Table 2.
Candidate genes with evidence for functional involvement in skeletal biology
| Signal | Genea | Gene Ontology or KEGG term | Mendelian disease (OMIM ID)b | Human phenotype | Mouse phenotypec | Selected references |
|---|---|---|---|---|---|---|
| 2 | FOSL2 | Osteoclast differentiation | NA | NA | Abnormal osteoblast and osteoclast morphology and physiology; abnormal bone morphology; decreased bone mineralization; etc. | Bozec (Nature 2008) |
| 3 | FOXP1 | Osteoclast differentiation and development | NA | NA | Abnormal osteoclastogenesis and bone resorption | Zhao (Dev Biol 2015) |
| 4 | COL8A1 | Downregulated in aged osteoblasts | Slightly elevated bone mineral content | Zhang (Biochem Biophys Res Comm 2018) | ||
| 5 | WWTR1 (TAZ) | Osteoclast differentiation, mesenchymal cell differentiation | NA | NA | Abnormal skeleton morphology and bone ossification; decreased body size | Hong (Science 2005) |
| 8 | IL17A [P] | Positive regulation of osteoclast development | NA | NA | NA | Kotake (Clin Invest 1999) |
| 9 | TBXAS1 | NA | Ghosal heamtodiaphyseal dysplasia (231095) | Increased bone density | NA | Genevieve (Nat Genet 2008) |
| 15 | BLNK | Osteoclast differentiation | NA | NA | NA | Shinohara (Cell 2008) |
| 18 | SLC9A3R1 (NHERF) | Wnt signaling pathway | Hypophosphatemic nephrolithiasis/osteoporosis-2 (612287) | Low bone mineral density | Decreased bone mineral content and density | Karim (NEJM 2008) |
| 19 | GRB2 [P] | Osteoclast differentiation | NA | NA | Abnormal mandible morphology | Levy-Apter (J Biol Chem 2014) |
| 21 | TGFB1 | Osteoclast differentiation | Camurati-Engelmann disease (131300) | Cortical thickening of the diaphyses of the long bones; some patients also show involvement of the skull; increased bone mineral density; osteopenia | Abnormal bone ossification; decreased osteoblast cell number; etc. | Kinoshita (Nat Genet 2000); Gao (Proc Natl Acad Sci 2004) |
| 22–23 | NRIP1 | NA | NA | Differentially expressed in low and high BMD samples; may interact with ESR1 | NA | Morón (Bone 2006); Li (Bone Joint Res 2016) |
| 24 | CITED1 | Negative regulation of osteoblast differentiation | NA | NA | NA | Yang (Endocrinology 2008) |
| 25–26 | ATP7A | NA | Menkes disease (309400), Occipital horn syndrome (304150) | Defective collagen cross-linking resulting in osteoporosis and pathological fracture | Abnormal skeleton morphology; osteoarthritis | Kim (Stem Cell Res Ther 2015) |
| S2 | HDAC4 | Osteoblast differentiation and development | NA | NA | Abnormal bone ossification; abnormal osteoblast cell number; skeletal phenotype; etc. | Vega (Cell 2004) |
| TWIST2 | Negative regulation of osteoblast differentiation | Ablepharon-macrostomia syndrome (200110); Barber-Say syndrome (209885) | Premature osteoblast differentiation, growth retardation | Abnormal osteoblast differentiation | Bialek (Dev Cell 2004) | |
| S3 | TET2 [P] | NA | Myelodysplastic syndrome, somatic (614286) | NA | Osteopetrosis, reduced osteoclast number | Chu (Genomics, Proteomics & Bioinf. 2018); Yang (Nat Comm 2018) |
| S6 | TEAD4 | Skeletal system development | NA | NA | NA | Matsumoto (J Clin Invest 2016); |
| TULP3 [P] | Bone development | NA | NA | Abnormal vertebrae morphology and development | Patterson (HMG 2009) | |
| S7 | PRKD1 | Positive regulation of osteoclast development | NA | NA | Reduced bone mineral density; decreased trabecular thickness | Bollag (Mol Cell Endocrinol 2018) |
| S9 | GNA11 | Skeletal system development | Hypocalcemia (615361); hypocalciuric hypercalcemia (145981) | Altered calcium levels; short stature | Decreased bone mineral content and density | Nesbit (NEJM 2013) |
| S9 | AES (TLE5) | Skeletal system development | NA | NA | NA | Zhao (BBRC 2017) |
| S11 | SOX11 | Positive regulation of osteoblast differentiation | Coffin-Siris syndrome 9 (615866) | Abnormal skeletal morphology | Abnormal bone mineralization and ossification; abnormal lumbar vertebrae morphology | Tsurusaki (Nat Commun 2014) |
| S12 | SLIT3 | NA | NA | Higher circulating levels associated with higher bone mass in postmenopausal women | Low bone mass | Kim (J Clin Invest 2018) |
| S13 | SMC3 | NA | Cornelia de Lange syndrome 3 (610759) | Growth retardation | Decreased bone mineral content | Andrade (Horm Res Paediatr 2017) |
a[P] Genes implicated by promoter-interaction map
bMendelian disease genes from the Online Mendelian Inheritance in Man (OMIM) database (https://www.ncbi.nlm.nih.gov/omim)
cMouse phenotypes from the Mouse Genome Informatics database (http://www.informatics.jax.org/)