Medicine » Immunology, Allergology and Rheumatology » "Topics in Osteoporosis", book edited by Margarita Valdes Flores, ISBN 978-953-51-1066-8, Published: May 15, 2013 under CC BY 3.0 license

Chapter 2

Genetic Diseases Related with Osteoporosis

By Margarita Valdés-Flores, Leonora Casas-Avila and Valeria Ponce de León-Suárez
DOI: 10.5772/55546

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Genetic Diseases Related with Osteoporosis

Margarita Valdés-Flores1, Leonora Casas-Avila1 and Valeria Ponce de León-Suárez1

1. Introduction

Osteoporosis is a disease entity characterized by the progressive loss of bone mineral density (BMD) and the deterioration of bone microarchitecture, leading to the development of fractures. Its classification encompasses two large groups, primary and secondary osteoporosis [1].

Primary osteoporosis is the disease’s most common form and results from the progressive loss of bone mass related to aging and unassociated with other illness, a natural process in adult life; its etiology is considered multifactorial and polygenic. This form currently represents a growing worldwide health problem due in part, to the contemporary environmental conditions of modern civilization. Risk factors that are considered as “modifiable” also play an important role and include physical activity, dietary habits and eating disorders. Furthermore, there is another group of associated risk factors that are considered “non-modifiable”, including gender, age, race, a personal and/or family history of fractures that in turn, indirectly reflect the degree of genetic susceptibility to this disease [2-4]. Secondary osteoporosis encompasses a large heterogeneous group of primary conditions favoring osteoporosis development. Table 1 summarizes some of the disease entities associated to primary and secondary osteoporosis.

Type of osteoporosis Causes
PrimaryMultifactorial, polygenic. Senile/Involutional
Drugs compromising bone quality: anticonvulsants, antidepressants, anticoagulants, antacids with aluminum, aromatase inhibitors, barbiturates, cimetidine, corticosteroids, glucocorticoids, birth control pills, cancer drugs, gonadotropin releasing hormone (GnRH), loop diuretics, methotrexate, phenobarbital, phenothiazines, among others.
Other entities: nephropathies, malabsorption syndromes, neoplasias, rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, any process leading to decreased mobility or prolonged immobility.
Metabolic diseases: diabetes, hyperthyroidism, hyperparathyroidism.
Hypogonadism: Turner and Klinefelter syndromes.
Behavioral disorders: anorexia nervosa, depression, prolonged physical inactivity, malnutrition, high caffeine intake, smoking and/or chronic alcoholism.
Monogenic diseases: osteogenesis imperfecta, glioma syndrome, osteoporosis.

Table 1.

Osteoporosis classification.

1.1. Genetic aspects of primary osteoporosis

This form of osteoporosis results from the interaction of several environmental and genetic factors, leading to difficulties in its study. It is not easy to define the magnitude of the effect of genetic susceptibility since it is a trait determined by multiple genes whose products affect the bone phenotype; moreover, the environmental factors compromising bone mineral density are also difficult to analyze. However, in spite of these barriers, research suggests that inherited factors affect BMD in ranges between 40 – 70% in the spine, 70 – 85% in the hip and 50 – 60% in the wrist. Bone density studies in monozygotic (MZ) and dizygotic (DZ) twins suggest that spinal and femoral neck BMD concordance is higher (6-8:1) in MZ versus DZ twins. Other studies have estimated that fracture predisposition heritability per se ranges between 25 – 35% and up to 40% of patients with osteoporotic fractures have a positive family history of fractures, thus reflecting the great influence of genetic factors in this disease. On the other hand, the geometry and length of the femoral neck, the bone’s properties on ultrasound, growth speed and bone remodeling variations are also dependent on genetic factors. The genes associated with the bone phenotype are distributed throughout the human genome and located in practically all chromosomes; their products fulfill specific functions and contribute in different manners to the genetic control of the bone tissue phenotype [5-12]. Some of these genes and their products are presented in Table 2 [13-23].

