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Genetic Disorders of Bone

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (10 December 2021) | Viewed by 50133

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Special Issue Editors

Dr. Susanna Balcells Comas

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1. Department of Genetics Microbiology and Statistics, Institute of Biomedicine of University of Barcelona (IBUB), Barcelona, Spain
2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Faculty of Biology, University of Barcelona, Barcelona, Spain
Interests: genetics; osteoporosis; atypical femoral fracture; high bone mass; osteogenesis imperfecta; functional validation of genetic variants; mendelian diseases of bone; intellectual disability;

Dr. Daniel Grinberg

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Department of Genetics Microbiology and Statistics, Institute of Biomedicine of University of Barcelona (IBUB); Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain
Interests: genetics; osteoporosis; atypical femoral fracture; high bone mass; osteogenesis imperfecta; functional validation of genetic variants; mendelian diseases of bone; intellectual disability; lysosomal diseases;

Dr. Natalia Garcia-Giralt

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Musculoskeletal Research Group, IMIM (Hospital del Mar Medical Research Institute), CIBERFES, ISCIII, 08003 Barcelona, Catalonia, Spain
Interests: bone phenotypes; atypical femoral fracture; healthy ageing; functional validation of genetic variants; musculoskeletal mendelian diseases; big data analysis;

Special Issue Information

Dear Colleagues,

In the past decade, massive sequencing has revolutionized genetic variant discovery and has allowed for the definition of many new Mendelian diseases, which were not amenable to linkage analysis. Genetic diseases affecting bone have not been an exception. Notably, osteogenesis imperfecta has witnessed the identification of a growing list of causal genes, beyond COL1A1 and COL1A2 and a large number of skeletal dysplasias have been genetically defined. Nonetheless, there are still some bone conditions awaiting the identification of their precise genetic cause. Likewise, during the past decade, an explosion of GWA studies on the polygenic basis of osteoporosis has uncovered hundreds of loci involved in the determination of bone mineral density (BMD) and osteoporotic fracture.

It is time to share and combine all this genetic information and to investigate the functional consequences at molecular, cellular, physiological, and organismal levels. The present “omics” era should allow for a fruitful integration of data from many different sources, including genomic (both germline and somatic variation), epigenomic, transcriptomic, proteomic, metabolomic, pharmacogenetic, and phenomic sources.

This Special Issue invites papers on genetic disorders of the bone and extracellular matrix in a broad sense, to highlight bone as an essential tissue and to provide new and detailed description of its workings in health and disease.

Dr. Susanna Balcells Comas
Dr. Daniel Grinberg
Dr. Natalia Garcia-Giralt
Guest Editors

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Keywords

Mendelian bone dysplasia
Bone fracture
Pharmacogenetics of bone
Polygenic risk score for osteoporosis
Somatic mutations in bone disorders
Omics aspects of bone diseases
Animal models for bone phenotypes

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Published Papers (12 papers)

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21 pages, 3168 KiB

Open AccessArticle

Whole Genome Sequencing Unravels New Genetic Determinants of Early-Onset Familial Osteoporosis and Low BMD in Malta

by Chanelle Cilia, Donald Friggieri, Josanne Vassallo, Angela Xuereb-Anastasi and Melissa Marie Formosa

