Genes involved in hereditary thrombocytosis
| Gene . | Protein . | Chromosome location . | Mutation . | Inheritance . | Molecular mechanism . |
|---|---|---|---|---|---|
| THPO | Thrombopoietin (TPO) | 3q27 | G>C in the splice donor site of intron 3 | Autosomal dominant | The mutation disrupts the inhibitory uORF leading to increase in mRNA translation. |
| G>T substitution in 5′UTR | Autosomal dominant | The mutation disrupts the inhibitory uORF leading to increase in mRNA translation. | |||
| Deletion of single G in 5′UTR | Autosomal dominant | The mutation disrupts the inhibitory uORF leading to increase in mRNA translation. | |||
| A>G mutation in intron 3 | Autosomal dominant | The A>G substitution in the +1 position of the splice donor of intron 3 leads to increase in mRNA translation. | |||
| T>C at the splice donor site of intron 2 | Autosomal dominant | The splice donor mutation leads to exon 2 skipping and loss of inhibitory 5′UTR sequence, leading to increased TPO expression. | |||
| MPL | Thrombopoietin receptor, MPL | 1p34 | S505N | Autosomal dominant | TPO-independent constitutive activation of MPL. |
| K39N (also called “MPL-Baltimore”) | Autosomal dominant with incomplete penetrance | This mutation is associated with incomplete processing and a reduction in MPL protein. | |||
| P106L | Autosomal recessive | The MPL P106L shows constitutive activity that can be further stimulated by TPO. | |||
| W515R | Autosomal dominant | The mutation increases MPL activity but to a lesser extent than the somatic MPLW515K/L/A mutations observed in MPNs. | |||
| JAK2 | Janus kinase 2, JAK2 | 9p24 | V617I | Autosomal dominant | JAK2V617I has weak constitutive signaling compared with JAK2V617F because of reduction in the threshold for cytokine-induced activation. |
| R867Q | Autosomal dominant | The mutation in JH1 domain abolishes a salt bridge, which is present in the inactive JH1 and is lost upon activation. | |||
| S755R/R938Q | Autosomal dominant | The S755R mutation interferes with an important salt bridge and inhibits the function of JH2 domain. The R938Q is located in a sensitive region of the JH1 near the ATP loop and substrate access site. | |||
| R564Q | Autosomal dominant | JAK2 R564Q exhibits similar levels of increased kinase activity compared with JAK2V617F but fewer growth-promoting effects. | |||
| H608N | Autosomal dominant | The mutation in this region may abrogate the function of the inhibitory JH2 domain, resulting in increased kinase activity. |
| Gene . | Protein . | Chromosome location . | Mutation . | Inheritance . | Molecular mechanism . |
|---|---|---|---|---|---|
| THPO | Thrombopoietin (TPO) | 3q27 | G>C in the splice donor site of intron 3 | Autosomal dominant | The mutation disrupts the inhibitory uORF leading to increase in mRNA translation. |
| G>T substitution in 5′UTR | Autosomal dominant | The mutation disrupts the inhibitory uORF leading to increase in mRNA translation. | |||
| Deletion of single G in 5′UTR | Autosomal dominant | The mutation disrupts the inhibitory uORF leading to increase in mRNA translation. | |||
| A>G mutation in intron 3 | Autosomal dominant | The A>G substitution in the +1 position of the splice donor of intron 3 leads to increase in mRNA translation. | |||
| T>C at the splice donor site of intron 2 | Autosomal dominant | The splice donor mutation leads to exon 2 skipping and loss of inhibitory 5′UTR sequence, leading to increased TPO expression. | |||
| MPL | Thrombopoietin receptor, MPL | 1p34 | S505N | Autosomal dominant | TPO-independent constitutive activation of MPL. |
| K39N (also called “MPL-Baltimore”) | Autosomal dominant with incomplete penetrance | This mutation is associated with incomplete processing and a reduction in MPL protein. | |||
| P106L | Autosomal recessive | The MPL P106L shows constitutive activity that can be further stimulated by TPO. | |||
| W515R | Autosomal dominant | The mutation increases MPL activity but to a lesser extent than the somatic MPLW515K/L/A mutations observed in MPNs. | |||
| JAK2 | Janus kinase 2, JAK2 | 9p24 | V617I | Autosomal dominant | JAK2V617I has weak constitutive signaling compared with JAK2V617F because of reduction in the threshold for cytokine-induced activation. |
| R867Q | Autosomal dominant | The mutation in JH1 domain abolishes a salt bridge, which is present in the inactive JH1 and is lost upon activation. | |||
| S755R/R938Q | Autosomal dominant | The S755R mutation interferes with an important salt bridge and inhibits the function of JH2 domain. The R938Q is located in a sensitive region of the JH1 near the ATP loop and substrate access site. | |||
| R564Q | Autosomal dominant | JAK2 R564Q exhibits similar levels of increased kinase activity compared with JAK2V617F but fewer growth-promoting effects. | |||
| H608N | Autosomal dominant | The mutation in this region may abrogate the function of the inhibitory JH2 domain, resulting in increased kinase activity. |
ATP, adenosine triphosphate; mRNA, messenger RNA; uORF, upstream open reading frame.