It is important to mention that the mechanisms conditioning the hereditary susceptibility to osteoporosis are determined, among other factors, by the presence of mutations or genetic polymorphisms (natural genomic variations) in one or several genes involved in bone phenotype genetic control. These polymorphisms follow a well-defined inheritance pattern and their distribution is different among racial groups and populations. There are several reports in the world literature, of associations between specific genetic variants and osteoporosis development or the risk of fractures; these risks may vary according to the fractures’ anatomic location [3, 4, 24-30]

Product Function Genes
Matrix componentsCOL1A1, COL1A2, OPN
Hormones and their receptors ESR1, ESR2, AR, VDR, PTHR1, CASR, PTH, CYP1A1, PRL, LEP, LEPR, INS, INSR
Participants in osteoblastogenic proccessesALOX12, ALOX15, BMP4, BMP7, IGF-1 LRP5, LRP6, SOST
Participants in osteoclastogenic proccessesP53, RANK, RANK-L
Citokines and their receptorsIL1α, IL1β, IL6, TNF, TNFR2

Table 2.

Genes involved in bone metabolism.

2. Mendelian diseases and osteoporosis

The description in the literature of some genetic diseases of monogenic inheritance and whose phenotype includes the loss or increase in bone mineral density and even fractures, has suggested and even proved that bone phenotype has an important genetic component. These diseases include idiopathic osteoporosis, osteogenesis imperfecta in all its variants, osteopetrosis, pycnodysostosis and the osteoporosis syndrome associated to pseudoglioma, among others. In some cases of severe osteoporosis, mutations in the estrogen and even the androgen receptor genes have been detected.

2.1. Idiopathic juvenile osteoporosis

This is an unusual variety of osteoporosis whose frequency has not been precisely determined. This disease may develop in females and males, usually around 7 – 10 years of age; children present difficulty in gait, pain in the lower extremities, ankles, knees, occasionally in the hip and fractures tend to develop particularly in long bones. Radiologically, it is characterized by diffuse osteopenia, metaphyseal fractures – especially of the femur -, and vertebral collapse that may lead to severe kyphoscoliosis or collapse of the thoracic cage. This disease is considered potentially reversible whereby in most cases, there is almost complete recovery of the bone tissue; growth, however, may be compromised.

In these patients, it is important to exclude other disease entities or conditions manifesting secondarily as osteoporosis. A differential diagnosis must be made with other genetic diseases, particularly the different variants of osteogenesis imperfecta; this is relatively easy due to its clinical characteristics, lacking in idiopathic osteoporosis. The genetic basis of this disease has of yet, not been established but it is possible that genetic mutations with preferential tissue expression in bone and with great impact on the tissue’s phenotype, may explain some of these cases [31, 32].

2.2. Osteogenesis imperfecta

Osteogenesis imperfecta, also known as “brittle bone disease”, has an estimated incidence of approximately 1 in 20 000 births. It has great phenotypic variability, different patterns of inheritance and a wide clinical spectrum ranging from very mild forms of the disease to severe cases with an unfavorable prognosis. It is caused by the defective synthesis of one of the two alpha chains of type I collagen (COL1A1 and COL1A2), leading to anomalies in these protein’s structure; it is normally constituted by 3 coiled sub-units, two α1 chains and one α2 chain. This type of collagen is considered the most abundant component of structural protein in bone as well as in ligaments, tendons, sclerae and skin. Quantitative or qualitative defects in this protein lead to bone fragility and hence, to an increased risk of fractures.

The genes encoding the α1 and α2 chains are located in the 17q21.31-q22 and 7q22.1 chromosomes, respectively. Aside from brittle bones, these patients may also present long bones with no curvatures, severe deformities preventing appropriate gait and even standing, conductive deafness due to malformations of the auditory canal, dentinogenesis imperfecta, joint hyperlaxity and intervertebral disc herniation. Patients with severe forms of the disease have a long history of fractures on mild impact and variable bone deformities. The most severe variants may even lead to fractures in utero and pre or perinatal death. Tables 3 and 4 shows different forms of the disease [33-35].