Genes 2022, 13(2), 204; https://doi.org/10.3390/genes13020204 - 23 Jan 2022

Cited by 2 | Viewed by 4298

Abstract

Background: Osteoporosis is a skeletal disease with a strong genetic background. The study aimed to identify the genetic determinants of early-onset familial osteoporosis and low bone mineral density (BMD) in a two-generation Maltese family. Methods: Fifteen relatives aged between 28–74 years were recruited. Whole genome sequencing was conducted on 12 relatives and shortlisted variants were genotyped in the Malta Osteoporotic Fracture Study (MOFS) for replication. Results: Sequential variant filtering following a dominant inheritance pattern identified rare missense variants within SELP, TGF-β2 and ADAMTS20, all of which were predicted to be likely pathogenic and participate in osteoimmunology. TGF-β2 c.1136C>T was identified in five individuals from the MOFS in heterozygosity, four of whom had osteopenia/osteoporosis at the lumbar spine and hip, and/or had sustained a low-trauma fracture. Heterozygosity for the ADAMTS20 c.4090A>T was accompanied by lower total hip BMD (p = 0.018) and lower total serum calcium levels in MOFS (p < 0.01), recapitulating the findings from the family. Women carrying at least one copy of the alternative allele (TC/CC) for SELP c.2177T>C exhibited a tendency for lower lumbar spine BMD and/or wrist fracture history relative to women with TT genotype. Conclusions: Our findings suggest that the identified variants, alone or in combination, could be causal factors of familial osteoporosis and low BMD, requiring replication in larger collections. Full article

(This article belongs to the Special Issue Genetic Disorders of Bone)

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19 pages, 12388 KiB

Open AccessArticle

Evolutionary Genetic Signatures of Selection on Bone-Related Variation within Human and Chimpanzee Populations

by Daryn A. Stover, Genevieve Housman, Anne C. Stone, Michael S. Rosenberg and Brian C. Verrelli

Genes 2022, 13(2), 183; https://doi.org/10.3390/genes13020183 - 21 Jan 2022

Cited by 3 | Viewed by 3243

Abstract

Bone strength and the incidence and severity of skeletal disorders vary significantly among human populations, due in part to underlying genetic differentiation. While clinical models predict that this variation is largely deleterious, natural population variation unrelated to disease can go unnoticed, altering our perception of how natural selection has shaped bone morphologies over deep and recent time periods. Here, we conduct the first comparative population-based genetic analysis of the main bone structural protein gene, collagen type I α 1 (COL1A1), in clinical and 1000 Genomes Project datasets in humans, and in natural populations of chimpanzees. Contrary to predictions from clinical studies, we reveal abundant COL1A1 amino acid variation, predicted to have little association with disease in the natural population. We also find signatures of positive selection associated with intron haplotype structure, linkage disequilibrium, and population differentiation in regions of known gene expression regulation in humans and chimpanzees. These results recall how recent and deep evolutionary regimes can be linked, in that bone morphology differences that developed among vertebrates over 450 million years of evolution are the result of positive selection on subtle type I collagen functional variation segregating within populations over time. Full article

(This article belongs to the Special Issue Genetic Disorders of Bone)

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11 pages, 2138 KiB

Open AccessArticle

Gene Network of Susceptibility to Atypical Femoral Fractures Related to Bisphosphonate Treatment

by Natalia Garcia-Giralt, Neus Roca-Ayats, Josep F Abril, Nuria Martinez-Gil, Diana Ovejero, Santos Castañeda, Xavier Nogues, Daniel Grinberg, Susanna Balcells and Raquel Rabionet

Genes 2022, 13(1), 146; https://doi.org/10.3390/genes13010146 - 14 Jan 2022

Cited by 7 | Viewed by 3147

Abstract

Atypical femoral fractures (AFF) are rare fragility fractures in the subtrocantheric or diaphysis femoral region associated with long-term bisphosphonate (BP) treatment. The etiology of AFF is still unclear even though a genetic basis is suggested. We performed whole exome sequencing (WES) analysis of 12 patients receiving BPs for at least 5 years who sustained AFFs and 4 controls, also long-term treated with BPs but without any fracture. After filtration and prioritization of rare variants predicted to be damaging and present in genes shared among at least two patients, a total of 272 variants in 132 genes were identified. Twelve of these genes were known to be involved in bone metabolism and/or AFF, highlighting DAAM2 and LRP5, both involved in the Wnt pathway, as the most representative. Afterwards, we intersected all mutated genes with a list of 34 genes obtained from a previous study of three sisters with BP-related AFF, identifying nine genes. One of these (MEX3D) harbored damaging variants in two AFF patients from the present study and one shared among the three sisters. Gene interaction analysis using the AFFNET web suggested a complex network among bone-related genes as well as with other mutated genes. BinGO biological function analysis highlighted cytoskeleton and cilium organization. In conclusion, several genes and their interactions could provide genetic susceptibility to AFF, that along with BPs treatment and in some cases with glucocorticoids may trigger this so feared complication. Full article

