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, Lawreen H. Connors

Research output: Contribution to journalArticlepeer-review

Abstract

Background: β2-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. Methods: Three 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. Results: The 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. Conclusions: This work provides both clinical and experimental evidence supporting the critical role of P32 residue replacement in β2M amyloid fibrillogenesis.

Original languageEnglish (US)
JournalAmyloid
DOIs
StateAccepted/In press - 2022

Keywords

  • Amyloid-forming propensity
  • P32L variant
  • β2M amyloidosis
  • β2M gene mutation

ASJC Scopus subject areas

  • Internal Medicine

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