2.3. Osteoporosis – Pseudoglioma Syndrome (OPPG)

This syndrome is an autosomal recessive disease characterized by bone and visual abnormalities including short stature, osteoporosis development during infancy, spontaneous fractures, scoliosis, platyspondyly and long bone deformities. A crucial associated finding is the presence of pseudoglioma that may be associated to microcephaly, blindness during childhood, cataracts and iris atrophy. Occasionally, some patients present interventricular septal defects and mental retardation. This disease is conditioned by mutations of the LRP5 gene, located on chromosome 11q13.4 and that encodes the low-density lipoprotein receptor-related protein 5 (LRP5). It was initially believed that this entity was another variant of osteogenesis imperfecta (OI) but the study of collagen in patients with OPPG established that this protein was normal and the hypothesis was discarded; however, this is still the most relevant differential diagnosis [36-41].

2.4. Neuromuscular disorders

Muscular dystrophies, peripheral neuropathies and muscle atrophies of hereditary origin, represent broad groups of diseases that aside from their characteristic clinical stigmata, can be associated with osteoporosis as one of their complications. As the disease progresses in these patients, there is increased difficulty and limitation in walking and periods of immobility become progressively more prolonged leading to the gradual loss of the mechanical stimuli that bone needs to maintain its strength and hence, favoring the development of osteoporosis. As all Mendelian diseases, these neuromuscular abnormalities follow different inheritance patterns and present phenotypic variability [42-44].

2.5. Inborn errors of metabolism

This group of genetic diseases encompasses a great number of inborn defects with repercussions in several aspects of carbohydrate, amino acid, protein, vitamin, mineral, complex molecule, neurotransmitter and energy metabolism. The genetic basis of most of these entities hinges on gene mutations encoding proteins, particularly enzymes, leading to partial or complete blockade of one or several metabolic processes. In these diseases, symptoms arise for different reasons, including: a deficit of the products generated by the compromised enzymatic reaction, accumulation of the precursor immediate to the defect, an increase in alternative products due to increased activation of alternate metabolic pathways or inhibition of these alternate pathways due to the accumulated substrate. In most cases, inheritance of these diseases is autosomal recessive and less frequently, X-linked recessive.

In cases of metabolic errors, osteoporosis tends to develop for different reasons: in some cases, it is secondary to nutritional deficiencies, progressive neurologic or muscular impairment or as a consequence of the therapeutic measures taken in the management of the primary disease: their secondary effects directly compromise bone quality (steroids, antiseizure drugs, etc.). The number of monogenic diseases whose phenotype may include osteoporosis is large and are shown in Tables 3-5, according to their Mendelian inheritance pattern [45-56].