(This article belongs to the Special Issue Genetic Disorders of Bone)

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12 pages, 2031 KiB

Open AccessArticle

Clinical and Genetic Characteristics of COL2A1-Associated Skeletal Dysplasias in 60 Russian Patients: Part I

by Tatyana Markova, Vladimir Kenis, Evgeniy Melchenko, Darya Osipova, Tatyana Nagornova, Anna Orlova, Ekaterina Zakharova, Elena Dadali and Sergey Kutsev

Genes 2022, 13(1), 137; https://doi.org/10.3390/genes13010137 - 13 Jan 2022

Cited by 8 | Viewed by 4248

Abstract

The significant variability in the clinical manifestations of COL2A1-associated skeletal dysplasias makes it necessary to conduct a clinical and genetic analysis of individual nosological variants, which will contribute to improving our understanding of the pathogenetic mechanisms and prognosis. We presented the clinical and genetic characteristics of 60 Russian pediatric patients with type II collagenopathies caused by previously described and newly identified variants in the COL2A1 gene. Diagnosis confirmation was carried out by new generation sequencing of the target panel with subsequent validation of the identified variants using automated Sanger sequencing. It has been shown that clinical forms of spondyloepiphyseal dysplasias predominate in childhood, both with more severe clinical manifestations (58%) and with unusual phenotypes of mild forms with normal growth (25%). However, Stickler syndrome, type I was less common (17%). In the COL2A1 gene, 28 novel variants were identified, and a total of 63% of the variants were found in the triple helix region resulted in glycine substitution in Gly-XY repeats, which were identified in patients with clinical manifestations of congenital spondyloepiphyseal dysplasia with varying severity, and were not found in Stickler syndrome, type I and Kniest dysplasia. In the C-propeptide region, five novel variants leading to the development of unusual phenotypes of spondyloepiphyseal dysplasia have been identified. Full article

(This article belongs to the Special Issue Genetic Disorders of Bone)

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15 pages, 632 KiB

Open AccessArticle

Osteogenesis Imperfecta: Search for Mutations in Patients from the Republic of Bashkortostan (Russia)

by Dina Nadyrshina, Aliya Zaripova, Anton Tyurin, Ildar Minniakhmetov, Ekaterina Zakharova and Rita Khusainova

Genes 2022, 13(1), 124; https://doi.org/10.3390/genes13010124 - 10 Jan 2022

Cited by 9 | Viewed by 3516

Abstract

Osteogenesis imperfecta (OI) is an inherited disease of bone characterized by increased bone fragility. Here, we report the results of the molecular architecture of osteogenesis imperfecta research in patients from Bashkortostan Republic, Russia. In total, 16 mutations in COL1A1, 11 mutations in COL1A2, and 1 mutation in P3H1 and IFIMT5 genes were found in isolated states; 11 of them were not previously reported in literature. We found mutations in CLCN7, ALOX12B, PLEKHM1, ERCC4, ARSB, PTH1R, and TGFB1 that were not associated with OI pathogenesis in patients with increased bone fragility. Additionally, we found combined mutations (c.2869C>T, p. Gln957* in COL1A1 and c.1197+5G>A in COL1A2; c.579delT, p. Gly194fs in COL1A1 and c.1197+5G>A in COL1A2; c.2971G>C, p. Gly991Arg in COL1A2 and c.212G>C, p.Ser71Thr in FGF23; c.-14C>T in IFITM5 and c.1903C>T, p. Arg635* in LAMB3) in 4 patients with typical OI clinic phenotypes. Full article

(This article belongs to the Special Issue Genetic Disorders of Bone)

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9 pages, 2150 KiB

Open AccessArticle

Identification of Compound Heterozygous Variants in LRP4 Demonstrates That a Pathogenic Variant outside the Third β-Propeller Domain Can Cause Sclerosteosis

by Yentl Huybrechts, Eveline Boudin, Gretl Hendrickx, Ellen Steenackers, Neveen Hamdy, Geert Mortier, Guillermo Martínez Díaz-Guerra, Milagros Sierra Bracamonte, Natasha M. Appelman-Dijkstra and Wim Van Hul

