Exon array analysis reveals genetic heterogeneity in atypical femoral fractures. A pilot study

Pérez-Núñez, Isabel; Pérez‐Castrillón, José Luis; Zarrabeitia, Marı́a T.; García-Ibarbia, Carmen; Martínez-Calvo, Laura; Olmos, José M.; Briongos, Laisa; Riancho, Javier; Camarero, Victoria; Jm, Muñoz; Cruz, Raquel; Riancho, José A.

doi:10.1007/s11010-015-2510-3

Cited by 25 publications

(21 citation statements)

References 26 publications

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“…Although the sample size was very small (13 AFF cases; 268 controls), patients tended to accumulate some rare variants, and consequently the number of risk variants was markedly different between patients and controls. These results suggest that AFF are polygenic in nature, associated with the accumulation of changes in the coding regions of several genes [108 ] . Most genes in the study did not have a well-established relation with bone metabolism.…”

Section: Atypical Femoral Fractures (Aff)mentioning

confidence: 84%

“…Isolated reports suggest that individuals with rare mutations of the alkaline phosphatase gene (ALPL) may have higher risk of developing AFF when treated with bisphosphonates [107 ] . However, ALPL mutations are very rare among patients with AFF, thus indicating that genetic variants of ALPL are not a major determinant of AFF risk [108,109 ] . There is very little information about the potential involvement of other genes in AFF.…”

Section: Atypical Femoral Fractures (Aff)mentioning

confidence: 99%

See 1 more Smart Citation

Genetic and acquired factors influencing the effectiveness and toxicity of drug therapy in osteoporosis

López-Delgado¹,

Riancho‐Zarrabeitia²,

Riancho³

2016

Expert Opinion on Drug Metabolism & Toxicology

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Section: Atypical Femoral Fractures (Aff)mentioning

confidence: 84%

Section: Atypical Femoral Fractures (Aff)mentioning

confidence: 99%

Genetic and acquired factors influencing the effectiveness and toxicity of drug therapy in osteoporosis

López-Delgado¹,

Riancho‐Zarrabeitia²,

Riancho³

2016

Expert Opinion on Drug Metabolism & Toxicology

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“…In a pilot study, Pérez‐Núñez and colleagues conducted an exon array analysis (Affymetrix Axion 2.0 exome array) in 13 women with AFFs and 268 controls that consisted of healthy women ( n = 87) and patients with postmenopausal osteoporosis without AFFs ( n = 181) (Table ). By including the osteoporosis patients in the control group, the investigators intended to avoid the finding of osteoporosis‐related variants rather than variants associated with AFFs.…”

Section: Resultsmentioning

confidence: 99%

Genetic Risk Factors for Atypical Femoral Fractures (AFFs): A Systematic Review

Nguyen¹,

Laarschot

Verkerk

et al. 2018

JBMR Plus

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Atypical femoral fractures (AFFs) are uncommon and have been associated particularly with long‐term antiresorptive therapy, including bisphosphonates. Although the pathogenesis of AFFs is unknown, their identification in bisphosphonate‐naïve individuals and in monogenetic bone disorders has led to the hypothesis that genetic factors predispose to AFF. Our aim was to review and summarize the evidence for genetic factors in individuals with AFF. We conducted structured literature searches and hand‐searching of conference abstracts/reference lists for key words relating to AFF and identified 2566 citations. Two individuals independently reviewed citations for (i) cases of AFF in monogenetic bone diseases and (ii) genetic studies in individuals with AFF. AFFs were reported in 23 individuals with the following 7 monogenetic bone disorders (gene): osteogenesis imperfecta (COL1A1/COL1A2), pycnodysostosis (CTSK), hypophosphatasia (ALPL), X‐linked osteoporosis (PLS3), osteopetrosis, X‐linked hypophosphatemia (PHEX), and osteoporosis pseudoglioma syndrome (LRP5). In 8 cases (35%), the monogenetic bone disorder was uncovered after the AFF occurred. Cases of bisphosphonate‐naïve AFF were reported in pycnodysostosis, hypophosphatasia, osteopetrosis, X‐linked hypophosphatemia, and osteoporosis pseudoglioma syndrome. A pilot study in 13 AFF patients and 268 controls identified a greater number of rare variants in AFF cases using exon array analysis. A whole‐exome sequencing study in 3 sisters with AFFs showed, among 37 shared genetic variants, a p.Asp188Tyr mutation in the GGPS1 gene in the mevalonate pathway, critical to osteoclast function, which is also inhibited by bisphosphonates. Two studies completed targeted ALPL gene sequencing, an ALPL heterozygous mutation was found in 1 case of a cohort of 11 AFFs, whereas the second study comprising 10 AFF cases did not find mutations in ALPL. Targeted sequencing of ALPL, COL1A1, COL1A2, and SOX9 genes in 5 cases of AFF identified a variant in COL1A2 in 1 case. These findings suggest a genetic susceptibility for AFFs. A large multicenter collaborative study of well‐phenotyped AFF cases and controls is needed to understand the role of genetics in this uncommon condition. © 2017 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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“…Mutations in CYP1A1 were found in the three sisters and one unrelated patient in our study and also reported elsewhere in two patients with AFF and glucocorticoid‐induced osteoporosis . Another study identified a missense variant in the PPEF2 gene significantly associated with AFF by exon array analysis of a small cohort . To date, this gene has no known function in bone metabolism.…”

Section: Atypical Femoral Fracturementioning

confidence: 99%

Bone development and remodeling in metabolic disorders

Serra-Vinardell

Roca-Ayats

De-Ugarte

et al. 2019

J of Inher Metab Disea

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There are many metabolic disorders that present with bone phenotypes. In some cases, the pathological bone symptoms are the main features of the disease whereas in others they are a secondary characteristic. In general, the generation of the bone problems in these disorders is not well understood and the therapeutic options for them are scarce. Bone development occurs in the early stages of embryonic development where the bone formation, or osteogenesis, takes place. This osteogenesis can be produced through the direct transformation of the pre‐existing mesenchymal cells into bone tissue (intramembranous ossification) or by the replacement of the cartilage by bone (endochondral ossification). In contrast, bone remodeling takes place during the bone's growth, after the bone development, and continues throughout the whole life. The remodeling involves the removal of mineralized bone by osteoclasts followed by the formation of bone matrix by the osteoblasts, which subsequently becomes mineralized. In some metabolic diseases, bone pathological features are associated with bone development problems but in others they are associated with bone remodeling. Here, we describe three examples of impaired bone development or remodeling in metabolic diseases, including work by others and the results from our research. In particular, we will focus on hereditary multiple exostosis (or osteochondromatosis), Gaucher disease, and the susceptibility to atypical femoral fracture in patients treated with bisphosphonates for several years.

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Exon array analysis reveals genetic heterogeneity in atypical femoral fractures. A pilot study

Cited by 25 publications

References 26 publications

Genetic and acquired factors influencing the effectiveness and toxicity of drug therapy in osteoporosis

Genetic and acquired factors influencing the effectiveness and toxicity of drug therapy in osteoporosis

Genetic Risk Factors for Atypical Femoral Fractures (AFFs): A Systematic Review

Bone development and remodeling in metabolic disorders

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