Disease Gene Product Genomic Location Reference
Hutchinson-Gilford progeria syndrome; HGPSLMNA Prelamin-A/C precursor (LMNA)1q2257, 58
Osteogenesis imperfecta, Type I; OI1COL1A1 Collagen, type I, alpha 1 (COL1A1)17q21.3333, 34
Osteogenesis imperfecta, Type II; OI2 COL1A1 Collagen, type I, alpha 1 (COL1A1) 17q21.33
33, 59
COL1A2Collagen, type I, alpha 2 (COL1A2)7q21.3
Osteogenesis imperfecta, Type III; OI3COL1A1 Collagen, type I, alpha 1 (COL1A1) 17q21.3333, 60
COL1A2Collagen, type I, alpha 2 (COL1A2)7q21.3
Marfan syndrome; MFSFBN1 Fibrillin 1 (FBN1)15q21.161, 62
Loeys-Dietz syndrome,
Type 1A; LDS1A
TGFBR1Transforming growth factor-beta receptor, Type I (TGFBR1)9q22.3363, 64
Loeys-Dietz syndrome,
Type 1B; LDS1B
TGFBR2Transforming growth factor-beta receptor, Type II (TGFBR2)3p24.165, 66
Loeys-Dietz syndrome,
Type 2B; LDS2B
TGFBR2Transforming growth factor-beta receptor, Type II (TGFBR2)3p24.163, 65
Loeys-Dietz syndrome, Type 3; LDS3MADH3/
Mothers against decapentaplegic homolog 3 (Drosophila) (SMAD3)15q22.3367, 68
Ehlers-Danlos syndrome, Type ICOL5A2 Collagen, type V, alpha 2 (COL5A2)2q32.269, 70
COL5A1 Collagen, type V, alpha 1 (COL5A1) 9q34.3
COL1A1 Collagen, type I, alpha 1 (COL1A1) 17q21.33
Ehlers-Danlos syndrome, Type IICOL5A1 Collagen, type V, alpha 1 (COL5A1) 9q34.370, 71
COL5A2Collagen, type V, alpha 2 (COL5A2) 2q32.2
Type IA; PHP1A
GNASGNAS complex locus (GNAS)
[Gs, alpha subunit, included]
20q13.3272, 73
Type IC; PHP1C
GNASGNAS complex locus (GNAS)
[Gs, alpha subunit, included]
20q13.3273, 74
Pseudopseudohypopara-thyroidism; PPHPGNAS
GNAS complex locus (GNAS)
[Gs, alpha subunit, included]
20q13.3273, 75
Epiphyseal dysplasia, multiple, 1; EDM1COMPCartilage oligomeric matrix protein (COMP) 19p13.1176, 77
Prader-Willi syndrome; PWSNDN
Necdin homolog (mouse) (NDN)
Small nuclear ribonucleoprotein-associated protein N (SNRPN/PWCR)
78, 79
Hajdu-Cheney syndrome; HJCYSNOTCH2Neurogenic locus Notch homolog protein 2 (NOTCH2)1p12-p1180, 81
Nephrolithiasis/osteoporosis, hypophosphatemic, 1; NPHLOP1SLC34A1Sodium-dependent phosphate transport protein 2A (SLC34A1/ .NPT2A)5q35.382, 83
Nephrolithiasis/osteoporosis, hypophosphatemic, 2; NPHLOP2SLC9A3R1/NHERFNa(+)/H(+) exchange regulatory cofactor NHE-RF1 (SLC9A3R1/ NHERF)17q25.184-86
Cardiomyopathy, dilated, with hypergonadotropic hypogonadismLMNAPrelamin-A/C precursor (LMNA)1q2287, 88
Dyskeratosis congenita, autosomal dominant, 1; DKCA1TERC Telomerase RNA component (TERC)
3q26.287, 88
Dyskeratosis congenita, autosomal dominant, 2; DKCA2TERT Telomerase reverse transcriptase (TERT)5p15.3389, 90
Dyskeratosis congenita, autosomal dominant, 3; DKCA3TINF2TERF1-interacting nuclear factor 2 (TINF2) 14q1291, 92
Pigmented nodular adrenocortical disease, primary, 1; PPNAD1PRKAR1AcAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A/ TSE1) 17q24.293, 94
Pigmented nodular adrenocortical disease, primary, 2; PPNAD2PDE11ADual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A (PDE11A)2q31.295, 96
Hyperostosis corticalis generalisata, benign form of worth, with torus palatinusLRP5 Low density lipoprotein receptor-related protein 5 (LRP5)11q13.297, 98
Van Buchem disease,
Type 2; HVB2
LRP5Low density lipoprotein receptor-related protein 5 (LRP5)11q13.399, 100
Osteopetrosis, autosomal dominant 1; OPTA1LRP5Low density lipoprotein receptor-related protein 5 (LRP5)11q13.3101, 102
Osteopetrosis, autosomal dominant 2; OPTA2CLCN7H(+)/Cl(-) exchange transporter 7 (CLCN7)16p13.3103, 104
ACTH-independent macronodular adrenal hyperplasia; AIMAHGNASGNAS complex locus (GNAS)
[Gs, alpha subunit, included]
20q13.32105, 106
Hyper-IgE recurrent infection syndrome, autosomal dominantSTAT3Signal transducer and activator of transcription 3 (STAT3)17q21.2107, 108
Coronary artery disease, autosomal dominant 2; ADCAD2 or CADOLRP6 Low density lipoprotein receptor-related protein 6 (LRP6)12p13.2109, 110
Avascular necrosis of femoral head, primary; ANFHCOL2A1 Collagen, type II, alpha 1 (COL2A1) 12q13.11111, 112
Spondyloepimetaphyseal dysplasia with joint laxity Type 2; SEMDJL2KIF22Kinesin-like protein KIF22 (KIF22)16p11.2113, 114
Spondyloepiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome, Type 2)TRPV4 Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) 12q24.11115, 116
Hypophosphatasia, adultALPLAlkaline phosphatase, liver/bone/kidney or alkaline phosphatase, tissue-nonspecific isozyme (ALPL)1p36.12117, 118
Cleidocranial dysostosis; CLCD RUNX2 Runt-related transcription factor 2 (RUNX2)6p21.1119, 120
Trichorhinophalangeal syndrome, type I; TRPS1TRPS1Zinc finger transcription factor Trps1(TRPS1) 8q23.3121, 122

Table 3.