Genes 2022, 13(1), 80; https://doi.org/10.3390/genes13010080 - 28 Dec 2021

Cited by 4 | Viewed by 2396

Abstract

Sclerosteosis is a high bone mass disorder, caused by pathogenic variants in the genes encoding sclerostin or LRP4. Both proteins form a complex that strongly inhibits canonical WNT signaling activity, a pathway of major importance in bone formation. So far, all reported disease-causing variants are located in the third β-propeller domain of LRP4, which is essential for the interaction with sclerostin. Here, we report the identification of two compound heterozygous variants, a known p.Arg1170Gln and a novel p.Arg632His variant, in a patient with a sclerosteosis phenotype. Interestingly, the novel variant is located in the first β-propeller domain, which is known to be indispensable for the interaction with agrin. However, using luciferase reporter assays, we demonstrated that both the p.Arg1170Gln and the p.Arg632His variant in LRP4 reduced the inhibitory capacity of sclerostin on canonical WNT signaling activity. In conclusion, this study is the first to demonstrate that a pathogenic variant in the first β-propeller domain of LRP4 can contribute to the development of sclerosteosis, which broadens the mutational spectrum of the disorder. Full article

(This article belongs to the Special Issue Genetic Disorders of Bone)

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10 pages, 2349 KiB

Open AccessArticle

Polymorphisms in Genes Involved in Osteoblast Differentiation and Function Are Associated with Anthropometric Phenotypes in Spanish Women

by Clara Pertusa, Sofía P. Ruzo, Layla Panach, Damián Mifsut, Juan J. Tarín, Antonio Cano and Miguel Ángel García-Pérez

Genes 2021, 12(12), 2012; https://doi.org/10.3390/genes12122012 - 17 Dec 2021

Cited by 1 | Viewed by 2580

Abstract

Much of the genetic variance associated with osteoporosis is still unknown. Bone mineral density (BMD) is the main predictor of osteoporosis risk, although other anthropometric phenotypes have recently gained importance. The aim of this study was to analyze the association of SNPs in genes involved in osteoblast differentiation and function with BMD, body mass index (BMI), and waist (WC) and hip (HC) circumferences. Four genes that affect osteoblast differentiation and/or function were selected from among the differentially expressed genes in fragility hip fracture (FOXC1, CTNNB1, MEF2C, and EBF2), and an association study of four single-nucleotide polymorphisms (SNPs) was conducted in a cohort of 1001 women. Possible allelic imbalance was also studied for SNP rs87939 of the CTNNB1 gene. We found significant associations of SNP rs87939 of the CTNNB1 gene with LS-sBMD, and of SNP rs1366594 of the MEF2C gene with BMI, after adjustment for confounding variables. The SNP of the MEF2C gene also showed a significant trend to association with FN-sBMD (p = 0.009). A possible allelic imbalance was ruled out as no differences for each allele were detected in CTNNB1 expression in primary osteoblasts obtained from homozygous women. In conclusion, we demonstrated that two SNPs in the MEF2C and CTNNB1 genes, both implicated in osteoblast differentiation and/or function, are associated with BMI and LS-sBMD, respectively. Full article

(This article belongs to the Special Issue Genetic Disorders of Bone)

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15 pages, 1280 KiB

Open AccessArticle

X-Linked Osteogenesis Imperfecta Possibly Caused by a Novel Variant in PLS3

by Petar Brlek, Darko Antičević, Vilim Molnar, Vid Matišić, Kristina Robinson, Swaroop Aradhya, Dalibor Krpan and Dragan Primorac

