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Case Reports
A novel substitution of proline (P32L) destabilises β2-microglobulin inducing hereditary systemic amyloidosis.
- Tatiana Prokaeva, Tracy Joshi, Elena S Klimtchuk, Victoria M Gibson, Brian Spencer, Omar Siddiqi, Dobrin Nedelkov, Yueming Hu, John L Berk, Sarah A M Cuddy, Surendra Dasari, April Chiu, Lauren A Choate, Ellen D McPhail, Haili Cui, Hui Chen, Eric J Burks, Vaishali Sanchorawala, and Lawreen H Connors.
- Amyloidosis Center, Boston University School of Medicine, Boston, MA, USA.
- Amyloid. 2022 Dec 1; 29 (4): 255262255-262.
Backgroundβ2-microglobulin amyloidosis was first described in the 1980s as a protein deposition disease associated with long-term haemodialysis. More recently, two inherited forms resulting from separate point mutations in the β2-microglobulin gene have been identified. In this report, we detail a novel β2M variant, P32L, caused by a unique dinucleotide mutation that is linked to systemic hereditary β2-microglobulin amyloidosis.MethodsThree family members from a Portuguese kinship featured cardiomyopathy, requiring organ transplantation in one case, along with soft tissue involvement; other involvements included gastrointestinal, neuropathic and sicca syndrome. In vitro studies with recombinant P32L, P32G, D76N and wild-type β2-microglobulin were undertaken to compare the biophysical properties of the proteins.ResultsThe P32L variant was caused by the unique heterozygous dinucleotide mutation c.154_155delinsTT. Amyloid disease featured lowered serum β2-microglobulin levels with near equal amounts of circulating P32L and wild-type proteins; amyloid deposits were composed exclusively of P32L variant protein. In vitro studies of P32L demonstrated thermodynamic and chemical instability and enhanced susceptibility to proteolysis with rapid formation of pre-fibrillar oligomeric structures by N- and C-terminally truncated species under physiological conditions.ConclusionsThis work provides both clinical and experimental evidence supporting the critical role of P32 residue replacement in β2M amyloid fibrillogenesis.
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