Autosomal dominant diseases with bone mineral density loss.

Disease Gene Product Genomic location Reference
Vitamin D hydroxylation-deficient rickets, Type 1A; VDDR1ACYP27B125-hydroxy-vitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1)12q13123, 124
Hemochromatosis; HFEHFE (C282Y y H63D) Hereditary hemochromatosis protein (HFE)6p22.2 125, 126
BMP2 [HFE hemochromatosis, modifier of]Bone morphogenetic protein 2 (BMP2)20p12.3
Beta-Thalassemiabeta-Thalassemia:HBBHemoglobin subunit beta (HBB)11p15.447, 48
Thalassemia, Hispanic gamma-delta-beta: LCRBLocus control region, beta (LCRB)11p15.5
Osteoporosis-pseudoglioma syndrome; OPPGLRP5 Low density lipoprotein receptor-related protein 5 (LRP5)11q13.2127, 128
Homocystinuria due to cystathionine beta-synthase deficiencyCBS/HIP4 Cystathionine beta-synthase (CBS)21q22.345, 46
HomocysteinemiaMTHFR (C677T)Methylenetetrahydrofolate reductase (MTHFR)1p36.6129, 130
CBSCystathionine beta-synthase (CBS)21q22.3
MS/MTR Methionine synthase (MTR/METH) 1q23
HomocysteinemiaMTHFR (C677T)Methylenetetrahydrofolate reductase (MTHFR)1p36.633, 131, 132
CBSCystathionine beta-synthase (CBS)21q22.3
MS/MTR Methionine synthase (MTR/METH) 1q23
Osteogenesis imperfecta, Type IX; OI9
[Osteogenesis imperfecta type II-B, III or IV PPIB related]
PPIB Peptidyl-prolyl cis-trans isomerase B (PPIB) 15q22.3135, 133
Propionic acidemiaPCCAPropionyl-CoA carboxylase alpha chain, mitochondrial (PCCA)13q32.3134, 135
PCCB Propionyl-CoA carboxylase beta chain, mitochondrial (PCCB) 3q22.3
Ehlers-Danlos syndrome, type VI; EDS6PLOD1 Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1) 1p36.2269, 136
Hypertrophic osteoarthropathy, primary, autosomal recessive, 1; PHOAR1HPGD 15-hydroxy-prostaglandin dehydrogenase [NAD+] (HPGD)4q34.1137, 138
Pituitary adenoma, ACTH-secreting; CUDPAIP AH receptor-interacting protein (AIP)11q13.2139, 140
Gaucher disease, Type I; GDIGBA Glucosylceramidase (GLCM/GBA)1q2249, 50
Paget disease, juvenile; JPDTNFRSF11B Tumor necrosis factor receptor superfamily, member 11b (TNFRSF11B)8q24.12141, 142
Pycnodysostosis; PKNDCTSK Cathepsin K1q21.3143, 144
Lipodystrophy, congenital generalized, type 4; CGL4PTRFPolymerase I and transcript release factor (PTRF)17q21.2145, 146
Niemann-Pick disease, Type ASMPD1 Sphingomyelin phosphodiesterase 1, acid lysosomal (SMPD1/ASM) 11p15.4147, 148
Niemann-Pick disease, Type BSMPD1 Sphingomyelin phosphodiesterase 1, acid lysosomal (SMPD1/ASM) 11p15.4147, 149
LathosterolosisSC5DL Lathosterol oxidase (SC5DL)11q23.3150, 151
Mucopolysaccharidosis Type IVA
(Morquio syndrome A)
N-acetyl-galactosamine-6-sulfatase (GALNS) 16q24.3152-154
Mucopolysaccharidosis Type IVB
(Morquio syndrome B)
GLB1 Beta-galactosidase1
Fibromatosis, juvenile hyaline; JHF ANTXR2 Anthrax toxin receptor 2
4q21155, 156
Aromatase deficiencyCYP19A1Cytochrome P450 19A1 (CYP19A1)15q21.2157, 158
Diastrophic dysplasiaSLC26A2 Sulfate transporter 2 (S26A2) 5q32159, 160
Desbuquois dysplasia; DBQDCANT1 Soluble calcium-activated nucleotidase 1 (CANT1) 17q25.3161, 162
Torg-winchester syndromeMMP2 72 kDa type IV collagenase (MMP2) 16q12.2163, 164
Geroderma osteodysplasticum; GOGORAB RAB6-interacting golgin (GORAB) 1q24.2165, 166
Lysinuric protein intolerance; LPISLC7A7 Y+L amino acid transporter 1 (YLAT1) 14q11.2167, 168
Cerebroretinal microangiopathy with calcifications and cysts; CRMCCCTC1 CST complex subunit CTC1 17p13.1169, 170
Exudative vitreoretinopathy 4; EVR4LRP5 Low density lipoprotein receptor-related protein 5 (LRP5) 11q13.2171, 172
Nestor-Guillermo progeria syndrome; NGPSBANF1Barrier to autointegration factor 1 (BANF1)11q13.1173, 174
Dyskeratosis congenita, autosomal recessive, 1; DKCB1NOLA3 / NOP10H/ACA ribonucleoprotein complex subunit 3 (NOP10/ NOLA3) 15q14175, 176
Macrocephaly, alopecia, cutis laxa, and scoliosisRIN2 Ras and Rab interactor 2
