent to a specialty laboratory for delineation of the mutation by direct genomic sequencing. The presently described combination of methods may have widespread utility in the diagnosis of genetic disease.

Address correspondence and reprint requests to Dr. Steve S. Sommer, Department of Biochemistry and Molecular Biology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905.

Received September 7, 1990. Accepted for publication in final form November 7, 1990.

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