Abstract
Osteoporosis is the most common metabolic bone disorder and nitrogen-containing bisphosphonates (BP) are a first line treatment for it. Yet, atypical femoral fractures (AFF), a rare adverse effect, may appear after prolonged BP administration. Given the low incidence of AFF, an underlying genetic cause that increases the susceptibility to these fractures is suspected. Previous studies uncovered rare CYP1A1 mutations in osteoporosis patients who suffered AFF after long-term BP treatment. CYP1A1 is involved in drug metabolism and steroid catabolism, making it an interesting candidate. However, a functional validation for the AFF-associated CYP1A1 mutations was lacking. Here we tested the enzymatic activity of four such CYP1A1 variants, by transfecting them into Saos-2 cells. We also tested the effect of commonly used BPs on the enzymatic activity of the CYP1A1 forms. We demonstrated that the p.Arg98Trp and p.Arg136His CYP1A1 variants have a significant negative effect on enzymatic activity. Moreover, all the BP treatments decreased CYP1A1 activity, although no specific interaction with CYP1A1 variants was found. Our results provide functional support to the hypothesis that an additive effect between CYP1A1 heterozygous mutations p.Arg98Trp and p.Arg136His, other rare mutations and long-term BP exposure might generate susceptibility to AFF.
Highlights
Osteoporosis, which leads to increased skeletal fragility, is the most common metabolic bone disorder and over recent decades nitrogen-containing bisphosphonates (BP) have been the first-line treatment to prevent osteoporotic fractures
CYP1A1 was presented as a possible candidate for BP-mediated atypical femoral fractures (AFF) susceptibility after the finding of a rare variant in a whole-exome sequencing (WES) study of these three AFF-affected sisters [16], and this candidacy was reinforced by the discovery of three additional rare
We tested the effect of these four CYP1A1 variants on protein activity and their interaction with clinically used BPs
Summary
Osteoporosis, which leads to increased skeletal fragility, is the most common metabolic bone disorder and over recent decades nitrogen-containing bisphosphonates (BP) have been the first-line treatment to prevent osteoporotic fractures. Since BP-related AFF have a very low incidence in the general population, it has been hypothesized that rare underlying genetic causes may increase the susceptibility to sustain them [8,9,15,16] In search of such rare variants, we previously performed whole-exome sequencing (WES) to investigate the genetic background of three sisters affected with AFF and three additional unrelated AFF cases, all with a history of long BP treatment [16]. We detected a heterozygous mutation in GGPS1 that showed a severe decrease in enzyme activity together with oligomerization defects [16] Besides this functionally valid candidate, another gene, CYP1A1, was found mutated in heterozygosis in all three sisters and one unrelated patient [16]. Through testing the CYP1A1 enzymatic activity under several BP treatments, we observed a negative effect of BP exposure regardless of the variant
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