20p11.23177, 178
Hypertrophic osteoarthropathy, primary, autosomal recessive, 1; PHOAR1HPGD 15-hydroxyprostaglandin dehydrogenase
4q34.1137, 179
Multiple joint dislocations, short stature, craniofacial dysmorphism, and congenital heart defectsB3GAT3Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3
11q12.3180, 181
Hyalinosis, infantile systemic; ISHANTXR2Anthrax toxin receptor 2
4q21.21182, 183
Ovarian dysgenesis 1; ODG1FSHRFollicle stimulating hormone receptor (FSHR)2p16.3184, 185
Epiphyseal dysplasia, multiple, with early-onset diabetes mellitusEIF2AK3Eukaryotic translation initiation factor 2 alpha kinase 3
2p11.2186, 187
Cerebrooculofacioskeletal syndrome 1; COFS1ERCC6DNA excision repair protein ERCC-6 10q11.23188, 189
Wilson disease; WNDATP7B Copper-transporting ATPase 2 (ATP7B) 13q14.3190, 191
Werner syndrome; WRN WRN/RECQL2 Werner syndrome ATP-dependent helicase (WRN / RECQL2) 8p12192, 193
Rothmund-thomson syndrome; RTSRECQL4ATP-dependent DNA helicase Q4 (RECQL4) 8q24.3194, 195
Schwartz-Jampel syndrome, Type 1; SJS1HSPG2 Basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2) 1p36.12196, 197
Perrault syndrome; prltsHSD17B4 Peroxisomal multifunctional enzyme type 2 (HSD17B4)5q23.1198, 199
Glycogen storage disease Ia; GSD1AG6PC Glucose-6-phosphatase, catalytic subunit (G6PC)17q21.31200, 201
Glycogen storage disease Ib; GSD1BSLC37A4 Glucose-6-phosphate translocase (SLC37A4)11q23.3200, 201
Cranioectodermal dysplasia 1; CED1IFT122 Intraflagellar transport protein 122 homolog (IFT122)3q21.3202, 203
Cerebrotendinous xanthomatosis; CTXCYP27A1 Sterol 26-hydroxylase, mitochondrial (CYP27A1/CP27A) 2q35204, 205
Arthropathy, progressive pseudorheumatoid, of childhood; PPACWISP3WNT1-inducible-signaling pathway protein 3 (WISP3)6q21206, 207
Genitopatellar syndrome; GTPTSKAT6B Histone acetyltransferase KAT6B 10q22.2208, 209
Congenital disorder of glycosylation, Type IIk; CDG2KTMEM165 Transmembrane protein 165 (TMEM165/TM165) 4q12210, 211
Cutis laxa, autosomal recessive, Type IA; ARCL1AFBLN5 Fibulin-5 (FBLN5) 14q32.12212, 213
Cutis laxa, autosomal recessive, Type IIB; ARCL2BPYCR1 Pyrroline-5-carboxylate reductase 1, mitochondrial (PYCR1/P5CR1) 17q25.3 166, 214
Cutis laxa, autosomal recessive, Type IIIB; ARCL3BPYCR1Pyrroline-5-carboxylate reductase 1, mitochondrial (PYCR1/P5CR1)17q25.3 212, 215
Niemann-Pick disease, Type BSMPD1 Sphingomyelin phosphodiesterase (SMPD1) 11p15.4149, 216
Trichothiodystrophy, photosensitive; TTDPERCC3TFIIH basal transcription factor complex helicase XPB subunit (ERCC3)2q14.3217, 218
GTF2H5General transcription factor IIH, subunit 5 (GTF2H5)6q25.3
ERCC2 TFIIH basal transcription factor complex helicase XPD subunit (ERCC2) 19q13.32
Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; CARASILHTRA1 Serine protease HTRA1 10q26.13219, 220
Weill-Marchesani syndrome 1; WMS1ADAMTS10 A disintegrin and metalloproteinase with thrombospondin motifs 10 (ADAMTS10/ATS10) 19p13.2221, 222
Laron syndromeGHR Growth hormone receptor (GHR)5p13-p12223, 224
Mandibuloacral dysplasia with type A lipodystrophy; MADALMNA Prelamin-A/C precursor (LMNA)1q22225, 226
Keutel syndromeMGP Matrix Gla protein (MGP) 12p12.3227, 228
Hypophosphatasia, childhoodALPL Alkaline phosphatase, liver/bone/kidney or alkaline phosphatase, tissue-nonspecific isozyme (ALPL / PPBT)1p36.12229, 230
Fanconi-Sickel syndrome; FBSSLC2A2 Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2 / GTR2) 3q26.2231, 232
Lactose intolerance, adult typeMCM6 DNA replication licensing factor MCM6 2q21.3233, 234
Trichohepatoenteric syndrome 1; THES1TTC37 Tetratricopeptide repeat domain 37 (TTC37)5q15235, 236
Costello syndromeHRAS GTPase HRas (HRAS/RASH) (HRAS / RASH) 11p15.5237, 238
Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiencyCYP21A2 Steroid 21-hydroxylase (CYP21A2) 6p21.33239, 240