Genes 2021, 12(12), 1851; https://doi.org/10.3390/genes12121851 - 23 Nov 2021

Cited by 12 | Viewed by 7609

Abstract

Osteogenesis imperfecta (OI) represents a complex spectrum of genetic bone diseases that occur primarily due to mutations and deletions of the COL1A1 and COL1A2 genes. Recent molecular studies of the network of signaling pathways have contributed to a better understanding of bone remodeling and the pathogenesis of OI caused by mutations in many other genes associated with normal bone mineralization. In this paper, a case of a rare X-linked variant of OI with a change in the gene encoding plastin 3—a protein important for the regulation of the actin cytoskeleton, is presented. A 16-year-old patient developed ten bone fractures caused by minor trauma or injury, including a compression fracture of the second lumbar vertebra during his lifetime. Next-generation sequencing analysis did not show pathologically relevant deviations in the COL1A1 and COL1A2 genes. Targeted gene analyses (Skeletal disorder panel) of the patient, his father, mother and sister were then performed, detecting variants of uncertain significance (VUS) for genes PLS3, FN1 and COL11A2. A variant in the PLS3 gene were identified in the patient, his mother and sister. Since the PLS3 gene is located on the X chromosome, the mother and sister showed no signs of the disease. Although the variant in the PLS3 gene (c.685G>A (p.Gly229Arg)) has not yet been described in the literature, nor is its pathogenicity known, clinical findings combined with genetic testing showed that this variant may explain the cause of X-linked OI in our patient. This rare case of the PLS3 variant of X-linked OI might point to a novel target for personalized therapy in patients with this severe disease. Full article

(This article belongs to the Special Issue Genetic Disorders of Bone)

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17 pages, 910 KiB

Open AccessArticle

Association of GC Variants with Bone Mineral Density and Serum VDBP Concentrations in Mexican Population

by Berenice Rivera-Paredez, Alberto Hidalgo-Bravo, Guadalupe León-Reyes, Bárbara Antuna-Puente, Yvonne N. Flores, Jorge Salmerón and Rafael Velázquez-Cruz

Genes 2021, 12(8), 1176; https://doi.org/10.3390/genes12081176 - 29 Jul 2021

Cited by 11 | Viewed by 2562

Abstract

Vitamin D-binding protein (VDBP) is encoded by the GC gene and is an active participant in the control of bone metabolism. However, the effect of its major variants on VDBP concentration and bone mineral density (BMD) remains unclear. Our aim was to analyze the effect of major GC variants on serum VDBP concentration and BMD. We recruited individuals from the Health Workers Cohort Study, which includes employees of the Mexican Institute of Social Security (IMSS). A total of 1853 adults were included. The single nucleotide polymorphisms (SNPs) rs7041 and rs4588 were genotyped to identify the three best characterized haplotypes of GC. Serum VBDP, 25(OH)D and BMD were also measured. Among women, the G allele of rs7041 was associated with higher VDBP and BMD compared to homozygous TT. The A allele of rs4588 was associated with lower VDBP and BMD compared to CC homozygous. In men, GC variants were only associated with VDBP levels. We did not observe an association between free/bioavailable 25(OH)D and BMD in men and women. Our results support an association of VDBP in bone health. The G and C alleles, from rs7041 and rs4588, respectively, are associated with high concentrations of VDBP and BMD in this sample of Mexican postmenopausal women. Full article

(This article belongs to the Special Issue Genetic Disorders of Bone)

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12 pages, 457 KiB

Open AccessArticle

SLC26A2-Associated Diastrophic Dysplasia and rMED—Clinical Features in Affected Finnish Children and Review of the Literature

