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Deletion of protein tyrosine phosphatase, non-receptor type 4 (PTPN4) in twins with a Rett syndrome-like phenotype.

Williamson SL, Ellaway CJ, Peters GB, Pelka GJ, Tam PP, Christodoulou J - Eur. J. Hum. Genet. (2014)

Bottom Line: Variants in other genes such as CDKL5 and FOXG1 are usually associated with individuals who manifest distinct phenotypes that may overlap with RTT.Even with this screening strategy, there are individuals in whom no causative variant can be identified, suggesting that there are other novel genes that contribute to the RTT phenotype.Our findings suggest that PTPN4 should be considered for addition to the growing list of genes that warrant screening in individuals with a RTT-like phenotype.

View Article: PubMed Central - PubMed

Affiliation: NSW Centre for Rett Syndrome Research, Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, New South Wales, Australia.

ABSTRACT
Rett syndrome (RTT), a neurodevelopmental disorder that predominantly affects females, is primarily caused by variants in MECP2. Variants in other genes such as CDKL5 and FOXG1 are usually associated with individuals who manifest distinct phenotypes that may overlap with RTT. Individuals with phenotypes suggestive of RTT are typically screened for variants in MECP2 and then subsequently the other genes dependent on the specific phenotype. Even with this screening strategy, there are individuals in whom no causative variant can be identified, suggesting that there are other novel genes that contribute to the RTT phenotype. Here we report a de novo deletion of protein tyrosine phosphatase, non-receptor type 4 (PTPN4) in identical twins with a RTT-like phenotype. We also demonstrate the reduced expression of Ptpn4 in a Mecp2 mouse model of RTT, as well as the activation of the PTPN4 promoter by MeCP2. Our findings suggest that PTPN4 should be considered for addition to the growing list of genes that warrant screening in individuals with a RTT-like phenotype.

No MeSH data available.


Related in: MedlinePlus

ChIP analysis of MeCP2-binding sites in SH-SY5Y cells. (a) Location of the amplicons in the PTPN4 gene. (b) Fold enrichment of MeCP2, no antibody and normal mouse serum ChIP from SH-SY5Y lysates across the PTPN4, JUNB and PORIN amplicons. Duplicate biological replicates were analysed in triplicate, P-values for each amplicon relative to the no antibody control (NS=not significant, **P≤0.01, ***P≤0.001). Error bars=SD.
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fig3: ChIP analysis of MeCP2-binding sites in SH-SY5Y cells. (a) Location of the amplicons in the PTPN4 gene. (b) Fold enrichment of MeCP2, no antibody and normal mouse serum ChIP from SH-SY5Y lysates across the PTPN4, JUNB and PORIN amplicons. Duplicate biological replicates were analysed in triplicate, P-values for each amplicon relative to the no antibody control (NS=not significant, **P≤0.01, ***P≤0.001). Error bars=SD.

Mentions: MeCP2 is a transcriptional regulator that can both activate and repress gene expression. As Ptpn4 expression is reduced in the absence of Mecp2, it is possible that MeCP2 may function to activate the expression of PTPN4. To test whether PTPN4 is a transcriptional target, we tested for MeCP2 binding to PTPN4 sequences using ChIP assays in the SH-SY5Y human neuroblastoma cell line. Two PCR amplicons were designed to amplify regions 5′ to exon 1 of PTPN4, containing the putative RNA polymerase II binding sites and the CpG island, respectively. An additional amplicon in intron 15 of PTPN4 was also designed as a gene-specific non-promoter sequence control (Figure 3a). As a positive control for MeCP2 binding, an amplicon in the promoter of a known MeCP2 target in SH-SH5Y cells, JUNB,9 was tested. For a negative control, intron 6 of PORIN was used. The MeCP2 ChIP studies revealed enrichment for all amplicons above that of the normal serum and no antibody control background levels (Figure 3b).


Deletion of protein tyrosine phosphatase, non-receptor type 4 (PTPN4) in twins with a Rett syndrome-like phenotype.

Williamson SL, Ellaway CJ, Peters GB, Pelka GJ, Tam PP, Christodoulou J - Eur. J. Hum. Genet. (2014)

ChIP analysis of MeCP2-binding sites in SH-SY5Y cells. (a) Location of the amplicons in the PTPN4 gene. (b) Fold enrichment of MeCP2, no antibody and normal mouse serum ChIP from SH-SY5Y lysates across the PTPN4, JUNB and PORIN amplicons. Duplicate biological replicates were analysed in triplicate, P-values for each amplicon relative to the no antibody control (NS=not significant, **P≤0.01, ***P≤0.001). Error bars=SD.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4538211&req=5

fig3: ChIP analysis of MeCP2-binding sites in SH-SY5Y cells. (a) Location of the amplicons in the PTPN4 gene. (b) Fold enrichment of MeCP2, no antibody and normal mouse serum ChIP from SH-SY5Y lysates across the PTPN4, JUNB and PORIN amplicons. Duplicate biological replicates were analysed in triplicate, P-values for each amplicon relative to the no antibody control (NS=not significant, **P≤0.01, ***P≤0.001). Error bars=SD.
Mentions: MeCP2 is a transcriptional regulator that can both activate and repress gene expression. As Ptpn4 expression is reduced in the absence of Mecp2, it is possible that MeCP2 may function to activate the expression of PTPN4. To test whether PTPN4 is a transcriptional target, we tested for MeCP2 binding to PTPN4 sequences using ChIP assays in the SH-SY5Y human neuroblastoma cell line. Two PCR amplicons were designed to amplify regions 5′ to exon 1 of PTPN4, containing the putative RNA polymerase II binding sites and the CpG island, respectively. An additional amplicon in intron 15 of PTPN4 was also designed as a gene-specific non-promoter sequence control (Figure 3a). As a positive control for MeCP2 binding, an amplicon in the promoter of a known MeCP2 target in SH-SH5Y cells, JUNB,9 was tested. For a negative control, intron 6 of PORIN was used. The MeCP2 ChIP studies revealed enrichment for all amplicons above that of the normal serum and no antibody control background levels (Figure 3b).

Bottom Line: Variants in other genes such as CDKL5 and FOXG1 are usually associated with individuals who manifest distinct phenotypes that may overlap with RTT.Even with this screening strategy, there are individuals in whom no causative variant can be identified, suggesting that there are other novel genes that contribute to the RTT phenotype.Our findings suggest that PTPN4 should be considered for addition to the growing list of genes that warrant screening in individuals with a RTT-like phenotype.

View Article: PubMed Central - PubMed

Affiliation: NSW Centre for Rett Syndrome Research, Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, New South Wales, Australia.

ABSTRACT
Rett syndrome (RTT), a neurodevelopmental disorder that predominantly affects females, is primarily caused by variants in MECP2. Variants in other genes such as CDKL5 and FOXG1 are usually associated with individuals who manifest distinct phenotypes that may overlap with RTT. Individuals with phenotypes suggestive of RTT are typically screened for variants in MECP2 and then subsequently the other genes dependent on the specific phenotype. Even with this screening strategy, there are individuals in whom no causative variant can be identified, suggesting that there are other novel genes that contribute to the RTT phenotype. Here we report a de novo deletion of protein tyrosine phosphatase, non-receptor type 4 (PTPN4) in identical twins with a RTT-like phenotype. We also demonstrate the reduced expression of Ptpn4 in a Mecp2 mouse model of RTT, as well as the activation of the PTPN4 promoter by MeCP2. Our findings suggest that PTPN4 should be considered for addition to the growing list of genes that warrant screening in individuals with a RTT-like phenotype.

No MeSH data available.


Related in: MedlinePlus