Table 4.

Autosomal recessive diseases with bone mineral density loss.

Disease Gene Product Genomic location Reference
Hypophosphatemic rickets, X-linked dominant; XLHR or HYPPHEX Phosphate-regulating neutral endopeptidase (PHEX/PEX)Xp22.11241, 242
Androgen insensitivity syndrome; AISAR Androgen receptor (AR) Xq12243, 244
Fragile X mental retardation syndromeFMR1 Fragile X mental retardation protein 1 (FMR1) Xq27.3245, 246
Fabry diseaseGLA Galactosidase, alpha (AGAL) Xq22.151, 52
Occipital horn syndrome; OHSATP7A Copper-transporting ATPase 1 (ATP7A) Xq21.1247, 248
Menkes diseaseATP7A Copper-transporting ATPase 1 (ATP7A) Xq21.1249, 250
Dyskeratosis congenita, X-linked; DKCXDKC1 H/ACA ribonucleoprotein complex subunit 4 (DKC1) Xq28251, 252
(glycerol kinase deficiency; GKD)
GK Glycerol kinase (GK) Xp21.2253, 254
Premature ovarian failure 2B; POF2BFLJ22792 / POF1B Protein POF1B Xq21.1-q21.2255, 256
Terminal osseous dysplasia; TOD or ODPFFLNA Filamin-A (FLNA) Xq28257, 258

Table 5.

