Fully 95% of subjects with essential polycythaemia and 50-60% of those with Essential thrombocythemia or Primary Myelofibrosis have a JAK2 V617F mutation. What is less well known is that this particular mutation arises preferentially in subjects with a certain haplotype- the so called 46/1 or GGCC haplotype, present in 50% of the general population. In the other 50%, myeloproliferative neoplasms (MPN) are distinctly uncommon.
In around 150 SNP haplotypes drawn from Caucasians in a British population, haplotype 46 and haplotype 1 were almost identical, except for a single base. These two haplotypes, together designated as 46/1 are found ("tagged") in 2 SNPs- rs 12343867 and rs 12340895. When the base present in either of these 2 SNPs is guanine rather than cytosine (GC or GG rather than CC), the V617F mutation is far more likely to arise (around 3.7 times more frequently than if the predisposing haplotype was not present). Why this happens is not known. MPN arising in non-46/1 haplotypes is not phenotypically different to that arising in 46/1 haplotypes.
A similar situation can be seen with Facioscapulohumeral dystrophy (FSHD), except that here the effect of the predisposing haplotype is even more dramatic. FSHD is caused by the accumulation of a toxic protein in muscle cells called DUX4. The DUX4 gene is present next to a microsatellite region called D4Z4 on chromosome 4q35 and is ordinarily not transcribed. Most subjects have 11-100 D4Z4 repeats of CpG and GpC nucleotide base sequences. Subjects with FSHD have only 1-10 such repeats in the D4Z4 region ("contraction" of D4Z4 region). The D4Z4 microsatellite region can be identified by digestion of DNA with a restriction endonuclease called EcoR1.
However D4Z4 is not exclusive to chromosome 4. This microsatellite sequence is also located on chromosome 10. However, here the contraction of the D4Z4 region does not lead to FSHD.
Here's the important bit. Simply having a contracted D4Z4 region on 4q35 will not lead to FSHD. For that to happen, you need a permissive haplotype located just next to the D4Z4 region called 4qA 161 (or rarely, some other 4qA haplotypes). If the person involved has a haplotype containing 4qB rather than 4qA or a non-permissive 4qA haplotype, FSHD will not develop.
Why does this happen? 4qA 161 is responsible for generating the polyadenylate (polyA) tail at the 3' end of the DUX4 mRNA that stabilises it and leads to its translation. Without the polyA tail, the mRNA would be unstable and would be destroyed.
Interestingly in procaryotes such as bacteria, the polyA tail serves the exact opposite function. Polyadenylated mRNA are tagged for destruction.
So why does contraction of the microsatellite D4Z4 region lead to de-repression of the toxic DUX4 mRNA? It is thought that the full length D4Z4 region keeps the DUX4 gene in a "compressed" state. In FSHD, the briefer D4Z4 sequence allows uncoiling of the DUX4 gene and its subsequent transcription, providing of course the polyA tail from the permissive 4qA 161 haplotype was also available.
In around 150 SNP haplotypes drawn from Caucasians in a British population, haplotype 46 and haplotype 1 were almost identical, except for a single base. These two haplotypes, together designated as 46/1 are found ("tagged") in 2 SNPs- rs 12343867 and rs 12340895. When the base present in either of these 2 SNPs is guanine rather than cytosine (GC or GG rather than CC), the V617F mutation is far more likely to arise (around 3.7 times more frequently than if the predisposing haplotype was not present). Why this happens is not known. MPN arising in non-46/1 haplotypes is not phenotypically different to that arising in 46/1 haplotypes.
A similar situation can be seen with Facioscapulohumeral dystrophy (FSHD), except that here the effect of the predisposing haplotype is even more dramatic. FSHD is caused by the accumulation of a toxic protein in muscle cells called DUX4. The DUX4 gene is present next to a microsatellite region called D4Z4 on chromosome 4q35 and is ordinarily not transcribed. Most subjects have 11-100 D4Z4 repeats of CpG and GpC nucleotide base sequences. Subjects with FSHD have only 1-10 such repeats in the D4Z4 region ("contraction" of D4Z4 region). The D4Z4 microsatellite region can be identified by digestion of DNA with a restriction endonuclease called EcoR1.
However D4Z4 is not exclusive to chromosome 4. This microsatellite sequence is also located on chromosome 10. However, here the contraction of the D4Z4 region does not lead to FSHD.
Here's the important bit. Simply having a contracted D4Z4 region on 4q35 will not lead to FSHD. For that to happen, you need a permissive haplotype located just next to the D4Z4 region called 4qA 161 (or rarely, some other 4qA haplotypes). If the person involved has a haplotype containing 4qB rather than 4qA or a non-permissive 4qA haplotype, FSHD will not develop.
Why does this happen? 4qA 161 is responsible for generating the polyadenylate (polyA) tail at the 3' end of the DUX4 mRNA that stabilises it and leads to its translation. Without the polyA tail, the mRNA would be unstable and would be destroyed.
Interestingly in procaryotes such as bacteria, the polyA tail serves the exact opposite function. Polyadenylated mRNA are tagged for destruction.
So why does contraction of the microsatellite D4Z4 region lead to de-repression of the toxic DUX4 mRNA? It is thought that the full length D4Z4 region keeps the DUX4 gene in a "compressed" state. In FSHD, the briefer D4Z4 sequence allows uncoiling of the DUX4 gene and its subsequent transcription, providing of course the polyA tail from the permissive 4qA 161 haplotype was also available.
