Table 2.
Fam20A genetic alterations in human disease
| Amino acid | Inheritance | Disease | Possible effect | Ref |
|---|---|---|---|---|
| L12Afs | Homo; CH | AI | Deletion/Hypomorphic | (124, 152, 153, 154) |
| C44Afs | CH | AI, NC | Deletion/Hypomorphic | (155) |
| A59Pfs | Homo | AI | 29 bp duplication/Hypomorphic | (156) |
| R73X | CH | AI, NC | Deletion/Hypomorphic, removes 87% of protein sequence | (153) |
| L117Cfs | Homo | AI, EC, NC | Nonfunctional | (157, 158) |
| R136X | Homo | AI, NC | Interfere with Fam20A–Fam20C dimer/tetramer formation, removes 75% of protein sequence | (125, 153, 159, 160) |
| L173R | Homo | AI, NC | Impaired folding, L173 participates in hydrophobic interactions | (153) |
| D197_I214delinsV | CH | AI | Fam20C interface, disulfide disruption, reduced secretion and activity | (124) |
| L205Cfs | CH | AI | Hypomorphic, alters 62% of protein sequence | (127, 153) |
| I214Nfs | CH | AI, NC | Destabilization, interferes with Fam20A–Fam20C dimer/tetramer formation, alters 60% of protein sequence | (153) |
| Q241-R271del | Homo | AI, NC | Interferes with Fam20A–Fam20C dimer/tetramer formation, destabilization | (159) |
| R243X | CH | AI, NC | Destabilization, R243 participates in polar contacts, removes 45% of protein sequence | (153) |
| E245Gfs | CH | AI, NC | Interferes with Fam20A–Fam20C dimer/tetramer formation, alters 55% of protein sequence | (155) |
| F252del | CH | AI, NC | Interferes with Fam20A–Fam20C dimer/tetramer formation | (153) |
| Y253C | CH | AI | Destabilization, Y253 participates in polar contacts, interferes with Fam20A–Fam20C dimer/tetramer formation | (127) |
| R271Sfs | Homo | AI | Destabilization, alters 50% of protein sequence | (124) |
| R276X | CH | AI | Loss of “kinase” domain, removes 49% of protein sequence | (124) |
| S303Cfs | Homo | AI, NC | Destabilization, alters 44% of protein sequence | (153) |
| F305Lfs | CH; Homo | AI, NC | Interferes with Fam20A–Fam20C dimer/tetramer formation | (153, 157, 158, 161) |
| E326Gfs | CH | AI | Destabilization, alters 40% of protein sequence | (157) |
| C330R | CH | AI | Disruption of disulfide | (162) |
| G331D | Homo | AI | Destabilization, introduces steric clash | (159) |
| R361C | CH | AI | Destabilization, R361 participates in polar contacts, interferes with Fam20A–Fam20C dimer/tetramer formation | (127) |
| R392Pfs | Homo | AI, NC | Destabilizing, alters 28% of protein sequence | (124, 163) |
| D403N | CH | AI | Impaired folding, disrupts multiple polar contacts | (72) |
| D410Pfs | CH | AI | Destabilization, D410 participates in polar contacts, alters 24% of protein sequence | (153) |
| F417Vfs | CH | AI | Destabilization, alters 23% of protein sequence | (127) |
| A432T | CH | AI | Destabilization, larger side chain introduces steric clashes | (162) |
| G436E | Homo | AI | Interferes with salt bridges | (157) |
| S450Pfs | Homo | AI, NC | Destabilization, alters 17% of protein sequence |
(153) |
| K457X | Homo | AI, NC | Destabilization, removes 16% of protein sequence | (153) |
| R478X | CH; Homo | AI, NC | Destabilization, R478 participates in polar contacts, removes 11% of protein sequence | (153, 159) |
| E483Kfs | Homo | AI, NC, EC | Destabilization, alters 11% of protein sequence | (164) |
| H494fs | CH | AI, NC, EC | Destabilizing, alters 9% of protein sequence | (154) |
| L495Tfs | Homo | AI, NC, EC | Destabilizing, alters 9% of protein sequence | (154) |
| L495Nfs | Homo | AI, NC | Destabilizing, alters 9% of protein sequence | (153) |
| I505Sfs | Homo | AI, NC | Destabilizing, I505 participates in multiple hydrophobic interactions, alters 6% of protein sequence. | (153) |
| T508Kfs | Homo | AI | Destabilizing, T508 participates in polar contacts, alters 6% of protein sequence | (165) |
| 54.7kb duplication | CH | AI | Unknown. | (162) |
AI, Amelogenesis imperfecta; CH, Compound heterozygous; del, deletion; delins, deletion and insertion; EC, Ectopic calcification; fs, Frameshift; Het, Heterozygous; Homo, Homozygous; NC, nephrocalcinosis; X, STOP/Termination.
Clinical presentation is heterogeneous and the classifications presented here reflect the symptomology reported in the literature.