X-linked recessive diseases with bone mineral density loss.

2.6. Genetic diseases of chromosomal origin and osteoporosis

Within the different categories of genetic diseases, we can include numeric or structural chromosomal abnormalities. Two of the most common chromosomal diseases are Turner’s syndrome and Klinefelter’s syndrome, both associated to X chromosome aneuploidy; in the first case, there is complete or partial absence of an X chromosome and less frequently, it can be caused by structural anomalies in the short arms of the X chromosome. In Klinefelter’s syndrome, there is an additional X chromosome and occasionally, there may be more than one extra X chromosome. In both syndromes, the phenotypic spectrum includes gonadal dysgenesis, in Turner’s syndrome there are fibrous bands instead of ovaries and in Klinefelter’s, the testicles are hypoplastic, leading in both cases to hypogonadism and a partial or complete deficit in the sex hormones that would normally be produced by the ovaries and testicles. Due to their lack, the development of normal secondary sexual characteristics is stunted and the various metabolic processes dependent on the hormones are also compromised. One of these metabolic processes occurs in bone [259-262].

Undoubtedly, bone metabolism is complex and the processes of osteoblastogenesis, osteoclastogenesis and remodeling must occur in a balanced manner; it is important to mention that the entire family of steroid hormone receptors (estrogen, androgen, vitamin D and retinoids), are expressed in bone, both in osteoblasts and osteoclasts as well as in chondrocytes. Within this microenvironment, the action of these hormones on their receptors is key to appropriate skeletal development; as a matter of fact, individuals with genetic mutations encoding any of these receptors develop, among other manifestations, bad quality bone mass. These hormones and their receptors play a pivotal role in female and male bone growth and may also favor epiphyseal closure at the end of the growth period. It is known that one of effects of steroid hormones on bone metabolism is resorption inhibition since they promote osteoclast apoptosis and decrease the frequency of remodeling unit activation. Therefore, the integral treatment of both entities includes hormone replacement that to a certain extent, will improve bone mass and will prevent or delay the development of osteoporosis [263, 264].

3. Conclusion

Bone metabolism and the large amount of processes that it involves, such as osteoblastogenesis, osteoclastogenesis and bone remodeling, must be kept in constant balance. Each one of these aspects of the physiology of bone shows a particular gene expression patterns, which may even differ according to conditions and tissue needs. As previously mentioned the number of genes involved is very large and sometimes their expression might be modified by multiple environmental conditions. It is important to mention that the expression of these genes is ubiquitous and is not restricted to the bone tissue, which explains why the phenotypic characteristics of a large number of monogenic and some polygenic entities include alterations on bone mineral density and on the microarchitecture of this tissue; this includes several degrees of osteopenia,osteoporosis or increased bone mineral density. Even a good number of these genes have been identified through the study of human disease whose phenotype includes altered bone mineral density. Without a doubt, the investigation of several processes that regulate bone metabolism will continue generating new knowledge that will allow better understanding of bone physiology and physiopathology of multiple diseases and possibly new therapeutic options in diseases which compromise the quality and function of the bone.



ESR1-Estrogen Receptor Alpha

ESR2-Estrogen Receptor Beta

AR-Androgen Receptor

VDR-Vitamin D Receptor

PTHR1-Parathohormone Receptor


CASR-Calcium Sensing Receptor

CYP1A1-Cytochrome P450, Subfamily A, Polypeptide 1



LEPR-Leptin Receptor


INSR-Insulin Receptor

ALOX12-Arachidonate 12-Lipoxygenase

ALOX15-Arachidonate 15-Lipoxygenase

BMP4-Bone Morphogenetic Protein 4

BMP7-Bone Morphogenetic Protein 7

IGF-1-Insulin-Like Growth Factor 1 (Somatomedin C)


P53-Protein 53

RANK-Receptor Activator Of Nf-Kb2

RANK-L.-Receptor Activator Of Nf-Kb2 Ligand

IL1β-Interleucin 1 Beta

IL6-Interleucin 6

TNF-Tumor Necrosis Factor

TNFR2-Tumor Necrosis Factor Receptor

APOE-Apolipoprotein E


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