by Helmi Härkönen, Petra Loid and Outi Mäkitie

Genes 2021, 12(5), 714; https://doi.org/10.3390/genes12050714 - 11 May 2021

Cited by 17 | Viewed by 4502

Abstract

Diastrophic dysplasia (DTD) is a rare osteochondrodysplasia characterized by short-limbed short stature and joint dysplasia. DTD is caused by mutations in SLC26A2 and is particularly common in the Finnish population. However, the disease incidence in Finland and clinical features in affected individuals have not been recently explored. This registry-based study aimed to investigate the current incidence of DTD in Finland, characterize the national cohort of pediatric subjects with DTD and review the disease-related literature. Subjects with SLC26A2-related skeletal dysplasia, born between 2000 and 2020, were identified from the Skeletal dysplasia registry and from hospital patient registry and their clinical and molecular data were reviewed. Fourteen subjects were identified. Twelve of them were phenotypically classified as DTD and two, as recessive multiple epiphyseal dysplasia (rMED). From the subjects with available genetic data, 75% (9/12) were homozygous for the Finnish founder mutation c.-26+2T>C. Two subjects with rMED phenotype were compound heterozygous for p.Arg279Trp and p.Thr512Lys variants. The variable phenotypes in our cohort highlight the wide spectrum of clinical features, ranging from a very severe form of DTD to milder forms of DTD and rMED. The incidence of DTD in Finland has significantly decreased over the past decades, most likely due to increased prenatal diagnostics. Full article

(This article belongs to the Special Issue Genetic Disorders of Bone)

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13 pages, 273 KiB

Open AccessArticle

Association of RANKL and OPG Gene Polymorphism in Arab Women with and without Osteoporosis

by Saba Abdi, Rawan A. Binbaz, Abdul Khader Mohammed, Mohammed G.A. Ansari, Kaiser Wani, Osama E. Amer, Abdullah M. Alnaami, Naji Aljohani and Nasser M. Al-Daghri

Genes 2021, 12(2), 200; https://doi.org/10.3390/genes12020200 - 29 Jan 2021

Cited by 18 | Viewed by 3933

Abstract

Receptor activator of the nuclear factor-κB ligand (RANKL) and osteoprotegerin genes (OPG) were identified as susceptible loci for postmenopausal osteoporosis (PMO) in various ethnicities, but neither have been studied in an Arabian population. Hence, the current study aimed to fill this gap. A total of 372 postmenopausal women (174 osteoporosis (OP) and 198 control group (CTRs)) were genotyped for four SNPs: rs2277438A/G and rs9533156T/C (RANKL), and rs2073618C/G and rs3102735T/C (OPG). Anthropometrics, bone mineral density, 25(OH)D and several other bone markers were measured. The frequency distribution of the heterozygous CG genotype of rs2073618 (OPG) was lower in the OP (36.8%) than in CTRs (47%) (OR: 0.6, 95% CI: 0.3–0.97; p = 0.041). No differences in the allelic/genotypic frequencies were detected between the two groups for all other studied SNPs. However, the heterozygous TC genotype of rs3102735 (OPG) was associated significantly with lower BMD at the femoral neck in OP subjects (p = 0.04). The homozygous rare CC genotype of rs9533156 (RANKL) was associated with lower 25(OH)D levels in CTRs (p = 0.032). In contrast, heterozygous AG genotype of rs2277438 (RANKL) is associated with lower 25(OH)D in the OP group (p = 0.02). Our results suggest that RANKL SNPs may impact 25(OH)D levels and that OPG SNP rs2073618A/G is a significant genetic risk factor for PMO Saudi Arabian women. Full article

(This article belongs to the Special Issue Genetic Disorders of Bone)

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52 pages, 3921 KiB

Open AccessReview

Wnt Pathway Extracellular Components and Their Essential Roles in Bone Homeostasis

by Núria Martínez-Gil, Nerea Ugartondo, Daniel Grinberg and Susanna Balcells

Genes 2022, 13(1), 138; https://doi.org/10.3390/genes13010138 - 13 Jan 2022

Cited by 25 | Viewed by 6204

Abstract

The Wnt pathway is involved in several processes essential for bone development and homeostasis. For proper functioning, the Wnt pathway is tightly regulated by numerous extracellular elements that act by both activating and inhibiting the pathway at different moments. This review aims to describe, summarize and update the findings regarding the extracellular modulators of the Wnt pathway, including co-receptors, ligands and inhibitors, in relation to bone homeostasis, with an emphasis on the animal models generated, the diseases associated with each gene and the bone processes in which each member is involved. The precise knowledge of all these elements will help us to identify possible targets that can be used as a therapeutic target for the treatment of bone diseases such as osteoporosis. Full article

(This article belongs to the Special Issue Genetic Disorders of Bone)

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